Chapter 18

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C H A P T E R

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Amygdala: Structure and Function

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Francisco E. Olucha-Bordonau1, Lluis Fortes-Marco2, Marcos Otero-García2, Enrique Lanuza2, Fernando Martínez-García2 1CIBERSAM,

Spain;

INCLIVA, Departament d’Anatomia i Embriologia Humana, Fac. Medicina, Universitat de València, of Functional and Comparative Neuroanatomy, Departaments de Biologia Funcional i de Biologia Cel.lular, Fac. CC. Biològiques, Universitat de València, Spain

2Laboratory

O U T L I N E Introduction

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Development and Territories in the Rat Amygdala Cortical Versus Subcortical Amygdala Heterogeneity in the Pallial Amygdala: Cortical versus Nuclear Organization

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The Lateropallial Amygdala: CxA, APir, BL and LOT The Ventropallial Amygdala: ACo, PLCo, PMCo, BM, AHi and La

The Subpallial Amygdaloid Territories and the Concept of Extended Amygdala The Two Poles of the Extended Amygdala: Common Properties of the Bed Nucleus of the Stria Terminalis and Centromedial Amygdala The Medial and Central Extended Amygdala Developmental Foundations of the Extended Amygdala Comparative Neuroanatomy of the Extended Amygdala: Developmental Restrictions in Mammals

Cytoarchitectonics and Chemoarchitectonics of the Amygdala The Pallial Amygdala The Deep Pallial Nuclei of the Amygdala The Cortical Amygdaloid Nuclei

Subpallial Amygdala Central Amygdala Medial Amygdala Amygdalo-striatal Transition Area

The Rat Nervous System, Fourth Edition http://dx.doi.org/10.1016/B978-0-12-374245-2.00018-8

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Intercalated Cell Masses The Bed Nucleus of the Stria Terminalis The Sublenticular Extended Amygdala

Functional Connectivity of the Amygdala Inputs to The Amygdala Input from The Olfactory Bulbs: The Chemosensory Amygdala Inputs From the Thalamus: Auditory, Visual, Gustatory and Somatosensory/Nociceptive Information Cortical Afferents to the Amygdala Sensory Input from the Brainstem and Ascending Modulatory Afferents Endocrine Input

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Intrinsic Connectivity of the Amygdala Connections within the Pallial Amygdala Connections Between the Pallial Amygdala and the Extended Amygdala Intrinsic Connections of the Extended Amygdala

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Outputs from the Amygdala

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Projections from the Pallial Amygdala Descending Projections of the Subpallial Amygdala

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Behavioral Neurobiology of the Amygdala The Role of the Amygdala in Fear and Aversion: Data from Standard Laboratory Paradigms

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Fear Acquisition and Fear Expression Conditioned Taste Aversion

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© 2015 Elsevier Inc. All rights reserved.


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18. AMYGDALA: STRUCTURE AND FUNCTION

Role of the Amygdala in Ethologically Relevant Fear and Aversive Responses The Amygdala and Appetitive Responses: Reward and Motivated Behavior Emotional Behaviors Elicited by Conspecifics: Sociosexual Behavior The Amygdala and Agonistic Behaviors

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The Amygdala and Sexual Behavior

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INTRODUCTION

The amygdala (from the Greek-Latin word for almond) is a structure located deep in the temporal lobe of the human brain, which is easy to recognize in the brain of other mammals (and non-mammals, Martínez-García et al., 2007) as a bump in the base of the caudal cerebral hemispheres apparently targeted by the lateral olfactory tract. In the last few decades, the amygdala has drawn much attention as the main neural center processing relevant stimuli to generate adaptive emotional responses. The idea of a role of the amygdala on emotion has derived from observations of the constellation of changes in behavior that followed lesions of the temporal lobe in monkeys; this is known as the Klüver–Bucy syndrome (Kluver and Bucy, 1997). Among other symptoms (hyperorality, hypersexuality), these lesions resulted in “psychic blindness”—a lack of fear to threatening conspecifics or to other fear-eliciting cues (e.g., snakes), which made animals tame and placid. The work of Weiskrantz (1956) demonstrated that the dramatic emotional deficits characteristic of the Klüver–Bucy syndrome were due to bilateral damage to the amygdala. Cerebrovascular accidents (De Benedictis et al., 2013) or herpes simplex virus infection in humans result in encephalitis affecting temporal structures including the amygdala, and produce a symptomatology reminiscent of the Klüver–Bucy syndrome (Bakchine et al., 1986). Different lines of evidence have confirmed the role of the p0020 amygdala in emotional evaluation of stimuli in humans. For instance, neuroimaging has shown that the amygdala is activated during recognition and the interpretation of emotions conveyed by facial expressions, especially those regarded as fearful or happy (Breiter et al., 1996). The amygdala also appears to be a partner of the p0025 hippocampus in memory acquisition. Whereas the hippocampus seems to be involved in explicit declarative memory, the amygdala appears to be related to implicit emotional memories (Bechara et al., 2003). Indeed, it has been shown in humans that the amygdala is activated during acquisition and extinction of emotional memories (LaBar et al., 1998). As we will discuss at the end of this chapter, the acquisition of emotional memories occurs p0015

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Is the Amygdala a Functional System?

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Abbreviation List

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Acknowledgments

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References

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by means of a Pavlovian conditioning (e.g., fear conditioning) that is mediated by synaptic plasticity occurring in the amygdala and other neural centers connected with it (e.g., frontal cortex). This has become a model for the research of learning and memory, which is currently one of the main topics of current functional studies on the amygdala (LeDoux, 2007). Several lines of evidence indicate that, in primates, p0030 the amygdala is involved in emotional evaluation of social stimuli, such as relevant faces (Gothard et al., 2007) or conspecific vocalizations (Kuraoka and Nakamura, 2007). This suggests an involvement of the amygdala in psychiatric disorders in which social interaction and emotionality are impaired, such as autism (Baron-Cohen et al., 2000), mood disorders (e.g., major depression; Weniger et al., 2006), anxiety, or post-traumatic stress (Parsons and Ressler, 2013). This has promoted studies on the amygdala as a mean of understanding these disorders and designing effective therapies. Rodents constitute the model-of-choice for experi- p0035 mentally testing and exploring these ideas on the functions of amygdala and the pathological consequences of its dysfunction. Most studies use rats and/or mice. Over the last 40 years, research in rats has revealed the underpinnings of Pavlovian fear conditioning, which has become the main model for the study of emotional learning (LeDoux, 2000; Maren, 2001). The combination of anatomical analysis, lesion, electrophysiological and behavioral studies has yielded important data regarding the biological mechanisms through which a given stimulus (usually a sound) acquires emotional value; these include the particular circuits in the amygdala where conditioned and unconditioned stimuli converge, and the mechanisms of synaptic plasticity mediating the subsequent emotional learning (Pape and Pare, 2010; Johansen et al., 2011). Novel experimental approaches (e.g., the use of viral particles, optogenetics), together with the use of genetically engineered mice, open new opportunities to further explore the role of specific genes of defined cell populations of the amygdala in this and other functions. A detailed understanding of the biology of the mouse (and the rat), especially of its socio-sexual behavior (Dixon, 2004; Brennan

IV. DIENCEPHALON, BASAL GANGLIA, AMYGDALA, AND SEPTUM

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DEVELOPMENT AND TERRITORIES IN THE RAT AMYGDALA

and Zufall, 2006; Chamero et al., 2012), can be helpful in understanding how different functions under amygdaloid command (emotional responses and learning; socio-sexual and defensive responses) relate to each other, and how its malfunctioning might result in psychiatric disorders in which these functions are altered. p0040 The rodent amygdala is targeted by the main and accessory olfactory bulbs. Since, in contrast to primates, rodents use mainly chemical signals (pheromones and odorants) for intraspecific communication, this apparently fits a role for the amygdala in intraspecies communication. However, a detailed analysis of the anatomy of the amygdala in rats and other mammals reveals that it is a heterogeneous structure, with several anatomical and functional divisions. Apparently, a portion of the amygdala, its corticomedial division, is dominated by chemosensory input, whereas the rest of the amygdala, namely its basolateral and central divisions, is mainly involved in emotional responses and emotional learning. This and other lines of evidence led Swanson and Petrovich (1998) to conclude that “terms such as ‘amygdala’ … combine cell groups arbitrarily rather than according to the structural and functional units to which they now seem to belong. The amygdala is neither a structural nor a functional unit.” In this chapter we discuss this view on the basis of current data on the anatomy and function of the amygdala of the rat. The section below (Development and Territories in the p0045 Rat Amygdala) deals with the anatomical complexity of the amygdala. Using data on the embryological origin of the cells composing the amygdaloid complex, we describe the pallial-subpallial division of the amygdala and the identity and boundaries of the territories derived from these divisions. Then, the section on Cytoarchitectonics and chemoarchitectonics of the amygdala is devoted to describing the architecture of the amygdala of the adult rat in some detail—the aim of this section is to help the reader in the sometimes difficult task of identifying and delineating the different nuclei and subnuclei of the amygdala, for which the use of histochemical markers is very useful. Section four (Functional Connectivity of the Amygdala) is an overview of the connections of the amygdala, which are arranged using a functional perspective in afferents, including sensory and modulatory inputs, intrinsic connections and efferent pathways mediating the influence of the amygdala in physiology and behavior. The final section of this chapter (Behavioral Neurobiology of the Amygdala) reviews the nuclei and circuits of the amygdala involved in some standard laboratory paradigms of emotion and emotional learning, as well as those implicated in ethologically relevant responses such as defensive reactions to predator cues or agonistic (aggressive) or sexual responses to conspecific and/or their chemosignals. Putting these data together, we finish by proposing an integrative model of the role of the amygdala in the control of behavior.

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In this chapter, we have followed the general scheme p0050 of divisions and nuclei reported in previous editions of this book by de Olmos and colleagues (Alheid et al., 1995; de Olmos et al., 2004).


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The cerebral hemispheres are classically divided into p0055 cortex and subcortex. The cerebral cortex is dorsal, superficial and shows a clear lamination (layering depending on the area); whereas the subcortex, which includes the striatum, pallidum, septum and basal forebrain, is ventral (relative to the lateral ventricles) and shows no layering (the olfactory tubercle being a clear exception to this rule). However, the amygdala is too complex to be classified as cortical or subcortical using these criteria. In the last decades, studies on the neurochemistry and p0060 development of the telencephalon have shown that the cerebral cortex is composed of two populations of neurons (see Chapter 3, Tangential Migration in the Telencephalon). On the one hand, the pyramidal cells are excitatory (e.g., glutamatergic) projection neurons that originate in the neuroepithelium of the embryonic pallium, and follow a radial migration to settle in one of the layers of the cortex as a function of their time of generation. On the other hand, most (if not all) the interneurons are GABAergic and have an extrinsic origin, as they are generated in the ganglionic eminences from where they follow a long tangential migratory pathway to reach the cortex (see Chapter 3, Tangential Migration in the Telencephalon; Nadarajah et al., 2003). Thus, neurochemical data relative to the distribution p0065 of GABAergic and glutamatergic cells can be useful to identify pallial and subpallial territories in the cerebral hemispheres, including the amygdala.

Cortical Versus Subcortical Amygdala

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The amygdala is located on the caudal edge of the p0070 cortex-subcortex boundary and is composed of a heterogeneous collection of cortical and subcortical nuclei. This was put forward by Swanson and Petrovich (1998), who realized that the amygdaloid nuclei belonging to the cortical amygdala, the basolateral division and the amygdalohippocampal transition show a very low density of GABA- (or glutamate decarboxylase-) immunoreactive cells, similar to the cerebral cortex. In contrast, the central and medial amygdaloid divisions display a high density of GABAergic cells, similar to the striatum and pallidum (Fig. 1A). This view has received solid support from develop- p0075 mental analysis in the mouse. Puelles et al. (2000) analyzed the pattern of expression of several genes involved


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(A)


(B)

(D)

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f0010 FIGURE 1 Pallial vs. subpallial amygdala. (A) Immunohistochemistry for glutamic acid decarboxylase (GAD) shows a high density of GABAergic neurons in the medial (Me) and central (Ce) amygdaloid nuclei (A), thus revealing the subpallial nature of these nuclei. In contrast, the cortical and basolateral divisions (as well as the amygdalo-hippocampal area, not shown) of the amygdala, which constitute its pallial derivatives, show a low density of GAD immunoreactive interneurons, many of which express calcium binding proteins such as calbindin (B) or parvalbumin (C). In addition, as in other pallial structures, many of the projection cells of the basolateral amygdala and amygdalohippocampal area display a clear pyramidal morphology in spite of the lack of lamination and polarity. (D) Amygdalo-striatal neurons in the posterior basolateral nucleus of the amygdala labelled retrogradely with biotinylated dextranamines. Golgi-like labeled neurons show a pyramid-like dendritic tree with an “apical dendrite” (arrows) and several basal ones, with a high density of dendritic spines; the axon leaves de cell body opposite to the “apical” dendrite (arrowhead). Calibration bars represent 500 µm (A) and 200 µm (B and C).

in regulating brain development, so that their patterns of expression in the neuroepithelium and/or mantle were largely conserved in evolution and gave information on fundamental traits of brain organization. Concerning the amygdala, this study led to two main conclusions. On the one hand, two genes that were expressed in the cerebral cortex, Pax-6 and Tbr-1 (a gene later found to be fundamental for differentiation of glutamatergic neurones, Hevner et al., 2006), were also expressed in the territories of the embryonic amygdala originating the cortical, basolateral and amygdalo-hippocampal divisions. In contrast, the central and medial divisions did not express these but other genes characteristic of the subpallial cerebral hemispheres (striatum and pallidum), such as Dlx-2 and Nkx-2. This constituted a clear demonstration that the amygdala was composed of a sum of pallial and subpallial structures. p0080 Second, Puelles et al. (2000) observed that one of the genes expressed in the whole cortex, Emx-1, was expressed in a portion of the pallial amygdala (basolateral nucleus and part of the cortical amygdala) but not in the rest (amygdalo-hippocampal, lateral and basomedial nuclei and the other nuclei of the cortical amygdala). This confirmed previous findings by Smith-Fernandez et al. (1998) suggesting that the embryonic pallium consisted of four, instead of three mediolateral territories. To the traditional medial, dorsal and lateral pallia, all of them composed of Emx-1 positive neurones, an Emx-1 negative territory, the ventral pallium, should be added.

The pallial amygdala derives not only from the lateral, but also from the ventral pallium.

Heterogeneity in the Pallial Amygdala: Cortical versus Nuclear Organization

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Like other parts of the lateral and ventral pallium p0085 (see Martínez-García et al., 2012), the pallial amygdala should be considered an allocortical structure. The allocortex shows a peculiar organization characterized by the presence of superficial, layered cortical areas plus non-layered structures (showing nuclear organization) immediately deep to them, which Holmgren and Elliot-Smith (see Puelles et al., 2007) named “hypopallial centers.” In the amygdala this organization is recognized in the presence of cortical amygdaloid nuclei, plus several nuclei deep to them, which we will describe as “deep pallial amygdala.” The cortical amygdaloid nuclei show a three-layered structure, with an outer molecular layer (or layer 1) in which a direct projection from the olfactory bulbs terminates in the most superficial sublayer (1a), plus two cellular layers (2-3), the outer one showing a higher cell density. Cortical amygdaloid nuclei are usually named according to their location as anterior cortical amygdala (ACo) and the posterolateral and posteromedial (PLCo and PMCo) nuclei. In addition, there are two rostral nuclei showing a cortical appearance that are associated to the olfactory tracts, named as the bed


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f0015 FIGURE 2 Organization of the pallial amygdala of the rat. The central figure is a schematic 3-dimensional view of the nuclei composing the pallial amygdala of the left hemisphere, showing their topological relationship and embryological origin. The location of the pallial amygdala within the cerebral hemispheres is indicated in a 3-dimensional reconstruction of the rat brain (lower left corner). Two pallial territories contribute to the amygdala. Derivatives from the lateral pallium (red-pink-orange) include, besides the piriform cortex, the transitional cortical amygdala, e.g., the CxA and amygdalo-piriform area (APir). Deep to them, the different divisions of the basolateral nucleus (BLV; BLA and BLP) constitute the deep lateropallial amygdala. This neurogenetic relationship of cortical and deep nuclei can be appreciated in the cytoarchitecture of the adult amygdala in both sagittal and coronal sections stained for Nissl, NADPH diaphorase (NADPHd) histochemistry or calretinin (CR) immunohistochemistry. Different lines of evidence suggest that layer 2 of the LOT is a lateropallial derivative originating in a region of the neuroepithelium lining the caudal lateral ventricle, next to the BLP (see text). The ventropallial derivatives (blue-purple) also include cortical nuclei, e.g., the anterior (ACo) and posterior cortical nuclei (PLCo and PMCo), plus nuclei deep to them belonging to the basolateral division (BMA, BMP and La), as well as the amygdalohippocampal area (AHi) deep to the PMCo. Again, the topographical relationships between the cortical and deep ventropallial nuclei in the adult brain reflect their common neurogenetic origins, as observed in sagittal and coronal sections. On each photograph the level relative to Bregma is indicated in millimeters. Calibration bar in the NADPHd-reacted lateral sagittal section (valid for the rest of the photographs) represents 500 µm.

nucleus of the accessory olfactory tract (BAOT) and the nucleus of the lateral olfactory tract (LOT). Finally, there are two nuclei that are interposed between the piriform and entorhinal cortices and the cortical amygdala. At anterior levels, the cortico-amygdala transition zone (CxA) is located between the ACo and the piriform cortex (Pir), whereas near the caudal edge of the amygdala, the amygdalo-piriform transition area (APir) is interposed beween the PLCo and the caudal Pir and lateral entorhinal cortex. In fact, sagittal sections (Fig. 2) reveal a clear continuity between the APir and the entorhinal cortex (rather than the piriform area), thus indicating an inappropriate name for this portion of the amygdala (amygdalo-entorhinal transition area would better define it). p0090 Deep to these cortical nuclei, the hypopallial nuclei (according to Homgren’s terminology) make up the basolateral division of the amygdala, composed of the lateral (La), basolateral (BL) and basomedial nuclei (BM), and

the amygdalo-hippocampal area (AHi). In spite of their nuclear organization, adult features support the cortical nature of these centers. First, most of the principal neurons of these divisions of the amygdala show a clear pyramidal morphology (Fig. 1D) and are glutamatergic (expressing vesicular glutamate transporter, Poulin et al., 2008). In contrast, a small proportion of the cells of the basolateral and amygdalo-hippocampal divisions are GABAergic interneurons that often co-express neuropeptides and/or calcium binding proteins (Fig. 1B,C). The most parsimonious view of amygdala devel- p0095 opment suggests that a given region of the embryonic neuroepithelium would generate at least two cell populations: (1) neurons that would migrate up to the surface of the brain where they would settle to configure a given cortical nucleus; and (2) cells that do not reach the surface of the brain in their migration, which would make up one or several nuclei of the deep pallial amygdala. In other words, each cortical nucleus should have one, or a


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few, deep pallial counterparts (hypopallium) originated in the same region of the neuroepithelium and, consequently, would occupy a position immediately deep to their cortical counterpart. This developmentally-based anatomical view is shown in the simplified 3-dimensional scheme of the structure of the pallial amygdala summarized in the central image of Fig. 2. As this scheme reveals, the pallial amygdala shows an organization more complex than other paleocortical regions (e.g., the piriform cortex), as it seems to include cortical (superficial) and deep nuclei (located next to the ventricular neuroepithelium) plus intermediate cell groups interposed between the first and the latter. s0030 The Lateropallial Amygdala: CxA, APir, BL and

LOT Their location directly adjacent to the piriform cortex suggests that the CxA and APir would constitute the cortical nuclei of the lateropallial amygdala. Their lateropallial nature is also supported by data on the expression of morphogenetic genes in the mouse. For instance, Medina et al. (2004) studied the pattern of expression of cadherin 8 and Emx1 in mouse embryos. As noted above, Emx1 is expressed by the lateral but not the ventral pallium (Puelles et al., 2000). Cadherin 8, on the other hand, labels the same territories but its expression pattern is spatially wider, as it includes superficial and deep territories, and temporally longer as it is expressed from very early embryonic stages to birth. This spatial distribution of cadherin 8 (Medina et al., 2004) reinforces the view that the lateral pallium includes a small portion of the cortical amygdala, immediately adjacent to the piriform cortex, that the authors interpret as the PLCo, but may well be the embryonic APir and CxA instead (see below). In addition, cadherin 8 is also expressed by a deep nucleus, the basolateral amygdaloid nucleus (BL), and by cells interposed between these cortical and deep nuclei which constitute an intermediate layer within the lateropallial amygdala. These cadherin 8-expressing areas of the amygdala are also rich in Emx1 positive cells, thus reinforcing the view that they are not ventropallial but lateropallial. p0105 These data fit neuroanatomical data in the adult rat. Thus, CxA is apparently superficial to the anterior BL (BLA) if one considers the ventral basolateral nucleus (BLV) as the intermediate structure linking both structures. In addition, the APir is superficial to the posterior BL (BLP), with which it shares some neurochemical attributes (see the next section). As a conclusion, the lateropallial amygdala would be composed of at least two superficial cortical nuclei—CxA and APir—and their respective deep pallial counterparts, BLA and BLP, plus intermediate nuclei (BLV and deep APir). p0110 In this scheme, the location of the LOT requires reconsideration, given its atypical location, origin and properties. In the first analysis of the distribution of p0100

pallial territories in the amygdala the LOT was simply neglected, but the lateral olfactory tract was considered a landmark of the surface of the ventral pallium throughout its length (Puelles et al., 2000). In line with this, Medina et al. (2004) found that presumptive markers of the ventral pallium were strongly expressed by cells in layer 2 of the LOT. However, Remedios et al. (2007) re-analyzed this issue and showed the presence, during mid-gestational development, of the so-called “caudal amygdaloid stream,” a previously ignored neural migratory stream that arises from a distinct portion of the neuroepithelium lining the caudo-ventral edge of the lateral ventricle and follows a rostral direction to the ventral surface of the cerebral hemisphere. Cells in the caudal migratory stream build up layers 2 and 3 of the LOT, whereas cells in layer 1 of the LOT have a distinct origin. In their migration, cells in caudal amygdaloid stream apparently interact with a dense palisade of radial glia, using a mechanism that is partially dependent on reelin. In fact, a detailed analysis of the amygdala of reeler mice (deficient in reelin) shows a deficient migration in the caudal amygdaloid stream resulting in a misallocation of the LOT, which is found in a deep position, next to the BL (Boyle et al., 2011). Therefore, cells in layers 2 and 3 of the LOT are gen- p0115 erated in the caudal edge of the lateral ventricle neuroepithelium and migrate to the anterior ventropallial amygdala. As Remedios et al. (2007) put forward, the region of the neuroepithelium giving rise to the caudal amygdaloid stream expresses no markers of the ventral pallium (Frp2) but markers of the rest of the pallium such as Emx-1. Although, as suggested by the authors, this is compatible with a dorsopallial nature of the LOT, it does not exclude a lateropallial origin which is indeed clearly supported by the analysis of gene expression in the LOT during development and adulthood. For instance, Remedios et al. (2004) analyzed the expression patterns of LIM only genes (Lmo) in the developing amygdala of mice and realized that layers 2/3 of the LOT shared intense expression of Lmo3 and Lmo1 (also Lmo4) with some components of the lateral pallium, such as the BL and piriform cortex. The expression of Lmo3 continues until adulthood (Hinks et al., 1997) where it labels the piriform cortex and the putative lateropallial amygdala including the BLA, BLP and BLV and their superficial counterparts CxA and APir. A part of the caudal edge of the ventral pallium also expressed Lmo3, including the lateral amygdaloid nucleus (La) and the PLCo/BMP. This gene is also strongly expressed by most cells in layers 2 and 3 of the adult LOT, but not by the surrounding rostral ventropallial amygdala (Allen Brain Atlas). Additional data on gene expression further support this view. For instance, in the mouse, gene Slc30a3 (which encodes a zinc transporter) is mainly expressed by the piriform cortex and endopiriform nucleus, plus the lateropallial


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amygdala, e.g., CxA, APir and BL, as well as in layers 2 and 3 of the LOT (Boyle et al., 2011). p0120 These data underline the atypical features of the LOT, and relates its principal cells (layers 2 and 3) with the caudal lateral pallium rather than with the rostral ventral pallium that surrounds it in the adult brain. s0035 The Ventropallial Amygdala: ACo, PLCo, PMCo,

BM, AHi and La The remaining pallial amygdaloid structures should be ascribed to the ventral pallium. This includes superficial (layered) structures (e.g., the anterior and posterior cortical nuclei), plus deep neural centers neurogenetically related to them (e.g., the BM, AHi and La). This is a complex pallial territory that again has deep nuclei located next to the lateral ventricle (La, posterior BM [BMP] and AHi), plus intermediate nuclei that have lost their contact with the neurogenetic epithelium from which they were generated (e.g., the anterior BM [BMA]). Their ventropallial origin is inferred from data on gene expression during development (mainly obtained in the mouse) as discussed above. However, the ventropallial nature of these amygdaloid nuclei also fits topological criteria. Thus, the ACo, PLCo, PMCo, BM and AHi are adjacent to the subpallial structures of the rostral (anterior amygdaloid area) and caudal amygdala (medial amygdaloid nucleus and intraamygdaloid bed nucleus of the stria terminalis [STIA]), whereas the La is adjacent to the striatum and/or central amygdala. Therefore, this portion of the amygdala constitutes the topologically ventralmost derivative of the telencephalic pallium. p0130 This scheme has two main exceptions. On the one hand, there is an apparent discontinuity within the deep ventropallial amygdala between the La and the BM, with the BL being interposed. We assume that the intermediate capsule constitutes the bridge connecting both structures. Second, at some levels the ACo (ventropallial) is laterally adjacent to the LOT (lateropallial). As discussed above, this is explained by the atypical migratory route that LOT cells undergo during development, resulting in an ectopic location. p0135 The neurogenetic relationships between the cortical and deep nuclei of the ventropallial amygdala allow not only understanding the organization of the amygdala but also interpreting histological preparations of adult material. Thus, the AHi is evidently deep to the PMCo (see sagittal sections in Fig. 2), a feature that suggests a common neurogenetic origin. In the same way, the BMA is deep to the ACo, whereas the BMP is deep to the PLCo (Fig. 2). p0125

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The Subpallial Amygdaloid Territories and the Concept of Extended Amygdala The rest of the amygdala is composed of cells derived from the telencephalic subpallium and other regions of

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the prosencephalon. This justifies their grouping under the name “subpallial amygdala.” As put forward by Swanson and Petrovich (1998) on the basis of the high density of GABAergic cells, the subpallial amygdala includes the medial (Me) and central nuclei (Ce), as well as the intercalated cell masses. Fibers connecting the amygdala with extracortical or p0145 extra-telencephalic centers use three main tracts: the stria terminalis, the ansa peduncularis and the posterior part of the anterior commissure. All three tracts are accompanied by cell groups which receive descending projections from portions of the amygdala proper with which they share some of their projection targets. As we will discuss, the anatomical and connectional relationships between the subpallial components of the amygdala proper and the cell groups associated to its major input/ output fiber tracts underpin the concept of extended amygdala (Fig. 3). This was profusely documented in previous editions of this book (Alheid et al., 1995; de Olmos et al., 2004) to which the reader is referred for further details. Interestingly, the developmental mechanisms leading to the organogenesis of the amygdala support the concept of extended amygdala and justify the use of this term as a synonym of the subpallial amygdala. As we will see, this view is also fully supported by comparative analysis of the amygdala of different vertebrates (Martínez-García et al., 2007, 2008). s0045 The Two Poles of the Extended Amygdala: Common Properties of the Bed Nucleus of the Stria Terminalis and Centromedial Amygdala The main pathways connecting the amygdala with p0150 the hypothalamus and brainstem use the stria terminalis (st). This tract leaves the amygdala right between the posterior Me and Ce (Fig. 4G,H). In this location, a group of cells surrounds the st making up the so-called intraamygdaloid bed nucleus of the stria terminalis (STIA). The st exits the amygdala just behind the internal capsule and runs rostrally just above it, where it is known as the supracapsular part of the ST (STS; Fig. 3). At the level of the interventricular foramen the st turns ventrally, medial to the internal capsule, thus entering the hypothalamus at preoptic levels, from where it runs caudally to reach more distant targets in the hypothalamus and brainstem. Throughout its course in the cerebral hemispheres, the fibers of the st are accompanied by cells that constitute the different divisions of the bed nucleus of the stria terminalis (ST). This includes the ST proper, a cell complex that surrounds the ventral sulcus of the lateral ventricle in close association with the anterior commissure, as well as the supracapsular stria terminalis (STS). The ST constitutes a nodal center of the extended amygdala (Fig. 3). A second major tract conveying output fibers of the p0155 amygdala is called the ansa peduncularis (Petrovich et al., 1996), which leaves the amygdala through the


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f0020 FIGURE 3 The extended amygdala of the rat. The 3-dimensional reconstruction of the extended amygdala of the rat reveals the location of the extended amygdala (EA) in the cerebral hemispheres and its annular morphology around the internal capsule. This can be appreciated in lateral (left upper corner) and dorsal views (left lower corner) of the brain and, next to them, of the isolated extended amygdala at higher magnification. The EA is composed of two main anatomical divisions, the centromedial amygdala caudally, and the bed nucleus of the stria terminalis (ST) rostrally. A rim of cells accompanying the st links both structures dorsal to the capsula, the supracapsular ST. In addition, several cell groups link the ST and centromedial amygdala ventral to the capsula and the lenticular nucleus, the so-called sublenticular extended amygdala (SLEA). A color code shows the main components of the extended amygdala: the medial EA (blue) is composed of the medial amygdala in the caudal pole of the EA, the posteromedial ST (rostrally) and a row of cells in the STS. The central EA (red), consists of the central amygdala caudally, the anterior and lateral ST and a portion of the intervening STS. The SLEA is depicted in green, as the medial and central components are not clearly separated there. Coronal (upper panel) and sagittal sections (lower panel) stained for NADPHd histochemistry (left column) or for the immunohistochemistry for calcitonin gene related peptide (CGRP; right column) allow distinguishing individual nuclei of the medial and central extended amygdala. Calibration bar, valid for all the photographs, represents 500 µm.

rostral medial and central amygdala to enter directly the substantia innominata (now reconsidered to be part of the ventral pallidum, see Paxinos and Watson, 2014), from where fibers diverge to several targets in and out of the cerebral hemispheres. This portion of the substantia innominata intermingled with the fibers of the ansa

peduncularis is another nodal center of the extended amygdala. Finally, some parts of the amygdala (LOT, Santiago and Shammah-Lagnado, 2004; posterior cortical amygdala, Savander et al., 1997; Kemppainen et al., 2002) are connected with the contralateral cerebral hemisphere, the commissural or decussating fibers crossing


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f0025 FIGURE 4 Cytoarchitecture of the amygdala of the rat. Coronal sections through the left amygdala of the rat stained with Giemsa (Nissl staining; upper rows) and for NADPHd histochemistry (lower rows). The boundaries of the different nuclei composing the amygdala are indicated using dotted lines. Calibration bar, 500 µm. IV. DIENCEPHALON, BASAL GANGLIA, AMYGDALA, AND SEPTUM

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the midline through the posterior part of the anterior commissure (acp). This part of the anterior commissure apparently joins the outer capsule in a location just anterior to the rostral edge of the subpallial amygdala (see coronal sections corresponding to levels −0.96 mm to 0.0 mm relative to bregma in Paxinos and Watson, 2014). In its course, the acp is accompanied by several cell groups usually named as the interstitial nuclei of the posterior limb of the anterior commissure (IPAC), which are immediately adjacent to the anterior amygdala (AA) and anterior aspect of the Ce. The IPAC and the sublenticular portion of the substantia innominata are jointly known as the sublenticular extended amygdala (SLEA; green in the 3-dimensional view of Fig. 3). p0160 Taken together, the subpallial portion of the amygdala proper (Me and Ce) plus the ST and the SLEA make up a ring-shaped structure that surrounds the internal capsule (see Fig. 3) and constitutes the subpallial or extended amygdala (EA), two terms we are using as synonyms. Thus conceived, the EA can be envisaged as a bipolar structure with the amygdala proper (subpallial part, centromedial amygdala) as the caudal pole, and the ST as the rostral one. The STS and SLEA connect both poles above (STS) and below the internal capsule (SLEA) (Fig. 3). Such grouping of otherwise apparently unrelated structures relies on their deep interconnections and on the fact that they share many hodological and neurochemical properties (see next section). p0165 The portion of the EA located in the amygdala proper, hereto named as “intraamygdaloid EA” or “centromedial amygdala,” and the “extraamygdaloid” components of the EA are deeply interconnected. The projections from Me and Ce to the ST were thoroughly analyzed by Dong et al. (2001) and their reciprocal connections were also revealed by injections in the ST (Dong and Swanson, 2003, 2004a, 2004b, 2006a, 2006b, 2006c). Similarly, the STS (Shammah-Lagnado et al., 2000) and SLEA (ShammahLagnado et al., 2000) are profusely interconnected with the centromedial amygdala, on the one hand, and with the ST on the other. p0170 In addition, as we discuss in detail below (see Connections Between the Pallial Amygdala and the Extended Amygdala below), elements of both poles of the EA share similar afferents from the pallial amygdala, some of their connections with the hypothalamus and brainstem (e.g., Bienkowski and Rinaman, 2013), as well as some key histochemical features (Fig. 3). s0050 The Medial and Central Extended Amygdala p0175

The interconnections of the Ce and the Me with the rest of EA are largely non-overlapping, thus depicting a bipartite organization of the EA. On the one hand, the medial extended amygdala (mEA) would be composed of the Me plus the portions of the ST, STS and SLEA with

which it is interconnected. On the other hand, the central extended amygdala (cEA) consists of the Ce plus a portion of the “extraamygdaloid” EA (ST and SLEA) with which it is profusely connected. Consequently, within each of these nuclei (the ST proper, supracapsular ST and SLEA), there are portions mainly connected with the Me, which would belong to the mEA, and other ones interconnected with the Ce instead, which would be ascribed to the cEA. A second line of evidence strongly supporting the notion of EA and its bipartite nature (mEA/cEA) is the pattern of connections with the pallial amygdala. As we will see in the section Functional Connectivity of the Amygdala, the intrinsic connectivity of the amygdala is dominated by important descending projections that connect the pallial with the subpallial or extended amygdala. In this context, the basolateral division of the amygdala projects massively to the Ce (BLP and APir and, to a lesser extent, BMP and La; Shammah-Lagnado et al., 1999). Not surprisingly, the same nuclei also project to the remaining elements of the cEA within the ST, STS and the SLEA (Shammah-Lagnado and Santiago, 1999; Bienkowski and Rinaman, 2013). The afferents to the medial amygdala have received much less attention. Using horseradish peroxidase, Ottersen (1982) traced the afferents to the medial amygdala of the rat and revealed that it receives its main pallial input from the posterior cortical amygdala (PMCo and PLCo) and AHi (to a lesser extent also from the anterior cortical amygdala), but not from the basolateral division of the amygdala. We have observed a similar situation in the mouse (Martínez-García et al., 2012). The projections from the posterior cortical amygdala (PLCo and PMCo), APir and AHi were traced by Canteras et al. (1992a), Dong et al. (2001), Jolkkonen et al. (2001b) and Majak and Pitkänen (2003) and confirm that they constitute the main pallial input to the mEA. Finally, chemoarchitecture also reinforces the bipartite structure of the extended amygdala and the concept of EA itself. The cEA contains the densest populations of neuropeptidergic cells of the cerebral hemispheres, including those immunoreactive for corticotropinreleasing factor (CRF), neurotensin (NT), substance P (SP), somatostatin (SS), neuropeptide Y (NPY), enkephalin (ENK) and galanin (GAL) (see Gray and Magnuson, 1987; Ju and Swanson, 1989; Moga et al., 1989). Most of these peptidergic cells are also GABAergic (Veinante et al., 1997; Day et al., 1999) and constitute the projection neurons of the central EA (Moga and Gray, 1985; Gray and Magnuson, 1987, 1992). These peptidergic cells of the cEA can be grouped in two main populations (Shimada et al., 1989). One of them is composed of neurons co-expressing CRF and NT or dynorphin, and the second population of neurons coexpresses substance SP and/or SS. These two populations


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show a symmetric distribution in the two poles of the central EA (e.g., the Ce and ST). For instance, CRF/NT neurons are mainly observed in the lateral aspect of the central amygdala (Gray and Magnuson, 1992) and in the dorsolateral and juxtacapsular ST (Ju and Swanson, 1989; Moga et al., 1989). On the other hand, most of the SP/SS (as well as the galanin-expressing neurons; Gray and Magnuson, 1987) are located in the medial Ce and in the ventral posterolateral ST (Gray and Magnuson, 1992). A third population of GABAergic and peptidergic cells, immunoreactive for enkephalin, was observed to be virtually restricted to the capsular division of the Ce (Poulin et al., 2008) and lateral ST (Poulin et al., 2006). p0200 The anterolateral ST and the Ce also share the presence of a dense innervation by fibers containing calcitonin gene-related peptide (CGRP; see Figs. 3 and 10), which conform a dense terminal field immediately lateral to the region containing most peptidergic cells. In fact, a very dense CGRP terminal field occupies the amygdalo-striatal region (AStr), fundus striati, the caudal edge of the striatum plus the capsular division of the Ce (CeC) (Kruger et al., 1988; Yasui et al., 1991; Dobolyi et al., 2005), whereas the lateral division of the Ce (CeL) shows sparser CGRP innervation with abundant perisomatic nests (Figs. 3 and 10). In the ST, CGRP innervation is very dense in its laterodorsal (STLD) and lateroventral (STLV) divisions (Fig. 3), from where it extends up to the rostral edge of the nucleus, just caudal to the nucleus accumbens (Dobolyi et al., 2005). Consequently, in both the Ce and ST, CGRP innervation extensively overlaps with the populations of peptidergic neurons (with some of which they establish synaptic contacts; Harrigan et al., 1994; Kozicz and Arimura, 2001), but extends more rostro-laterally. CGRP innervation is also observed in the sublenticular extended amygdala including parts of the substantia innominata and IPAC (Dobolyi et al., 2005). p0205 Regarding the mEA, its main features are related to the fact that it contains the key nodes of the socio-sexual brain (Newman, 1999); see the section Behavioral Neurobiology of the Amygdala). Thus, its two main components, the Me and the medial posterior ST (mainly the posteromedial and posterointermediate parts) share the following properties: (1) They are targeted by a direct projection from the accessory olfactory bulbs, which terminate in the whole Me (anterior and posterior divisions) and the medial posteromedial ST (STMPM) and seems immunoreactive for neuropilin-2 (see Fig. 13C); (2) They include nuclei that show sexual dimorphism regarding their neural number (Hines et al., 1992; Morris et al., 2008) and the expression of several markers, notably arginine-vasopressin (AVP; see Fig. 13D and inset). Thus, as compared to females or castrated males, intact males show a high density of AVP expressing cell bodies in the medial posterointermediate (STMPI) and in the

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medial posterolateral (STMPL) parts of the ST, on the one hand, and in the STIA on the other (DeVries et al., 1985; Otero-García et al., 2013); (3) This is due, at least in part, to the fact that the Me and ST (especially its posteromedial aspect) contain cells expressing very high levels of receptors for sexual steroids (both during postnatal and adult life), including alpha and beta estrogen receptors (Simerly et al., 1990; Shughrue and Merchenthaler, 2001; Cao and Patisaul, 2013) and androgens (Simerly et al., 1990); and (4) Sexual dimorphism is mainly due to the postnatal and adult influence of testosterone acting on androgen or estrogen receptors, as the mEA contains the main neuronal populations expressing aromatase (the enzyme catalyzing aromatization of testosterone to estrogen) in the cerebral hemispheres (Roselli et al., 1998). Developmental Foundations of the Extended Amygdala The anatomical and neurochemical similarities between the intraamygdaloid (Ce and Me) and extraamygdaloid (ST and SLEA) counterparts of the central and medial EA are reflecting their developmental relationships. Studies in mice by the group of Loreta Medina have analyzed the pattern of gene expression during development and the loci of neurogenesis and migratory streams that mediate the construction of the EA in the mouse. According to their results, the central extended amygdala (Bupesh et al., 2011a) is composed of derivatives from the dorsal (enkephalin-expressing projection cells) and ventral lateral ganglionic eminence (CRF/NTexpressing cells), as well as from the medial ganglionic eminence (somatostatin-expressing cells). As we have discussed, all three kinds of cells populate the Ce and the antero-lateral ST. These data have reinforced previous ideas suggesting that the cEA is a continuum of striatal (originating in the lateral ganglionic eminence) and pallidal cells (from the medial ganglionic eminence) distributed in the ST and Ce as well as the intervening structures surrounding the internal capsule. The developmental origin of the medial extended amygdala is even more complex (Bupesh et al., 2011b). Whereas most of the cells of the mEA arise in and migrate from the caudoventral medial ganglionic eminence (an area previously known as the anterior peduncular area), which has a pallidal nature, it also includes cells originated in the ventral pallium and in two territories of the hypothalamic neuroepithelium, e.g., commissural preoptic area and the supraopto-paraventricular domain (García-Moreno et al., 2010). With the exception of the cells originating in the ventral pallium, which are restricted to the posterodorsal part of the Me (MePD), the remaining neuroepithelial domains contribute to both the Me and posteromedial ST. Therefore, the similarities observed between the cell populations in the two poles of the extended amygdala


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(centromedial amygdala and ST) are reflecting their common embryonic origin in different domains of the subpallial telencephalon and hypothalamic neuropithelium. The mixture of cells with different neurogenetic origin in the centromedial amygdala and ST (lateral and medial ganglionic eminences, commissural preoptic, supraoptoparaventricular hypothalamus and ventral pallium) makes the extended amygdala a distinct region of the subpallial telencephalon, not comparable to either the striatum or the pallidum. This is reflected by the peculiar features of the EA, such as its specific pattern of connectivity. Thus, whereas in the rest of the subpallium projections are unidirectional, e.g., the striatum projects to the pallidum but no pallidostriatal projections exist, within the EA, the intraamygdaloid (centromedial amygdala) and “extraamygdaloid” EA (e.g., ST) are reciprocally connected. s0060 Comparative Neuroanatomy of the Extended

Amygdala: Developmental Restrictions in Mammals p0225 The apparent continuity between the ST and the centromedial amygdala was put forward by Johnston (1923) on the basis of his comparative analysis of the anatomy of the cerebral hemispheres in vertebrates, a view that has been confirmed by more recent analysis of the comparative neuroanatomy of the amygdala (Martínez-García et al., 2007). Non-mammalian amniotes (extant reptiles and birds) lack an isocortex (dorsal pallium) but show, instead, an enlarged ventral pallium which is known as the dorsal ventricular ridge. A thorough analysis of the development, genoarchitecture, neurochemistry and connections of the lateral caudo-ventral cerebral hemispheres in mammals, birds and reptiles allowed Martínez-García et al. (2007) to identify the main divisions and nuclei of the amygdala of non-mammals, and their putative homologies with the mammalian amygdala. Concerning the subpallial amygdala, the main conclusion was that in the brain of non-mammals the two components of the extended amygdala (centro-medial amygdala and ST) are not separated but constitute a unitary structure, associated with the st, anterior commissure and ventral amygdalofugal pathway. This apparent fusion of the centromedial amygdala and the ST is likely due to the absence of internal capsule and cerebral peduncle in the cerebral hemispheres of non-mammals, related to the lack (reptiles) or diminution (birds) of the descending extratelencephalic projections of the cortex (e.g., corticothalamic, corticopontine and corticospinal projections). As a consequence, in non-mammals, the st or equivalent tracts connecting the amygdala with the rest of the brain leave the amygdala medially next to the anterior commissure and the ventral amygdalofugal pathway (see Lanuza et al., 1997) and there are no barriers (internal capsule) for neuronal migration in the basal forebrain during embryonic development.

In contrast, in mammals the internal capsule and p0230 cerebral peduncle appear as large, extremely dense bundles of fibers already in early stages of embryonic development; as early as day E13 in the rat (the peak of neurogenesis in the subpallial amygdala, Bayer, 1980, 1987). In this and later stages, these tracts constitute a physical barrier that might hinder the migration of cells from the ganglionic eminences or the diencephalon to the amygdala, as well as the development of the axonal bundles connecting the amygdala with the rest of the brain. In conclusion, the presence of two separated structural p0235 units in the extended amygdala (centromedial amygdala and ST) is a feature restricted to mammals, probably due to developmental constraints related to the presence of the internal capsule and cerebral peduncle. This fact “isolates” the amygdala from the rest of the brain during the second half of embryonic development, thus causing the subpallial amygdala and the fiber bundles associated to it to form a ring-shaped structure around the internal capsule (Fig. 3). Consequently, the EA splits in two main structures, one rostromedial to the internal capsule, the ST, and another one caudolateral to the capsule, the centromedial amygdala.

CYTOARCHITECTONICS AND CHEMOARCHITECTONICS OF THE AMYGDALA

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As explained in Development and Territories in the Rat p0240 Amygdala above, the amygdala results from the assembling of derivatives of several territories of the pallium and subpallial forebrain that, during development, migrate and mix up to shape differentiated cell groups. In this section, we describe the resulting architecture of the amygdaloid complex of the adult rat, which is composed by three distinct anatomical components, namely the amygdala proper (Fig. 4), the bed nucleus of the ST (Fig. 5) and the sublenticular extended amygdala (Fig. 6). Tables 1 and 2 provide the hierarchical classification of the nuclei composing the amygdaloid complex, in which the first level is the dichotomy pallial versus subpallial.

The Pallial Amygdala

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The pallial amygdala is composed of cortical (superfi- p0245 cial) and deep nuclei. The deep nuclei are the La, BL, BM plus the anterior amygdala (rostrally) and the amygdalohippocampal area (AHi) at caudal levels. Although the three former nuclei (La, BL and BM) are usually grouped under the term basolateral division, we do not use this term as it unreasonably excludes other deep pallial nuclei and it coincides in name with the BL thus generating confusion. On the other hand, the cortical amygdala


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f0030 FIGURE 5 Cytoarchitecture of the bed nucleus of the stria terminalis (ST) of the rat. Coronal sections through the left ST of the rat stained with Giemsa (Nissl staining; upper row) and for NADPHd histochemistry (lower rows). Dotted lines trace the boundaries of the different nuclei of the ST. Calibration bar, 500 µm.

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FIGURE 6 Cytoarchitecture of the sublenticular extended amygdala (SLEA) of the rat. Coronal sections through the left SLEA of the rat stained with Giemsa (Nissl staining; upper row; A and C) and for NADPHd histochemistry (lower row; B and D). The cytoarchitectonic boundaries of the SLEA are traced with discontinuous lines. Calibration bar, 500 µm.

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Hierarchy of Nuclei of the Pallial Components of the

Cortical pallial

Lateropallial

Medial nucleus

Nucleus of the lateral olfactory tract Bed nucleus of the accessory olfactory tract Cortex amygdala transition zone Amygdalopiriform transition area

LOT BAOT

Medial nucleus anterodorsal part

MeAD

Medial nucleus anteroventral part

MeAV

CxA APir

Medial nucleus posterodorsal part

MePD

Medial nucleus posteroventral part

MePV

Ventropallial Anterior cortical amygdaloid nucleus Posterolateral cortical amygdaloid nucleus Posteromedial cortical amygdaloid nucleus Deep pallial

TABLE 2 Hierarchy of Nuclei of the Subpallial Components of the Amygdala

ACo PLCo PMCo

Lateropallial Basolateral

Central nucleus Central nucleus medial division

CeM

Central nucleus lateral division

CeL

Central nucleus capsular division

CeC

Amygdalostriatal transition area

ASt

Anterior amygdaloid area

AA

Intercalated nuclei

I

Bed nucleus of the stria terminalis • Basolateral anterior nucleus • Basolateral posterior nucleus • Basolateral ventral nucleus

BLA BLP BLV

Bed nucleus of the stria terminalis, intraamygdala part

STIA

Bed nucleus of the stria terminalis, supracapsular part

STSC

BMA BMP

Bed nucleus of the stria terminalis, medial division

STM

Bed nucleus of the stria terminalis, medial anterior

STMA

LaDL

Bed nucleus of the stria terminalis, medial ventral

STMV

LaVL

Bed nucleus of the stria terminalis, medial posterior

STMP

Bed nucleus of the stria terminalis, lateral division

STL

AHiPM

Bed nucleus of the stria terminalis, lateral dorsal

STLD

AHiAL

Bed nucleus of the stria terminalis, lateral intermediate

STLI

Bed nucleus of the stria terminalis, lateral juxtacapsular

STLJ

Bed nucleus of the stria terminalis, lateral posterior

STLP

Bed nucleus of the stria terminalis, fusiform nucleus

Fu

s0075 The Deep Pallial Nuclei of the Amygdala

Bed nucleus of the stria terminalis, parastrial nucleus

PS

s0080 THE LATERAL NUCLEUS OF THE AMYGDALA

Bed nucleus of the anterior commissure

BAC

Sublenticular extended amygdala

SLEA

Sublenticular substantia innominate

SI

Interstitial nucleus of the posterior limb of the anterior commissure

IPAC

Basomedial • Basomedial anterior • Basomedial posterior Ventropallial Lateral • Lateral amygdaloid nucleus, dorsolateral part • Lateral amygdaloid nucleus, ventrolateral part • Lateral amygdaloid nucleus, medial part

LaM

Amygdalohippocampal transition area • Amygdalohippocampal posteromedial • Amygdalohippocampal anterolateral

should include not only the anterior (ACo) and posterior nuclei (PLCo and PMCo) but also the cortical areas interposed between the amygdala and the piriform and entorhinal cortices, the CxA and the APir, as well as the LOT and the BAOT.

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In coronal sections, the La appears as a triangular cell group spanning virtually the whole rostrocaudal extent of the amygdala, delineated by the external and intermediate capsules at rostral and intermediate levels, and laterally adjacent to the ventral sulcus of the lateral ventricle caudally. The La is composed of small-to-medium


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FIGURE 7 Acetylcholinesterase reactivity in the amygdala of the rat. Four selected coronal sections (A–D from rostral to caudal) through the left amygdala reacted for the histochemical detection of acetylcholinesterase (AChE). Note the strong reactivity of the LOT and BL, and the moderate but heterogeneous reactivity of the CxA, PMCo, La, Ce and AHi. Arrowheads in layer 1 of the MeAV (B), MePV (C) and PMCo (D) delineate the input from the accessory olfactory bulb which is reactive for AChE. Calibration bar, 500 µm.

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sized neurons with a rough triangular shape resembling the pyramidal morphology (Alheid et al., 1995), without a dominant orientation. In Nissl stained sections, a zone showing a low cell density separates the La from the ventrally adjacent BL. Acetylcholinesterase (AChE) histochemistry provides a better way of delineating both nuclei, since the La shows a pale staining which contrasts with the intense labeling of the BL (Fig. 7). p0255 On the basis of their differential staining with AChE (Fig. 7B–D) and Timm staining (e.g., zinc histochemistry), three subnuclei are distinguished in the La (i.e., dorsolateral [LaDL]), ventrolateral (LaVL) and medial (LaM). Thus, the LaDL and LaVL show moderate to intense staining in AChE but faint staining with Timm histochemistry, while the LaM shows the reverse pattern (Jacobowitz and Palkovits, 1974; Haug, 1976; Ben-Ari et al., 1977; Perez-Clausell et al., 1989). This division of the La is also supported by connectional data. The three subnuclei show differential connections with the thalamus and cortex (Romanski et al., 1993) and the intranuclear connections of the La are specifically directed from LaDL to the other two subnuclei (Pitkänen et al., 1997). In agreement with its pallial nature, the La is comp0260 posed of glutamatergic principal neurons and smaller populations of interneurons expressing GABA/GAD (Fig. 1A), calcium binding proteins such as parvalbumin (PV), calbindin (CB; Fig. 1B,C) or calretinin (CR, Fig. 2), NADPH diaphorase (NADPHd; Figs. 3 and 4), and some neuropeptides such as somatostatin or enkephalin (Asan, 1998).

Within the circuitry of the amygdala involved in p0265 fear acquisition and expression, the La amygdala is usually considered the sensory interface (see Functional Connectivity of the Amygdala), since it receives the bulk of the thalamic afferents. Part of this input is revealed by immunohistochemistry for calcitonin gene related peptide (CGRP), which in the La stains a sparse network of CGRPergic fibers (see Fig. 3, coronal section through the amygdala) that are known to arise from the lateral subparafascicular nucleus of the thalamus (Yasui et al., 1991). This CGRP-rich projection has additional amygdaloid targets, mainly in the central extended amygdala (see Fig. 3), and it is known to be involved in fear acquisition (Kocorowski and Helmstetter, 2001). THE BASOLATERAL NUCLEUS OF THE AMYGDALA

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The basolateral nucleus (BL) is a large cell group p0270 located just ventral the La. It is usually divided into three divisions (anterior, posterior and ventral) which, in Nissl stained material, differ in the size and appearance of their neurons. Thus, anterior (BLA) and posterior (BLP) are composed of round-shaped cell bodies, but cells in the BLA are large as compared to those in the BLP, thus justifying the names magnocellular (BLA) and parvocellular (BLP) used by some authors (Swanson, 1998). In contrast, the ventral (BLV) is composed of fusiform cells, usually oriented in a dorso-ventral direction, that are interposed between the CxA (rostrally) or the ventral edge of the piriform cortex (caudally) and the BLA,


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which is immediately deep to it. At caudal levels of the amygdala, the BLV is replaced by the APir. p0275 Using AChE histochemistry BLA and BLP stand out because of their intense staining (Fig. 7B–D), which allows easy delineating of their boundaries with the surrounding nuclei, but the BLV shows faint reactivity. On the other hand, NADPHd histochemistry renders a differential staining of the three subnuclei of the BL. Thus, neuropile staining is relatively intense in the BLP and lighter in the BLA, whereas the BLV seems virtually unstained, but shows a population of intensely stained neurons, at least at rostral levels (Fig. 4D). p0280 Another common feature of the BLA and BLP is the intense innervation by tyrosine- hydroxylase (TH) immunostained fibers (the BLP showing a higher density of TH-positive fibers), which contrasts with the scarce innervation of the adjacent BM and La (Asan, 1998).

THE AMYGDALOHIPPOCAMPAL AREA

s0090 THE BASOMEDIAL NUCLEUS OF THE AMYGDALA

The Cortical Amygdaloid Nuclei s0105 The cortical amygdala appears to be interposed p0300 between the piriform cortex (rostrally), the entorhinal cortex (caudally), and the medial amygdala (Fig. 2). Like other areas of the paleocortex, the different “nuclei” of the cortical amygdala are superficial, three-layered areas, with a superficial molecular layer (layer 1) that receives input from the main and/or accessory olfactory bulbs (reactive for calretinin and, in the case of the vomeronasal input, for neuropilin-2), a densely packed cell layer (layer 2) and a deeper layer 3 showing a lower density of neurons. In some instances, the boundaries between layer 3 and the deep nuclei are very diffuse (e.g., between the ACo/PLCo and BM; see Fig. 4). As indicated in Table 1, the cortical amygdala includes the nuclei of the LOT and BAOT and the anterior cortical amygdala (ACo) at rostral levels, plus the posterolateral (PLCo) and posteromedial (PMCo) nuclei at caudal levels. In addition, two transitional areas are distinguished: the cortex-amygdala transition zone (CxA) is interposed between the ACo and the piriform cortex, whereas the APir is located between the posterior piriform or the entorhinal cortex and the PLCo.

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The basomedial nucleus (BM) is a heterogeneous cell mass located deep in most of the cortical amygdala. It is usually divided into two distinct subnuclei named topographically as basomedial anterior (BMA) and basomedial posterior (BMP). The BMA is composed of small, densely packed neurons that are located just deep to the anterior cortical amygdala (ACo), whereas the BMP is a loose group of large cells located deep in the posterolateral cortical amygdala (PLCo). As their main histochemical features, both subnuclei can be easily distinguished using NADPHd, since the BMA is the most intensely stained cell group of the pallial amygdala, but the BMP shows a much lighter staining. Also immunohistochemistry for the calcium binding protein parvalbumin (PV), GABA or its synthetizing enzyme GAD65, renders a differential staining of both subnuclei with the BMA showing more immunoreactive cells than the BMP (Fig. 1A).

s0095 THE ANTERIOR AMYGDALOID AREA p0290

The anterior amydaloid area (AA) surrounds the nucleus of the lateral olfactory tract and the bed nucleus of the accessory olfactory tract (Fig. 2, anterior coronal section; Fig. 4A,B; Fig. 6) dorsally and medially. It is composed of an area of loosely distributed large cells, which shows moderate neuropile staining and sparse darkly stained cells with NADPHd. Using AChE histochemistry, the AA displays a staining intensity intermediate between that of the putamen and the one of the cortical and medial amygdala, which shows lighter staining. The AA is usually divided into dorsal (AAD) and ventral regions (AAV). Although the boundaries between both subareas are quite fuzzy, it seems that the AAV is part of the pallial amygdala, as it expresses emx2 in mouse embryos whereas the AAD is subpallial (Tole et al., 2005).

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As its name indicates, the AHi is a cell group appar- p0295 ently interposed between the caudalmost medial aspect of the amygdala and the subicular area of the caudal hippocampal formation, as can be appreciated in the medial sagittal section of Fig. 2. It occupies a location just deep to the PMCo (Fig. 2; Fig. 4K,L; Fig. 8C,D) and their relative boundaries are not easy to delineate in Nissl stained sections. However, several histochemical and immunohistochemical techniques render differential staining that distinguishes both nuclei, such as NADPHd (Fig. 4K,L), or AChE histochemistry which results in an intense neuropil staining in AHi that contrasts with the pale reactivity of the PMCo (Fig. 7D). Neuropilin-2 renders the reverse pattern, with the PMCo showing faint staining and the AHi being unstained (Fig. 8E).

THE NUCLEI OF THE OLFACTORY TRACTS (LOT AND BAOT)

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The LOT looks as a structure that is embedded in the p0305 anterior amygdala, among the two divisions of the AA and the anterior medial amygdala. In Nissl stained sections (Fig. 6C), the LOT shows a clear lamination with layer 1 containing the fibers of the lateral olfactory tract revealed using calretinin immunostaining (see the anterior frontal section in Fig. 2), a wide, densely packed layer 2 and a triangular shaped layer 3 composed of relatively smaller neurons. The LOT shows peculiar chemoarchitectonic properties that probably reflect its peculiar developmental history (see Development and Territories in the Rat Amygdala


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f0045 FIGURE 8 Architecture and chemoarchitecture of the cortical amygdala of the rat. (A) Coronal section through the anterior amygdala immunoreacted for calretinin (CR) shows a high density of CR-immunoreactive cells in layers 2 and 3 of the anterior cortical amygdaloid nucleus (ACo), plus the massive input from the olfactory bulbs to the ACo, CxA and medial amygdala. (B) A detail of the posterolateral cortical amygdala (PLCo) stained with Giemsa showing the heterogeneity of this area of the cortical amygdala, which includes discontinuities in layer 2 and the presence of densely-packed clusters of small cells in layer 3 (asterisk). (C) The PLCo also shows a specific population of parvalbumin (PV) imunostained small neurons, likely interneurons. (D and E) show adjacent coronal sections through the posterior amygdala, stained with Giemsa (D) and immunostained for neuropilin-2 (E). Neuropilin-2 is a marker of the input from the accessory olfactory bulb, thus allowing a precise delineation of the PMCo and its boundaries with the PLCo. Calibration bars 500 µm (A, D and E) and 100 µm (B and C).

above). Thus, Timm staining (Fig. 9A) reveals that the LOT has a density of heavy metals (e.g., Zn) much higher than the surrounding structures (ACo, AA), but similar to the piriform cortex, thus reinforcing the view that it has a lateropallial origin. Although, like other regions of the pallium the LOT probably gives rise to glutamatergic projections, cells in its layer 2 express a type of glutamate vesicular transporter, type 2 (Fig. 9B) not present in other areas of the pallial amygdala. In addition, whereas calretinin (CR) immunohistochemistry delineates the LOT as an unstained area surrounded by reactive structures (anterior coronal section in Fig. 2), immunohistochemistry for cholecystokinin (CCK) reveals a population of small cells (likely interneurons) in its layer 2 (and a lower density in layer 3; Fig. 9C). These data suggest that the LOT is peculiar not only in the properties of its projection neurons, but also in the kind of interneurons it contains. Finally, in contrast to the neighboring nuclei, AChE histochemistry

stains the neuropile of the LOT with intensity comparable to the BL (Fig. 7A), with which the LOT shares other features (e.g., commissural connections, see Cytoarchitectonics and Chemoarchitectonics of the Amygdala above). The BAOT is a small nucleus located immediately p0310 medial and caudal to the LOT. The BAOT and LOT share a similar layering, although the BAOT displays a less conspicuous layer 2. Comparison of immunostaining for CR (Fig. 9D), which labels the input from the main and the accessory olfactory bulbs, with that for neuropilin-2, which specifically labels the input from the accessory olfactory bulb, indicates that both bulbs show orderly projections to different sublayers of layer 1 of the BAOT. Even if these properties make the LOT and BAOT similar nuclei, they differ substantially in other respects, such as the presence (BAOT) or absence (LOT) of CR-immunoreactive neurons (compare Fig. 9D with the rostral coronal section in Fig. 2).


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FIGURE 9 Chemoarchitecture of the nuclei of the lateral (LOT) and accessory olfactory tract (BAOT). (A) The histochemistry for heavy metals (Timm staining) shows the high reactivity and clear-cut lamination of the nucleus of the lateral olfactory tract (LOT), comparable to that of the piriform cortex. In contrast, the ACo and the anterior amygdala show fainter reactivity. (B) Cells in layer 2 of the LOT are strongly immunoreactive for type 2 vesicular transporter of glutamate. (C) The LOT also shows a distinct population of small interneurons immunoreactive for cholecystokinin (CCK), which are mainly present in layer 2. (D) Immunoreactivity for calretinin (CR) reveals a heterogeneous staining of the cortical and deep structures of the anterior pallial amygdala. This includes the input from the olfactory bulbs to the cortical amygdala (layer 1) and the strong immunoreactivity (including many positive cells) of the bed nucleus of the accessory olfactory tract (BAOT). Calibration bars, 500 µm (A and D), 200 µm (B) and 100 µm (C).

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f0050 s0115 THE CORTEX AMYGDALA TRANSITION AREA p0315

The CxA is located at the rostral edge of the amygdala, where it appears as the ventralmost portion of the piriform cortex, from which it differs in the thickness and cell density of layers 2 and 3 (see Figs. 4A,B and 6A–D). Medially it is bounded by the ACo. As a defining histochemical feature, the CxA displays a moderate neuropile staining with AChE histochemistry, relatively denser than the adjoining areas (piriform cortex and ACo) (Fig.7A,B). Another neurochemical feature of the CxA in which it differs from the ACo is the low immunoreactivity for CR, which is nearly restricted to the olfactory fibers reaching the superficial half of its layer 1 (Figs. 8A and 9D). Finally, the CxA, but not the ACo, shows parvalbumin-immunoreactive cells in its layer 3.

s0120 THE ANTERIOR CORTICAL AMYGDALA p0320

The ACo is an area just medial to the CxA in the rostral edge of the cortical amygdala and extends caudally up to intermediate amygdaloid levels, where it occupies nearly the whole mediolateral extent of the cortical amygdala (Figs. 4C–F, 7B, 8A and 9D). At more caudal levels, it becomes sandwiched between the PLCo (lateral to it) and the Me (medial to it). Throughout its rostro-caudal extent the ACo shows a relatively diffuse lamination, as compared to the CxA and PLCo, accompanied with a high cell density in both cell layers (2 and 3), also in layer 1 that shows many cells for a molecular layer (see Figs. 4 and 6). As discussed above, the boundaries between layer 3 of ACo and

the nucleus just deep to it, the BMA, are fuzzy. In addition, both nuclei share a high cell density, their intense reactivity for NADPHd histochemistry (Figs. 4 and 6) and the generally high immunoreactivy for calretinin (see anterior coronal section in Fig. 2; Figs. 8A and 9D) resulting, in part, from the high density of intensely immunoreactive cells. THE POSTEROLATERAL CORTICAL AMYGDALA

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The PLCo occupies the lateral aspect of the cortical p0325 amygdala at intermediate and caudal levels, just medial to the piriform cortex (rostrally) and the APir (caudally) and lateral to the ACo (at anterior levels) or the PMCo (caudally). Throughout its rostro-caudal extent, the PLCo is superficial to the BMP. In contrast to the adjoining ACo, the PLCo shows a cell-dense layer 2 neatly distinguishable from layer 3. However, the PLCo is cytoarchitectonically heterogeneous, showing discontinuities in layer 2 and clusters of small cells immersed in layer 3 (in an area named as parvocellular PLCo by Alheid et al., 1995) (see Fig. 4 and detail in Fig. 8B). Neurochemically, the PLCo shows important populations of cells immunoreactive for parvalbumin (Fig. 8C), CB and CR (see caudal frontal section in Fig. 2). In addition, the PLCo (and the BMP deep to it) is characterized by a generally poor reactivity for NADPHd, as compared to the adjoining ACo (and deep BMA). At caudal levels, however, the PLCo (and the BMP deep to it) is also heterogeneous concerning its NADPHd reactivity (Fig. 4). The heterogeneities of the PLCo have been analyzed in


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detail by Majak and Pitkänen (2003)—where the reader is referred to for further details—who called this area periamygdaloid cortex. s0130 THE POSTEROMEDIAL CORTICAL AMYGDALA p0330

The PMCo is only present at levels caudal to the medial amygdala. As a cytoarchitectonic feature, it shows a very thin layer 2 and a broad layer 3 with a high cell density, so that at low magnification these layers are hardly distinguishable from each other. Like the PLCo, the PMCo is not uniform as it shows zones of higher or lower cell density and thickness of layers 2-3 (Figs. 4K and 8D), as well in the distribution or some markers (NADPHd, Fig. 4L). The PMCo is superficial to the amygdalohippocampal transition area, and the boundary between them is not clear in Nissl stained sections but becomes apparent with specific markers (AChE, neuropilin-2, see The Amygdalohippocampal Area above).

s0135 THE AMYGDALO-PIRIFORM TRANSITION AREA p0335

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The APir looks as an invagination of the medio-caudal edge of the piriform cortex (Figs. 4K and 8D). However, sagittal sections (Fig. 2, lateral section) clearly show that it is a structure interposed between the entorhinal cortex and the BLP, thus deserving the name amygdaloentorhinal area. The relationship between the BLP and the APir is not merely topographical (as becomes evident in Nissl-stained coronal sections; Fig. 4K) but the two nuclei also share some histochemical properties: they display AChE and NADPHd reactivity, as well as a dopaminergic innervation (Asan et al., 1998).

Subpallial Amygdala As explained above (see The Subpallial Amygdaloid Territories and the Concept of Extended Amygdala), the subpallial derivatives of the amygdala constitute what is usually known as the extended amygdala. Within the amygdala proper, this includes the central and medial nuclei of the amygdala, plus a group of cell masses intermingled among different nuclei of the amygdala known as intercalated nuclei. The second major component of the extended amygdala is the bed nucleus of the ST, which anatomically includes an intraamygdaloid portion (STIA) a supracapsular portion (STS) and the ST proper. The third component of the subpallial amygdala is composed of a few cell groups located just ventral to the lenticular nucleus, thus being called the sublenticular extended amygdala (SLEA) (Fig. 3).

s0145 Central Amygdala p0345

The central nucleus of the amygdala is a roughly spherical cell group located in the rostral and dorsomedial aspect of the amygdaloid complex. At rostral levels (Fig. 4A–F), it is just ventral to the amygdalo-striatal

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transition area, lateral to the intermediate capsule, and dorsal to the BMA and Me. At caudal levels (Fig. 4G-H), it is sandwiched between the intermediate capsule (laterally) and the intraamygdaloid stria terminalis (STIA) and the stria terminalis (medially). On the bases of cytoand chemoarchitectonics three subdivisions are usually considered in the Ce, namely a capsular part associated with the intermediate capsule (CeC), a medial part perforated by the commissure and components of the stria terminalis (CeM) and a lateral part (CeL) that is interposed between the two others. The CeM is composed of small cells packed in clusters p0350 and is crossed by fiber bundles apparently belonging to the stria terminalis. In contrast to the other divisions of the Ce, the CeM is characterized by intense NADPHdreactivivity, including some small NADPHd-positive cells (Fig. 4D,F), and moderate reactivity for AChE histochemistry (Fig. 7B). In addition, the CeM is rich in cells expressing substance P, somatostatin and galanin (Cassell et al., 1986; Gray and Magnuson, 1987). The CeL consists of a group of small cells densely p0355 packed in the center of the central nucleus, which neuropil is negative for NADPHd (Figs. 4D,F) and AChE histochemistry (Fig. 7B). The most distinctive neurochemical feature of the CeL is the presence of a dense population of CRF positive neurons (Fig. 10C) which co-express neurotensin (Gray and Magnuson, 1992). The expression of calbindin is also strong in many neurons of the CeL (Fig. 10D). In addition, the CeL shows a moderate CGRP-ergic innervation characteristically composed of perineuronal nests (Fig. 10A), as well as dense CCK (Fig. 10B) and SP-positive (Fig. 11A) innervations. The CeC is composed of loosely packed neurons p0360 (in comparison with the CeM and CeL). Similar to the CeL, its neuropile is not stained with the histochemical detection of NADPHd (Fig. 4D,F) or AChE (Fig. 7B). A cell group immunoreactive for enkephalin has been described to be virtually restricted to the capsular division of the Ce (Poulin et al., 2008). The CeC also shares with the CeL a very crowded density of CGRP-ergic fibers (Figs. 3 and 10A), which extend into the adjoining amygdalo-striatal transition area (AStr), as well as dense CCK (Fig. 10B) and SP-ergic innervation (Fig. 11A). Finally, we want to note an interesting (currently unexplained) mismatch between the high concentration of relaxin3 receptor (RXFP3) present in the central nucleus (especially in CeL and CeC) and its very scarce innervation by relaxin3 fibers (Ma et al., 2007). Medial Amygdala s0150 The medial amygdala is the cell group located on the p0365 ventromedial corner of the amygdala. The lateral boundary of the Me is delimited at rostral levels by the Ce, BMA and ACo (Fig. 4C–F), and at caudal levels by the STIA, BMP and PLCo (Fig. 4G,H). The Me is composed of two


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FIGURE 10 Chemoarchitecture of the central amygdala (Ce). Frontal sections through the amygdala immunoreacted for the neuropeptides calcitonin gene related peptide (CGRP, A), cholecystokinin (CCK, B), corticotropin releasing factor (CRF, C) and for the calcium binding protein calbindin (CB, D). The results illustrate the differential distribution of markers in the three divisions of the central amygdala. Calibration bars: 200 µm (A) and 100 µm (B–D).

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main divisions (i.e., anterior and posterior), which can be further subdivided in dorsal and ventral subdivisions. Both in the anterior and posterior Me, the dorsal subdivision makes up the bulk of the nucleus while the ventral subdivision is comparatively smaller. The Me is organized in a nearly laminar structure. The superficial, molecular layer is composed in part of fibers arising mainly from the accessory olfactory bulbs (see below Input from the Olfactory Bulbs: the Chemosensory Amygdala). The molecular layer displays intense calretinin (Fig. 8A) and neuropilin-2 (Fig. 11B,D) immunoreactivity. Deep in the molecular layer, the medial amygdala cells are smallto medium-sized and densely packed. These cells tend to be fusiform in shape and arranged in parallel rows. p0370 Although there are no clear cytoarchitectonic boundaries between the different medial amygdala subnuclei, neurochemical markers allow their delimitation. The medial anterodorsal (MeAD) is an elongated nucleus composed of small densely packed cells in the intermediate region between the limit with lateral hypothalamus or optic tract medially and the Ce and BMA laterally. The calretinin/neuropilin-2-positive superficial layer is quite narrow (Figs. 8A and 11B). Cells are arranged in two layers, one adjacent to the superficial molecular layer, which displays dense cell packaging, and the other more deeply located and displaying looser cell packaging. The MeAD is intensely reactive for NADPH-d (Fig. 4F) and displays a dense plexus of SP-positive terminals (Fig. 11B) (Ribeiro-da-Silva and Hokfelt, 2000). The release of

substance P in the medial amygdala has been correlated with the role of this peptide in anxiety responses (Ebner et al., 2004). The medial anteroventral nucleus (MeAV) is a small nucleus characterized by showing a very intense NADPH-d reactivity (Fig. 4B,D,F) and, in contrast to the MeAD, it is negative for SP (Fig. 11A). In addition, the calretinin-positive molecular layer is quite wide and the cell layer also contains calretinin-positive neurons (Fig. 8A). The medial posterodorsal subnucleus (MePD) is encapsulated by the optic tract medially and the STIA and the fibers of the ST laterally. The molecular layer is wider than that of the MeAD, as revealed by the neuropilin-2 immunoreactivity (Fig. 11D), and the cells are organized as described for the MeAD, in a band of small cells densely packed adjacent to the molecular layer and a deep group with larger, more loosely packed cells. Between the two groups a clear area is fairly visible. The differentiation between these two cellular areas also becomes evident in NADPHd reacted sections where the superficial group display a more intense reaction than the deep one (Fig. 4H). In addition, the superficial cell layer is positive for SP (Fig. 11C). The medial posteroventral nucleus (MePV) is a cell group of small cells densely packed in the medialmost corner of the amygdala. It is characterized by a very dense NADPH-d reactivity. Noteworthy, the Me is the amygdaloid structure showing the densest relaxin-3 positive fibers (concentrated


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FIGURE 11 Chemoarchitecture of the medial amygdala (Me). Sections through the intermediate-to-posterior amygdala showing the immunoreactivity for substance P (A and C) and neuropilin-2 (B and D) in the subnuclei of the medial amygdala of the rat. Neuropilin-2 immunostaining reveals a more important vomeronasal input to the MeV and MePD than the MeAD. Calibration bar, valid for all the photographs: 500 µm.

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in the MeAD, MeAV and MePV). Correspondingly, it contains a high concentration of the relaxin-3 receptor RXFP3 (Ma et al., 2007). s0155 Amygdalo-striatal Transition Area p0395

The AStr is a cell group observed mainly at rostral levels, just dorsal to the Ce and separating it from the overlying caudoputamen (Fig. 4A–F). It consists of medium sized neurons and its chemoarchitecture show similar features to the caudoputamen. In fact, it is strongly reactive with the AChE histochemistry (Fig. 7B) and the detection of NADPHd shows a pale neuropil containing some well labeled multipolar NADPHd positive neurons (Fig. 4B,D,F). Also in a similar way to the caudoputamen, the AStr receives dopaminergic innervation (Fig. 12C).

s0160 Intercalated Cell Masses p0400

The intercalated cell masses are several small groups of densely packed small GABAergic neurons located at the boundaries of different amygdaloid nuclei. They appear to be associated with the intermediate and outer capsules that surround the La and BL (Figs. 4C,D and 12). Although the intercalated nuclei may appear randomly distributed, each one has a precise size, shape and location (Fig. 12). Thus we name the intercalated nuclei according to their location as external intercalated nuclei (Iex), associated to the external capsule, the apical intercalated nuclei (Iap) that are located where the

external and intermediate capsule meet, the anterior commissural intercalated group (Iac) associated with the bundles of the posterior part of the anterior commissure, the intermediate capsular intercalated nuclei (Iic), the main intercalated mass (Im), the intercalated mass of the basolateral nuclei (Ibl) and the intercalated nucleus of the intraamygdaloid stria terminalis (Ist). All these intercalated masses share similar neurochemical features. They are composed of small densely packed cells that are positive for GABA or GAD immunoreactivity (Fig. 12A), and they receive dense innervation by fibers expressing cholecystokinin (CCK, Fig. 12B) and by dopaminergic fibers, as revealed with immunohistochemistry for tyrosine hydroxylase (Fig. 12C). However, the intercalated cell masses associated with the external capsule and those of the intermediate capsule have been shown to differ in relevant aspects regarding their connectivity and functional role (Marowsky et al., 2005). The Bed Nucleus of the Stria Terminalis s0165 The nucleus of the ST is composed of several discrete p0405 groups of neurons associated to the fiber tracts of the stria terminalis, constituting a continuous cellular mass along and surrounding the tract. The ST is composed of three divisions (intraamygdaloid [STIA], supracapsular [STS] and septal [or ST proper]). At septal levels a clear difference can be observed between the anterior subnuclei, which belong to the central extended amygdala,


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(C) FIGURE 12 The intercalated nuclei of the amygdala. (A) Immunohistochemistry for glutamate decarboxylase 65 (GAD65), a reliable marker of GABAergic cells, intensely stain the intercalated nuclei of the amygdala (A). Most intercalated nuclei are associated to the external (Iex) or intermediate capsule (Iic) but some of them are embedded in the BM or BL (Ibl). Most of the intercalated nuclei receive prominent CCK (B) and dopaminergic innervation (C), as revealed with immunohistochemical detection of the catecholamine synthetizing enzyme tyrosine hydroxylase (TH). The panel on the right shows a 3-dimensional reconstruction of the amygdala of the rat, in which the location of the intercalated nuclei and the topographical relationships with the surrounding cell groups are highlighted. Calibration bar: 200 µm.

and the posterior subnuclei, which are part of the medial extended amygdala (maybe with the exception of its lateralmost part, see below), as described in The Medial and Central Extended Amygdala above. These subdivisions can also be recognized in the STIA and STS, where they are located in lateral (related to cEA) and medial (related to mEA) positions. p0410 The STIA is composed of scattered small neurons occupying an area limited laterally by the BLA and the Ce,

and medially by the MePD, where numerous thin fiber bundles can be observed to cross among the cell bodies and run dorsally to enter the stria terminalis (Fig. 4G,H). It is characterized by scattered vasopressin-positive cell bodies (Otero-García et al., 2013) and a NADPHd-negative neuropile (Figs. 3 and 4H) that clearly distinguishes it from the medially adjacent MePD. It lacks CGRPergic innervation, which is helpful to differentiate it from the laterally adjacent Ce (Figs. 3 and 10A).


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FIGURE 13 Chemoarchitecture of the bed nucleus of the stria terminalis (ST). Coronal sections through the anterior aspect of the ST (A and B) immunohistochemistry for cholecystokinin (CCK, A) and corticotropin releasing factor (CRF, B) as two examples of markers of the central extended amygdala. Dense CCKimmunoreactive innervation is observed in the laterodorsal (STLD) and lateral juxtacapsular nuclei (STLJ), whereas the STLD also displays a group of CRFimmunoreactive neurons. In the posterior ST (C,D) direct afferents from the accessory olfactory bulbs labeled with neuropilin-2 immunostaining reach the medial subdivision of the posteromedial ST (STMPM; C). An adjacent section (D) was stained for NADPH diaphorase (NADPHd, blue reaction) plus arginine-vasopressin immunohistochemistry (AVP, brown reaction). Reactivity delineates the three main subdivisions of the posteromedial BST. The inset shows a group of vasopressinergic neurons (arrowheads) in the posterior BST, which are sexually dimorphic (more abundant in males) and testosterone dependent. These images correspond to an adult male rat. Calibration bars: 500 µm (A, C and D), 200 µm (B) and 100 µm (inset).

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The STS is composed of a group of cells surrounding mainly the medial aspect of the stria terminalis. It contains large neurons packed in clusters. This area is characterized by a highly intense NADPHd positive neuropil. Although it contains only a few groups of cells, connective studies reveal clear differences between the medial and lateral components (Shammah-Lagnado et al., 2000). The septal part of the ST (or stria terminalis proper) is p0420 a heterogeneous mass of cells. Its anterior subdivision is composed of a number of subnuclei related to the CeA, as revealed by the expression of peptidergic cells and its afferent connections (Dong et al., 2001). Within the anterior ST, lateral (STL), medial (STMA) and ventral (STMV) subnuclei can be distinguished (Fig. 5A–D). Within the lateral group, which is strongly innervated with CGRP (Fig. 3) and contains CRF-positive neurons (Fig. 13B), it is useful to distinguished juxtacapsular (STLJ) (densely innervated with colecistokinin fibers, Fig. 13A), laterodorsal (STLD) and lateroventral (STLV) parts. The posterior ST occupies the area limited medially p0425 by the stria medullaris and the fornix and laterally by the internal capsule (Fig. 5E,F). At this level, two areas can be defined, the lateral posterior area (STLP) and the medial group, in which posteromedial (STMPM), posterointermediate (STMPI) and posterolateral (STMPL) subnuclei can be recognized (Figs. 5E,F and 13D). The p0415

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STMPM is distinctly label by neuropilin-2-positive fibers originated by the accessory olfactory bulb (Fig. 13C), and the STMPL and STMPI contain a sexually dimorphic (in favor of males) group of vasopressinergic cells (Fig. 13D) (Otero-García et al., 2013). The Sublenticular Extended Amygdala s0170 This component of the subpallial amygdala corre- p0430 sponds to a rather diffuse and poorly defined area in which the cells are intermingled with the fiber tracts of the ansa peduncularis (see The Two Poles of the Extended Amygdala: Common Properties of the ST and Centromedial Amygdala above). It includes the substantia innominata (SI, as classically defined, see Alheid et al., 1995) and the interstitial nucleus of the posterior limb of the anterior commissure (IPAC). In the SI, NADPH-d histochemistry reveals a moderately stained neuropil and large reactive neurons (Fig. 6B,D). It also contains a vast variety of cholinergic (Fig. 7A), GABAergic and glutamatergic neurons (Gritti et al., 2006). The interstitial nucleus of the posterior limb of p0435 the anterior commissure is a rostral extension of the anterior amygdaloid area (Fig. 6A,B). It extends from the ventral tip of the external capsule to the posterior limb of the anterior commissure. The cells of the IPAC are loosely organized and surround the fiber tracts that run towards the posterior limb of the anterior


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commissure. Neurochemical markers permit the differentiation of a lateral (VIP-negative) and a medial (VIP-positive) part of the IPAC (Gartner et al., 2002), and it has been suggested that only the medial IPAC would actually be part of the extended amygdala, with the lateral part being more related to the fundus striati (Gartner et al., 2002). s0175

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FUNCTIONAL CONNECTIVITY OF THE AMYGDALA The different subdivisions of the rat amygdala described in the previous sections display a complex pattern of connections that underlies the diversity of behavioral roles in which the amygdala is involved (see Behavioral Neurobiology of the Amygdala below). Firstly, the amygdala receives inputs arising from sensory unimodal centers and from multimodal associative structures, as well as hormonal and modulatory inputs. Secondly, a complex network of intrinsic connections allows an important degree of intra-amygdaloid processing. Finally, two main output stations (the medial and central extended amygdala) project to hypothalamic and brainstem structures to drive appropriate behavioral responses that include endocrine and vegetative components.

Inputs to The Amygdala

s0185 Input from The Olfactory Bulbs: The p0445

Chemosensory Amygdala One of the anatomical landmarks of the vertebrate amygdala is the input from the olfactory bulbs. The original anatomical observations revealed non-overlapping projections from the main and the accessory olfactory bulbs to the amygdala (Scalia and Winans, 1975; ProSistiaga et al., 2007). The olfactory connections targeted the CxA, LOT, ACo and PLCo. In contrast, the accessory olfactory bulbs appeared to innervate the BAOT, Me, PMCo and the STMPM. In these pioneer studies, only the anterior part of the medial amygdala (MeA) was found to receive both olfactory and vomeronasal information (Scalia and Winans, 1975). These data led to the so-called “dual olfactory hypothesis,” according to which the olfactory and vomeronasal information were processed in parallel in the brain in different structures (Raisman, 1972). However, recent studies have shown that a majority of the chemosensory structures of the amygdala actually receives convergent olfactory and vomeronasal inputs (Pro-Sistiaga et al., 2007). The CxA, ACo and LOT receive a small vomeronasal afferent in addition to the well-known olfactory input; whereas the MeA, the BAOT and the AA receive a small olfactory projection in addition to the vomeronasal input (Gutierrez-Castellanos et al., 2010).

The projections from the olfactory bulbs to the amyg- p0450 dala originate in the mitral cells, wich are thought to be glutamatergic (see The Olfactory System, Chapter 27) and rich in calretinin (Wouterlood and Hrtig, 1995; Fig. 2). The projection of the mitral cells of the accessory olfactory bulb is positive for neuropilin-2 (Fig. 11) and acetyl cholinesterase (Fig. 7B–D), allowing a clear chemoarchitectonical identification of the vomeronasal amygdala (see Cytoarchitectonics and Chemoarchitectonics of the Amygdala, above). In addition, the corticomedial amygdala receives p0455 indirect chemosensory inputs through an intricate set of interconnections with the olfactory cortex (see Connections Within the Pallial Amygdala below, and associated sections). Inputs From the Thalamus: Auditory, Visual, Gustatory and Somatosensory/Nociceptive Information Although none of the major sensory thalamic relays (visual: lateral geniculate complex; auditory: ventral division of the medial geniculate complex; somatosensory: ventral posterior thalamic complex) project directly to the amygdala, non-chemosensory information reaches the deep pallial amygdala and Ce using thalamic, cortical and brainstem relays. Thalamoamygdaloid projections arise mainly from the midline and posterior intralaminar nuclei (Turner and Herkenham, 1991). The projections from the posterior intralaminar complex (medial and dorsal subdivisions of the medial geniculate complex, suprageniculate, lateral subparafascicular and posterior intralaminar nucleus; Fig. 14B) have been shown to convey auditory (LeDoux et al., 1990a), somatosensory (LeDoux et al., 1987; Bordi and LeDoux, 1994) and visual (Doron and LeDoux, 1999; Linke et al., 1999) information mainly to the La and Ce (Turner and Herkenham, 1991), although tracer injections in the posterior intralaminar thalamus give rise to considerable anterograde labeling in the ACo, Me and BAOT (Turner and Herkenham, 1991). Therefore, part of the chemosensory amygdala may also receive nonchemosensory information. The La and Ce apparently also receive gustatory and oral somatosensory information by means of a minor afferent from the parvicellular part of the ventral posterior thalamic nucleus. Additional thalamic sensory input arise from visceroceptive (central medial, interanteromedial and paraventricular) thalamic nuclei (Turner and Herkenham, 1991; Nakashima et al., 2000), which innervate mainly the Ce, and the La, BL and BM. Finally, the mediodorsal thalamic nucleus is reciprocally connected with the BL (van Vulpen and Verwer, 1989; McDonald, 1987) Additional information about thalamic projections to the amygdala can be obtained in Thalamus, Chapter 16—see Fig. 6 of Chapter 16.


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FUNCTIONAL CONNECTIVITY OF THE AMYGDALA

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f0075 FIGURE 14 Afferents to the amygdaloid complex of the rat. A large injection of the retrograde tracer fluorogold in the amygdala, encompassing the central nucleus and part of the La, BM and BL, results in retrograde labeling in many centers of the forebrain midbrain and brainstem. In the cortex, abundant retrogradely labeled cells are seen in the fronto-temporal cortex (not shown) and in the ventral hippocampus (A). In B, retrograde labeling is visible in the posterior thalamus, including the posterior intralaminar nucleus (PIL) and medial division of the medial geniculate nucleus (MGM), as well as in the dopaminergic cells of the substantia nigra pars compacta (SNc) (and ventral tegmental area, not shown). Other monoaminergic cell groups also show retrograde labeling. Thus labeled cells are seen in the dorsal raphe nucleus (DR, picture C) and other parts of the serotonergic raphe complex (not shown) and in the adrenergic locus coeruleus (LC, picture D). The parabrachial complex (PB, picture D) also shows retrograde labeling (bilaterally). Picture E shows the labeling in the Ce resulting from an injection of biotinylated dextranamines in the parabrachial nucleus. Dextranamines work as both anterograde and retrograde tracers. Consequently, in the Ce anterogradely labeled fibers are seen in the capsular division (CeC), whereas the lateral (CeL) and medial divisions (not shown) are rich in retrogradely labeled cells. Finally, picture F illustrates the anterograde labeling in the lateral amygdala following a dextranamine injection in the prefrontal cortex encompassing both the prelimbic and infralimbic areas. Labeled fibers are seen in the LaM (plus intercalated nuclei, not shown). Calibration bars: 200 µm (A, C and D), 500 µm (B) and 100 µm (E and F). s0195 Cortical Afferents to the Amygdala

The amygdala receives significant input from a number of cortical areas, including the olfactory cortex (piriform and entorhinal), gustatory cortex, secondary and high order visual, auditory and somatosensory cortical areas, the prefrontal cortex and the hippocampus and parahippocampal structures (for an excellent review see McDonald, 1998). The piriform cortex shows important projections to the cortical amygdala (Luskin and Price, 1983), which consequently can be envisaged as a tertiary olfactory center. Noteworthy, the posterior piriform cortex also projects to the La, BL and BM (Luskin and Price, 1983; McDonald, 1998). Therefore, the basolateral complex may associate chemosensory and non-chemosensory stimuli. Regarding the projections from the auditory, visual p0480 and somatosensory cortices, they originate mainly from secondary and associative sensory areas and innervate the deep pallial amygdala, especially the La and BL p0475

(McDonald, 1998). These projections form a cascade from the primary sensory cortex to the amygdala, as described for the auditory (Mascagni et al., 1993; Romanski and LeDoux, 1993; Shi and Cassell, 1999), and visual temporo-perirhinal cortical areas (Shi and Davis, 2001), as well as for the somatosensory parietal posterior insular cortex (Shi and Cassell, 1998a). In contrast to other sensory cortices, projections from p0485 the gustatory and visceroceptive afferents to the amydala originate in both primary and secondary associative areas in the insular cortex (Shi and Cassell, 1998b). The amygdaloid targets of these projections include the cortical, olfactory-recipient amygdala and the La, BL, BM and Ce nuclei (McDonald, 1998). Besides the afferents from the sensory cortex, the p0490 amygdala also receives significant input from the hippocampal formation and prefrontal cortex. Hippocampal afferents arise from the hippocampus proper, subiculum and entorhinal cortex (Canteras and Swanson,


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1992; McDonald and Mascagni, 1997; McDonald, 1998; Fig. 14A) and terminate in the BL, La as well as AHi and APir areas (Pitkänen et al., 2000). These hippocampoamygdaloid connections probably convey contextual information, both spatial and temporal (Ergorul and Eichenbaum, 2004). In fact, hippocampal lesions eliminate the acquisition of contextual fear conditioning, without affecting cue-induced fear conditioning (Phillips and LeDoux, 1992). Remarkably, the ventral hippocampus displays particularly dense projections to the amygdala, including nuclei of the chemosensory amygdala (Cenquizca and Swanson, 2007). In addition, some of the parahippocampal areas (especially the entorhinal cortex) also innervate the CeL, the Me and the STIA (Canteras and Swanson, 1992). p0495 Finally, the amygdala also receives important projections from the prefrontal cortex (McDonald, 1998), which originate in medial (prelimbic, infralimbic, and anterior cingulate) and ventrolateral (orbital) areas and innervate mainly the La and BL (Fig. 14F), parts of the cortical amygdala (ACo and PLCo) and central EA (McDonald et al., 1999). The prefrontal afferents from the prelimbic and infralimbic areas have been shown to be involved in gating fear responses and fear extinction respectively, thus playing a key role in the control of fear behavior and its adjustment to factors such as cognitive, contextual and mnemonic information, and the internal state (Sotres-Bayon and Quirk, 2010). Regarding the amygdaloid afferents from the orbitofrontal cortex, they seem to signal information about outcome expectancies (Schoenbaum et al., 2009), and therefore may be used to adjust emotional responses to unexpected outcomes. s0200 Sensory Input from the Brainstem and Ascending

Modulatory Afferents The gustatory/visceroceptive brainstem centers, e.g., nucleus of the solitary tract and parabrachial pons (Ricardo and Koh, 1978; Saper and Loewy, 1980; Fig. 14D,E) innervate some of the amygdaloid targets of the insular cortex, thus mediating convergence of cortical and subcortical gustatory-visceroceptive inputs in the Ce and La nuclei (McDonald, 1998). p0505 In addition to these ascending sensory inputs, some neurochemically defined centers may exert modulatory effects onto the amygdala (among other telencephalic structures). These modulatory inputs include cholinergic afferents from the basal forebrain (the nucleus basalis-substantia innominata (Hecker and Mesulam, 1994), dopaminergic input from the ventral tegmental area-substantia nigra (Hasue and Shammah-Lagnado, 2002), noradrenergic input from the locus coeruleus and medullary adrenergic cell groups (Asan, 1998; Myers and Rinaman, 2002), serotoninergic afferents from the raphe nucleus (Ma et al., 1991; Fig. 14C) and p0500

the recently described relaxinergic projection from the nucleus incertus (nucleus O; Olucha-Bordonau et al., 2003; Ryan et al., 2011), apparently involved in anxiety and depression (Ryan et al., 2013). As AChE histochemistry suggests (Fig. 7), cholinergic p0510 afferents from the basal forebrain target mainly the BL, LOT (Hecker and Mesulam, 1994) and, to a minor extent, the CxA and parts of the central EA. More recently, additional cholinergic projections to the amygdala have been described arising from the parabigeminal, laterodorsal tegmental and pedunculopontine cholinergic cell groups (Usunoff et al., 2006). The cholinergic input to the Ce has been shown to play a role in the enhanced attentional processing of a conditioned stimulus when its predictive value is altered (Chiba et al., 1995; Han et al., 1999). The dopaminergic cell groups of the ventral tegmen- p0515 tal area-substantia nigra innervate mainly the BL, CxA, and the central EA (Ce and posterolateral ST; Fallon et al., 1978; Asan, 1998; Brinley-Reed and McDonald, 1999; Hasue and Shammah-Lagnado, 2002). The dopaminergic innervation of the amygdala has been shown to play a modulatory role in the retrieval of fear memories (Nader and LeDoux, 1999a, 1999b). s0205 Endocrine Input In addition to the neural inputs already described, p0520 the amygdala contains neurons expressing receptors for steroid hormones, including androgen, estrogen and corticosteroids (Simerly et al., 1990; Cintra et al., 1991). The cells expressing receptors for sexual steroids are located mainly in the structures composing the medial EA (Me and posteromedial ST) although also in the chemosensory cortical nuclei (e.g., ACo, PLCo and PMCo). The sensitivity to sex hormones in these amygdaloid structures allows the integration of chemosensory and endocrine information to control socio-sexual behavior (Petrulis, 2013; see also Behavioral Neurobiology of the Amygdala below). Corticosteroids receptors, in contrast, are mainly p0525 expressed in neurons of the central EA (Cintra et al., 1991; Honkaniemi et al., 1992), so that the behavioral responses mediated by the central EA outputs might be modulated by the stress-induced levels of corticosteroids. The basolateral amygdala also displays low levels of glucocorticoid receptors, which might mediate the enhancement of memory consolidation induced by stressful experiences (Roozendaal and McGaugh, 1997).

Intrinsic Connectivity of the Amygdala

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The stimuli that converge in the amygdala are pro- p0530 cessed there by a sophisticated set of intra-amygdaloid connections that mediate high-order associative


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processes. We will first pay attention to the pathways interconnecting pallial amygdaloid centers, then we will describe the projections connecting the pallial with the extended amygdala and, finally, we will review the complex set of connections within the extended amygdala. s0215 Connections within the Pallial Amygdala p0535

In contrast to the subpallium (e.g., striato-pallidum) the cerebral cortex shows abundant intrinsic, corticocortical connections. This is also the rule for the pallial amygdala: the cortical (superficial) and deep pallial nuclei (basolateral division and amygdalo-hippocampal transition) project not only to extraamygdaloid cortical areas (see Projections From the Pallial Amygdala below), but also to other nuclei of the pallial amygdala.

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Olfactory-vomeronasal convergence, however, is not a simple summation of both chemosensory stimuli. In some neurons of the PMCo both stimuli potentiate each other, whereas in other neurons one of the stimuli suppresses activation by the other. The direct and indirect (intraamygdaloid) convergence of olfactory and vomeronasal information may allow association of odors (neutral stimuli) with emotional stimuli such as sexual pheromones or predator signals detected by the vomeronasal system, so that the animal learns to show anticipatory responses (at a distance) to conditioned olfactory signals of potential mates (attraction) or predators (defensive responses) (Moncho-Bogani et al., 2002; Martínez-García et al., 2009). INTRINSIC CONNECTIONS BETWEEN THE CORTICAL AMYGDALA AND THE BASOLATERAL AMYGDALA: NEURAL SUBSTRATE FOR ODOR EMOTIONAL TAGGING?

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s0220 THE CORTICAL AMYGDALA: CHEMOSENSORY CONVERGENCE AND ODOR-PHEROMONE ASSOCIATION

The cortical amygdaloid nuclei can be considered as specialized areas of the olfactory cortex (paleocortex). As such, they share with the piriform cortex the presence of important intrinsic antero-posterior projections (which terminate in layers 1b to 3), usually known as “associational fibers.” In the amygdala, these connections are represented by the reciprocal connections between the PMCo and PLCo and the projections of both posterior nuclei to the ACo, CxA, LOT and BAOT (Luskin and Price, 1983; Canteras et al., 1992a; Kemppainen et al., 2002). Similarly, the anterior cortical amygdaloid areas (Luskin and Price, 1983) including the LOT (Santiago and Shammah-Lagnado, 2004) give rise to projections to the posterior cortical amygdala (Santiago and Shammah-Lagnado, 2005). Being just part of the “associational fibers” of the paleocortex, these projections extend beyond the limits of the amygdala to also include intricate reciprocal connections of the cortical amygdala with the piriform cortex (anterior and posterior; McDonald, 1998; Majak et al., 2004), anterior olfactory nucleus, and entorhinal cortex (Luskin and Price, 1983; Majak and Pitkänen, 2003; Santiago and Shammah-Lagnado, 2005). Like other regions of the olfactory cortex, some of the cortical amygdaloid nuclei (LOT, ACo and PLCo/ PMCo) give rise to homotopic contralateral projections through the anterior commissure (Savander et al., 1997; Kemppainen et al., 2002; Majak and Pitkänen, 2003; Santiago and Shammah-Lagnado, 2004). p0545 This set of intrinsic connections contributes to the association of olfactory and vomeronasal stimuli in the cortical amygdala. In fact, using single unit recording in the hamster, Licht and Meredith (1987) showed convergence of olfactory and vomeronasal inputs onto single neurons of the PMCo, a nucleus usually considered as a pure vomeronasal center, as it receives input from the accessory but not the main olfactory bulb.

By analogy to the piriform cortex, where “associational fibers” also arise in the endopirifom nucleus (especially those directed caudally; Behan and Haberly, 1999), the deep nuclei of the pallial amygdala (basolateral division) also project to the areas of the olfactory cortex, including the cortical amygdaloid nuclei. Even if they are quite prominent, these projections have received minor attention. The BM (especially the BMA) projects to the ACo, CxA, PLCo and PMCo (Petrovich et al., 1996; Savander et al., 1996); the La projects to parts of the PLCo (the so-called periamygdaloid nucleus) and the PMCo; the BL projects to the LOT, AA and ACo (Savander et al., 1995); and the deep APir projects mainly to the ACo and LOT (ShammahLagnado and Santiago, 1999; Jolkkonen et al., 2001a). These projections also extend beyond the boundaries of the amygdala to reach portions of the piriform cortex (McDonald, 1998; Majak et al., 2004). Another typical feature of the olfactory cortex is the presence of superficial-to-deep intrinsic projections (e.g., piriform to endopiriform). These projections are also present in the cortical amygdala. Thus, the PMCo and PLCo project to the BM and La (Canteras et al., 1992a; Kemppainen et al., 2002; Majak and Pitkänen, 2003), the ACo projects to the BMA (Petrovich et al., 1996) and the APir, whether superficial or deep, shows remarkable projections to the BL and BM (especially to the BMA and BLP; Jolkkonen et al., 2001a). This complex set of interconnections is further enriched by the presence of homotopic and heterotopic commissural pathways through the anterior commissure, arising from the BL and BMP (Savander et al., 1997; Kemppainen et al., 2002; Majak and Pitkänen, 2003; Santiago and Shammah-Lagnado, 2004). These projections allow olfactory (and, to a lesser extent, vomeronasal) stimuli to reach diverse nuclei

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of the basolateral amygdala, where they can converge with other stimuli. This is further achieved thanks to the prominent projections arising in different divisions of the medial amygdala (mainly, but not exclusively, MeA and MePD) to the AA, BMA and BMP (Canteras et al., 1995; Pardo-Bellver et al., 2012). Although the role of these superficial-to-deep projections of the amygdala is not yet clear, there is evidence indicating that they might be involved in odor fear conditioning, i.e., acquisition of fear to specific odors after their association with an aversive stimulus (e.g., an electric shock). In fact, this kind of odor-related emotional learning results in enduring plastic changes in the olfactory cortex and cortical amygdala (Sevelinges et al., 2004) that follow fast, transient changes in the basolateral amygdala (Hegoburu et al., 2009). p0570 These data contrast with the view that the amygdala is a heterogeneous group of functionally unrelated structures (Swanson and Petrovich, 1998). Their interconnections indicate a functional interdependence between the chemosensory (corticomedial) and basolateral divisions of the amygdala, which strongly supports the concept of amygdala as a functional system. s0230 THE INTRINSIC CIRCUITRY OF THE BASOLATERAL DIVISION: A CIRCUIT FOR ASSOCIATIVE LEARNING p0575

The detailed work by Asla Pitkänen and co-workers (1997) revealed important connections linking the different nuclei of the basolateral division of the amygdala and amygdalo-hippocampal area. Their data suggest that the La constitutes the sensory interface of the basolateral division of the amygdala, since it is the main target for thalamic and cortical afferents (see Inputs from the Thalamus: Auditory, Visual, Gustatory and Somatosensory/Nociceptive Information and Cortical Afferents to the Amygdala above) and seems exclusively involved in intra-amygdaloid projections (but see Novejarque et al., 2011). The La is reciprocally connected with the BL and BM, which show few interconnections between them, and all three nuclei project to the AHi. In contrast to the La, which shows minor projections to the Ce, the BL, BM and AHi project massively to the extended amygdala (Pitkänen et al., 1995) and to extra-amygdaloid centers that control behavior, emotion and motivation. This set of interconnections allows multiple opportunities for sensory convergence in the deep pallial amygdala, leading to many forms of emotional learning (see Behavioral Neurobiology of the Amygdala below).

s0235 Connections Between the Pallial Amygdala and the

Extended Amygdala p0580 The basic circuitry of the cerebral hemispheres includes pallio-subpallial excitatory pathways (e.g., corticostriatal projections arising from virtually every area

of the cerebral cortex). Within the amygdala, these pathways are represented by connections linking the cortical and deep nuclei of the pallial amygdala with the extended amygdala (Fig. 15). In addition, and in clear contrast with the general scheme of connections of the rest of the cerebral hemispheres, the subpallial amygdala (especially the medial EA) projects back to the pallial amygdala. PALLIAL AMYGDALOID PROJECTIONS TO THE CEA

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The afferents to the central EA have been traced p0585 in detail using retrograde and anterograde tracers (McDonald et al., 1999; Shammah-Lagnado and Santiago, 1999; Dong et al., 2001). Besides the descending afferents from the cortex reviewed above (see Cortical Afferents to the Amygdala), both the Ce and the antero-lateral ST receive massive projections from the BMA, BLP (to a lesser extent from the BLA) and APir, which apparently mediate the control of (conditioned) fear responses by the basolateral amygdala (see Outputs from the Amygdala and The Role of the Amygdala in Fear and Aversion: Data from Standard Laboratory Paradigms below). Neurons in the BL also project to the intercalated cell masses of the amygdala (IMs), which in turn project to the Ce, both projections being arranged topographically (Royer et al., 1999). Since the IMs are composed of GABAergic neurons, this pathway could mediate feedforward inhibition of Ce by the BL, a process that might have an important role in fear control. Therefore, the BL is able to both activate (direct pathway) and inhibit (feed-forward inhibition through the IMs) fear reactions mediated by Ce outputs (Fig. 16). The balance between the activity of the direct and indirect pathways is the basis of the control of fear. Thus, during stress or other hyperdopaminergic emotional states, activation of the dopaminergic inputs to the IMs (Figs. 12C and 16) elicit a D1-mediated hyperpolarization of their GABAergic cells that results in enhanced fear responses associated with heightened emotional states (Marowsky et al., 2005). In contrast, extinction of learned fear is dependent on the reduction of excitability of Ce projection neurons by the medial prefrontal cortex (Quirk et al., 2003). This could be mediated by prefrontal activation of a portion of the intercalated cell masses resulting in neat decrease of Ce excitability (Likhtik et al., 2008; Fig. 16). This circuit works, therefore, as a gate for fear control by other centers (see also Cortical Afferents to the Amygdala above). PALLIAL AMYGDALOID PROJECTIONS TO THE MEDIAL EA

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Anterograde tracing of the efferents of the pallial p0590 amygdala reveals that the Me receives afferents from the ACo, BMA, BMP (Petrovich et al., 1996), PLCo (Majak and Pitkänen, 2003), the PMCo and AHi (Canteras et al., 1992a; Kemppainen et al., 2002). The same pallial areas


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15 Descending projections from the amygdala to the bed nucleus of the stria terminalis in the rat. Retrograde labeling following an injection of the retrograde tracer fluorogold in the anterior bed nucleus of the stria terminalis. Sparse labeled cells are observed in a broad region of the sublenticular substantia innominata (A), in the anterior amygdala (both dorsal and ventral divisions; (B) and in portions of the cortical amygdala (ACo), piriform cortex and hippocampus (B–D). In contrast, the Ce and the BMA show a high density of labeled cells (C). In the Ce, labeled cells are concentrated in its medial division (CeM). Calibration bars: 200 µm (A) and 500 µm (B–D).

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f0085 FIGURE 16 The intrinsic circuitry of the amygdala and fear control. Schematic drawing illustrating the interplay between the local circuitry of the amygdala and the cortical (prefrontal and hippocampal) and midbrain dopaminergic inputs, in the modulatory control of fear in different situations. The intercalated nuclei play a key role in that respect, due to their ability to control amygdala responses through feed-forward inhibition of the basolateral and central amygdaloid nuclei. The excitatory inputs from the cortex to the intercalated nuclei would mediate a decrease in fear (e.g., prefrontal-mediated fear extinction). Interneurons within the basolateral amygdala would also contribute to context dependent extinction (e.g., feed forward inhibition of the hippocampal input). In contrast, stress and other situations concurrent with a high activity of the dopaminergic cell groups, would inhibit the GABAergic neurons of the intercalated nuclei (which receive a strong dopaminergic input) using D1-dependent mechanisms, thus releasing their inhibitory control over the projection neurons of the central amygdala. For further details, see text.


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project to the posteromedial ST (Dong et al., 2001), the rostral pole of the medial EA. p0595 This leads to two main conclusions. First, the areas of the pallial amygdala projecting to the medial EA are the same ones that receive projections from it (at least from the Me, see the next section). Some of these nuclei also give rise to the pallial component or the stria terminalis, which terminate in the medial portion of the preoptic, anterior tuberal and premammillary hypothalamus and to the lateral septum, i.e., the main nodes of the network for sociosexual behavior in the forebrain (see Emotional Behaviors Elicited by Conspecifics: Sociosexual Behavior below). Other areas of the pallial amygdala like BMA of APir display important projections to the BST (Fig. 15.C,D). s0250 PROJECTIONS OF THE EXTENDED AMYGDALA BACK TO THE PALLIAL AMYGDALA

Another atypical hodological property of the extended amygdala is that, in contrast to other regions of the subpallium, it shows ascending projections to the pallial amygdala. These projections are much more important from the medial EA than from the central EA. In both cases, however, they reciprocate the descending palliosubpallial projections. Thus, both the Ce (Jolkkonen and Pitkänen, 1998) and the anterior and lateral ST (Dong and Swanson, 2003, 2004a) show scarce projections to the BLP, which is the main source of descending pathways to the central EA (McDonald et al., 1999; Shammah-Lagnado and Santiago, 1999; Dong et al., 2001). On the other hand, the Me (Canteras et al., 1995; p0605 Pardo-Bellver et al., 2012) and the medial posterior ST (Dong and Swanson, 2004b) show massive backprojections to the AHi and BMP and scarcer ones to the PMCo and BMA. Since the medial EA contains the main targets of the vomeronasal (and olfactory) inputs from the olfactory bulbs, an interpretation of these backprojections as part of the circuitry processing chemosensory information would explain why subpallio-pallial projections are more important within the medial than the central EA (see The Cortical Amygdala: Chemosensory Convergence and Odor-Pheromone Association above). p0600

s0255 Intrinsic Connections of the Extended Amygdala s0260 THE CANONICAL CIRCUIT OF THE EXTENDED AMYGDALA p0610

As reviewed above, the concept of extended amygdala is based on the similarities and interconnections of Ce and Me with specific portions of the ST and of the sublenticular basal forebrain (The Subpallial Amygdaloid Territories and The Concept of Extended Amygdala above). Using these same criteria, the medial EA can be further subdivided, whereas the central EA seems more homogeneous. This is appreciated if one analyzes the intrinsic interconnections of the Ce and Me with the ST (Fig. 15C).

The three main subnuclei of the central amygdala, p0615 CeM, CeL and CeC, show similar projections to the anterior and lateral ST (Fig. 15B ,C), the only difference being the relative scarcity of the projections from the CeL to the STLP and from the CeC to the STLD (Dong et al., 2001). In contrast, the main divisions of the medial amygdala, MeA, MePD and MePV, show common but also markedly different projections to the ST. They share moderately dense projections to the STMA, but projections to the STMV arise mainly from the MeA. The main differences, however, pertain to the projections to the medial posterior ST. The MePD projects nearly exclusively to the STMPM, whereas the MeA and MePV share massive projections to the SMPI and STMPL, but barely project to the STMPM (Dong et al., 2001; Pardo-Bellver et al., 2012). The ascending pathways from the ST to the Me reciprocate the descending projections (Dong and Swanson, 2004b). CONNECTIONS BETWEEN THE MEDIAL AND CENTRAL EA

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Whereas other areas of the telencephalic subpallium p0620 (striato-pallidum) lack interconnectivity (e.g., there are no connections between the dorsal and ventral striatum), the two divisions of the extended amygdala are interconnected. These projections are asymmetric, however; whereas the medial EA projects to the central EA, there are no projections from the central back to the medial EA. Thus, anterograde tracer injections in the Ce (Jolkkonen and Pitkänen, 1998) render no labeling in the Me and very scarce labeling (if at all present) in the STMP (Dong et al., 2001). In contrast, tracer injections in the MeA result in anterograde labeling in the CeM and CeC, and labeling is restricted to the CeC after injections in the posterior Me (Canteras et al., 1995). Apparently, the CeL does not receive afferents from the Me. These data lead to two main conclusions. First, the p0625 projections from the Me to the anterior and lateral ST do not fit the definition of extended amygdala, because this portion of the ST is part of the central EA, in view of its afferents from the Ce and its neurochemical properties (e.g., neuropeptidergic projection cells; see The Subpallial Amygdaloid Territories and the Concept of Extended Amygdala above). This strongly suggests that the pathway from the Me to the anterior and lateral ST should be envisaged as part of the projection system from the medial EA to the central EA. The second conclusion is that, since the medial EA is p0630 involved in processing chemosensory information, especially semiochemicals for intraspecific and interspecific communication, the projections from the medial to the central EA ensure that chemosignals elicit strong emotional reactions mediated by the descending pathways of the central EA (see the next section and Behavioral Neurobiology of the Amygdala below), associated to sociosexual and defensive behaviors.


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Outputs from the Amygdala The amygdala originates ascending projections directed to telencephalic structures (mainly from the pallial amygdala) and descending pathways to the hypothalamus (from the pallial and subpallial amygdala) and brainstem (mainly from the EA). Amygdalo-telencephalic projections may be involved in the formation of emotional memories and the control of attention and motivation; whereas descending amygdalofugal projections probably control the expression of emotional behaviors.

s0275 Projections from the Pallial Amygdala s0280 AMYGDALO-CORTICAL PATHWAYS: EMOTION AND COGNITION p0640

In contrast to the situation in primates (Amaral and Price, 1984), where the amygdala has substantial projections to most sensory cortical areas (e.g., visual, auditory and somatosensory), in rodents amygdalo-cortical projections reach mainly associative frontotemporal areas. These include projections to the prefrontal cortex (McDonald, 1991a) and to the cortex surrounding the rhinal fissure, which includes the perirhinal and insular areas (McDonald and Jackson, 1987). These projections are reciprocal (see Cortical Afferents to the Amygdala above).

AMYGDALA-PERIRHINAL PATHWAYS Amygdaloid s0285 p0645 projections to the perirhinal cortex arise from the

La, BL, BM and LOT (Krettek and Price, 1974, 1977; Pikkarainen and Pitkänen, 2001). These projections mainly reach layers II, III and V of the perirhinal cortex (Petrovich et al., 1996). Electrophysiological studies on this pathway have focused on the epileptiform activity in the perirhinal cortex. In this direction, it has been found that amygdala kindled rats display lower threshold for excitability and enhanced synchronized activity in the perirhinal cortex (Matsumoto et al., 1996). In addition, it has been observed that, while stimulation of the amygdala or superficial perirhinal cortex alone are unable to elicit seizure propagation to the entorhinal cortex, simultaneous stimulation of both structures results in spreading seizures to the entorhinal cortex and dentate gyrus (Kajiwara et al., 2003). These authors proposed that, since the superficial layers of the perirhinal cortex receive multimodal information, this cortical area may act as an emotiondriven gate controlling the sensory input to the hippocampal formation.

AMYGDALA-INSULAR PROJECTIONS The amygdala s0290 p0650 is reciprocally connected to the insular cortex, includ-

ing the gustatory cortex (Saper, 1982; Shi and Cassell, 1998b). The basolateral division of the amygdala is the

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main source of projection to the insular cortex (Sripanidkulchai et al., 1984). Electrical or chemical stimulation of the basolateral amygdala results in a decrease of spontaneous discharge of the insular neurons, but inhibition of the amygdala does not change spontaneous activity of insular neurons (Hanamori, 2009). In that respect, the insular-amygdala reciprocal projections are supposedly related to conditioned taste aversion. In fact, glutamate infusion in the amygdala enhances conditioned taste aversion through NMDA receptors in the insular cortex (Ferreira et al., 2005). Reciprocal connections between the gustatory insular cortex and the BL (and maybe La and BM) nuclei are needed during the expression of taste neophobia (Lin and Reilly, 2012; see also the next section on Conditioned Taste Aversion). AMYGDALA-PREFRONTAL PROJECTIONS As dis- s0295 cussed above, the reciprocal connections between the p0655 prefrontal cortex and the BL are involved in the control of extinction of fear memories (see text above and Pallial Amygdaloid Projections to the CEA). Lesions in the amygdala affect the acquisition of fear extinction, while lesions in the prefrontal cortex affect the recall of the extinction memories (Sierra-Mercado et al., 2011). The medial prefrontal cortex receives its amygdaloid p0660 afferents from the BL (Fig. 17F). Stimulation in the BL induces inhibitory responses in the medial prefrontal cortex (Perez-Jaranay and Vives, 1991). Although most of the neurons in the BL projecting to the prefrontal cortex are glutamatergic (McDonald, 1996), they preferentially contact with parvalbumin (GABAergic) neurons of the prefrontal cortex (Gabbott et al., 2006). Accordingly, spontaneous activity of medial prefrontal neurons is reduced by a conditioned tone and this depression is mediated by amygdala afferents (García et al., 1999). In addition, amygdala terminals also target corticospinal medial prefrontal neurons (Gabbott et al., 2012). AMYGDALO-HIPPOCAMPAL PROJECTIONS The s0300 amygdalo-hippocampal connections are also involved p0665 in the process of fear extinction (see Fig. 16). It is known that the acquisition and extinction of fear memories are context-dependent, and the hippocampus is involved in the generation of this context dependency (SierraMercado et al., 2011). Although different regions of the amygdala proj- p0670 ect to the hippocampus and parahippocampal areas (Pikkarainen et al., 1999), the main source of such projections is the BL, which also provides projections to the prefrontal cortex (Fig. 17F). The BL heavily targets the stratum oriens and stratum radiatum of CA3 and CA1 and the subiculum, mainly at the ventral hippocampus. The BM also projects to the stratum lacunosummoleculare of CA1 (see also Hippocampal Formation, Chapter 20—Figure 10 of Chapter 20). Finally, the medial


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f0090 FIGURE 17 Efferents of the amygdala of the rat. This figure illustrates some of the efferents of the amygdala by showing the retrograde labeling in different amygdaloid nuclei after the injection of tracers (fluorogold or dextranamines) in their targets. (A) Shows retrogradely labeled cells in the anterior amygdaloid area (AA) after an injection in the anterior area of the hypothalamus. (B and C) Illustrate the retrograde labeling in the posterodorsal medial amygdala (MePD) and intraamygdaloid ST (STIA) (B) as well as in several subnuclei of the ST proper (C). On the other hand, an injection aimed at the periaqueductal gray (PAG) renders dense retrograde labeling in the lateral ST (D) and CeM (E). Finally, two different tracers were injected in the prefrontal cortex (black labeling) and the hippocampus (brown labeling) respectively. Labeling in the BLA and BLP (F) indicate that the basolateral nucleus is the origin of most of the projections of the amygdala back to the cortex. Calibration bars: 200 µm (A, B and E), 100 µm (C and D) and 50 µm (F).

subucleus of La projects to layer III of the entorhinal cortex, the subiculum and parasubiculum. In general, it is assumed that the amygdaloid nuclei that project to the hippocampal formation give rise to segregated rather than overlapping terminal fields (Pikkarainen et al., 1999). From a functional point of view, the stimulation of the amygdala results in disorganization of the maps of the hippocampal place cells and modifications of their firing rates (Kim et al., 2012). In addition, this amygdalahippocampal pathway modulates the effect of glucocorticoid hormones on memory retrieval (Roozendaal et al., 2003). s0305 AMYGDALO-THALAMIC EFFERENTS p0675

The main targets of the amygdalo-thalamic projections are the mediodorsal nucleus, the paraventricular and the parataenial thalamus and the zona incerta (Reardon and Mitrofanis, 2000). No systematic studies have been done in rodents regarding the amygdalothalamic pathway, but in primates the projections to the anterior medial thalamic nucleus arise in the La, BL and BM (Xiao and Barbas, 2004). The midline and intralaminar thalamic nuclei receiving projections from the amygdala correspond to the so-called dorsal group

involved in visceral emotional functions (Van der Werf et al., 2002). In particular, the projections to the paraventricular thalamic nucleus originate in CRF positive neurons of the central EA (Otake and Nakamura, 1995). Dorsal intralaminar midline nuclei receive projections from the periaqueductal gray, which supposedly modulate autonomic- and nociceptive-related circuits associated with coping strategies and defensive behaviors (Krout and Loewy, 2000a). Another important afferent to these nuclei comes from the parabrachial nuclei, which also convey visceral and nociceptive information to the amygdala-thalamus-prefrontal circuit (Krout and Loewy, 2000b). As detailed in the thalamus chapter, the dorsal intralaminar thalamic nuclei project back to the prefrontal cortex providing an additional indirect pathway from the amygdala to the prefrontal cortex. AMYGDALO-STRIATAL PATHWAYS: THE AMYGDALA AND REWARD

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According to its cortical (pallial) nature, the pallial p0680 amygdala gives rise to important projections to part of the striatum, mainly to the ventral striatal structures, including the nucleus accumbens, the olfactory tubercle, and the associated islands of Calleja


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(Wright et al., 1996). The amydaloid nuclei that project more densely to the ventral striatum are the BL, BM and AHi, which innervate mainly the accumbens shell and core and the olfactory tubercle (Kelley et al., 1982; Brog et al., 1993; Wright et al., 1996). In addition, more restricted projections to the accumbens shell and the olfactory tubercle arise from parts of the cortical (chemosensory) amygdala, including the LOT (Santiago and Shammah-Lagnado, 2004), PLCo (Ubeda-Bañón et al., 2007) and PMCo (Ubeda- Bañón et al., 2008). p0685 There is functional evidence showing that the activity of the amygdalo-accumbens pathway has important effects on dopamine transmission in the nucleus accumbens and on its putative outcomes on reward behavior. Stimulation of the basolateral amygdala results in a long-lasting increase in dopamine efflux in the nucleus accumbens, an effect mediated by a direct action over dopaminergic terminals in the nucleus accumbens. This increase is, in fact, similar to that observed when presenting a natural reward like food (Ahn and Phillips, 1999). Interestingly, it has been shown that if neurons of the nucleus accumbens become depolarized before the arrival of dopamine, then dopamine has an excitatory effect through D1 receptors; in contrast, if neurons have not been depolarized, then dopamine has an inhibitory effect (Hernandez-Lopez et al., 1997; Kalivas and Nakamura, 1999). The previous depolarization through the amygdala pathway may predispose the detection of a positive stimulus (Phillips et al., 2003; Waraczynski, 2006). As a conclusion, the amygdala may provide a source for preparing the nucleus accumbens to reinforce positive events (see The Amygdala and Appetitive Responses: Reward and Motivated behavior below). p0690 Additional amygdalo-striatal projections innervate the dorsal striatum. These projections originate mainly from the BL, with a smaller contribution from the BM and La, and innervate parts of the caudatus-putamen (CPu) (Kelley et al., 1982; McDonald, 1991b; Wright et al., 1996). Remarkably, the amygdaloid projections to the CPu are bilateral and symmetrical, with each part of the amygdala projecting to equivalent striatal areas in both hemispheres. These significant projections may play a role in instrumental learning (Balleine et al., 2003). p0695 Several nuclei of the pallial amygdala also give rise to important projections to the hypothalamus, mainly the AHi and BMP. These amygdalo-hypothalamic pathways course through the ST and are rich in zinc (PerezClausell et al., 1989). These projections primarily innervate the medial column of the hypothalamus: medial preoptic nucleus, anterior hypothalamic nucleus and ventromedial hypothalamic nucleus, also caudally reaching the ventral premammillary nucleus. These pathways might contribute to the amygdaloid control

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of sociosexual behavior (Petrovich et al., 2001, see also Emotional Behaviors Elicited by Conspecifics: Sociosexual Behavior below). Descending Projections of the Subpallial Amygdala

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PROJECTIONS FROM THE CENTRAL EXTENDED AMYGDALA

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As a general rule, the pathways from the central p0700 extended amygdala are involved in expression of fear and anxiety (LeDoux et al., 1988). The descending projections arise from the CeM and the STL (Fig. 17D,E). In most cases, the target areas also send projections back to the central EA (Rizvi et al., 1991). Although their patterns of descending projections are similar (Dong and Swanson, 2003, 2004b, 2006a, 2006b, 2006c), the lateral division of the ST and the CeM have different roles. Thus, the CeM is mainly involved in short-duration responses, defined as phasic fear; whereas the STL plays a role in long-duration fear responses, defined as sustained fear or anxiety (Walker et al., 2009). It must be pointed out, however, that while both Ce and ST induce visceral and behavioral output through descending projections, most of the behavioral and pharmacological studies have focused on the Ce. AMYGDALO-HYPOTHALAMIC PATHWAYS Pathways from the central EA mainly innervate the lateral, dorsomedial and ventromedial hypothalamic areas, as well as the paraventricular hypothalamic nuclei (Ono et al., 1985; Prewitt and Herman, 1998). The dorsomedial nucleus (DM) is the hypothalamic site for cardiovascular regulation. Indeed, it has been shown that the DM mediates cardiovascular changes induced by stimulation of the amygdala (Soltis et al., 1998; Fontes et al., 2011), thus suggesting a role of this pathway in cardiovascular components of fear. Projections from the central EA targeting the paraventricular hypothalamus are thought to mediate fearrelated stress responses (Prewitt and Herman, 1998), a view based on the changes of circulating levels of stress hormones resulting from experimental manipulations of the amygdala. Thus, amygdalectomy decreases corticosterone levels in plasma (Feldman and Conforti, 1981), and similar effects follow bilateral lesions of the stria terminalis (Gray et al., 1993). Conversely, amygdala stimulation increases circulating corsicosterone (Redgate and Fahringer, 1973). Moreover, bilateral lesions of the central EA decrease CRH-like immunoreactivity in the median eminence (Beaulieu et al., 1989). Therefore, threat-elicited stress responses may be conveyed through projections from the central EA to the HPA hypothalamic centers (Prewitt and Herman, 1998). The anterior amygdala also projects to the anterior hypothalamus (Fig. 17A), but the role of this pathway is unknown.


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s0330 AMYGDALO-PERIAQUEDUCTAL PATHp0720 WAYS Descending projections from the central EA

also reach the ventrolateral column of the periaqueductal gray (PAG), a pathway associated to the freezing response (Rizvi et al., 1991). This pathway arises from neurons immunopositive to CRF, somatostatin and substance P (Gray and Magnuson, 1992) in the CeL, CeM and ST. The main role of the PAG has been associated to an p0725 expression of fear rather than its acquisition or extinction. However, a role of the PAG in these processes cannot be ruled out. For example, naloxone (opioid inhibitor) infusion in the PAG disrupts extinction recall and, at the same time, reduces Erk phosphorylation in both amygdala and prefrontal cortex (Parsons et al., 2010). The CeM also projects to the rostrolateral PAG, a region critical for behaviors ranging from hunting to maternal care (Mota-Ortiz et al., 2009). p0730 Finally, the projection from the central amygdala to the PAG also seems to be involved in the mechanisms for endogenous analgesia. Thus, it has been shown that stimulation of the central or medial amygdala reduces pain (formalin test, vocalization or tail-flick; Mena et al., 1995). These effects can be blocked by reversible inactivation of the PAG (Oliveira and Prado, 2001). PARABRACHIAL NUCLEI The central amygdala s0335 p0735 maintains reciprocal projections with the parabrachial

area (Takeuchi et al., 1982). However, whereas the cells of origin of the amygdalo-parabrachial pathway are located in the CeL, the parabrachio-amygdaloid terminals innervate the CeC (Fig. 14D,E). The integrity of this circuit is critical for taste prop0740 cessing, including acquisition and retrieval of conditioned taste aversion (Bielavska and Roldan, 1996). In fact, the Ce displays neurons responsive to gustatory stimulation (Nishijo et al., 1998), but electrical stimulation of the Ce depresses parabrachial activity in response to gustatory stimulation, while amygdaloid lesions increase these responses (Lundy and Norgren, 2001; Huang et al., 2003). Therefore, the Ce exerts an inhibitory control onto the parabrachial nucleus (Jia et al., 2005), thus being able to regulate the ascent of gustatory information. In addition to a role in gustatory perception, the cenp0745 tral amygdala pathway to the parabrachial nucleus is involved in the control of water and sodium intake thus providing a mechanism to saline homeostasis (AndradeFranzé et al., 2010). DORSAL VAGAL COMPLEX Projections from the s0340 p0750 CeM (and CeL) and STL target the vagal complex,

including the dorsal motor nucleus and the nucleus tractus solitarii. These projections arise from cells rich in CRF, neurotensin and/or somatostatin neurons (Gray

and Magnuson, 1987), and are thought to control the gastrointestinal activity associated with fear-anxiety (Zhang et al., 2003). PROJECTIONS FROM THE MEDIAL EXTENDED AMYGDALA

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As described above (see Development and Territories in p0755 the Rat Amygdala and Cytoarchitectonics and Chemoarchitectonics of the Amygdala), the medial EA contains sexually dimorphic nuclei that express receptors for sex steroids. Accordingly, the projections arising from the medial EA target the forebrain structures of the “sociosexual brain,” including the lateroventral septum and the medial hypothalamus (Newman, 1999). Of note, the structures innervated by the efferents of the medial EA are also the target of projections originated by the structures of the pallial amygdala associated with the medial EA (see The Medial and Central Extended Amygdala above). Within the telencephalon, the Me and the posterome- p0760 dial ST project back to the accessory olfactory bulb (de Olmos et al., 1978), and both structures, together with the AHi, project to the ventralmost aspect of the lateral septum. This latter projection contains vasopressin (at least in some of its cells of origin) and is sexually dimorphic in favor of males (DeVries and Buijs, 1983; Wang et al., 1993). Evidence in rats, mice and hamsters suggest that this projection is involved in agonistic aggression, an important component of socio-sexual behavior (Veenema et al., 2010). In addition to the dimorphic projection to the sep- p0765 tum, the medial EA gives rise to dense projections to the hypothalamus that mainly target the medial preoptic nucleus, anterior hypothalamic nucleus, ventromedial hypothalamic nucleus, and ventral premammillary nucleus (Canteras et al., 1995; Dong and Swanson, 2004b; Choi et al., 2005). These projections overlap to an important extent with the hypothalamic afferents originated by the BM and AHi, and therefore both the pallial amygdala and the subpallial medial extended amygdala interact to control the different components of sociosexual behavior. These amygdalohypothalamic pathways are largely reciprocated by ascending hypothalamo-amygdaloid projections (e.g., Canteras et al., 1992b).

BEHAVIORAL NEUROBIOLOGY OF THE AMYGDALA

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The amygdala is now recognized as a key neural cen- p0770 ter for the control of emotional behaviors in mammals (LeDoux, 2000) and other vertebrates (Martínez-García et al., 2007). However, for the most part of the twentieth-century, the amygdala was viewed as a mere secondary olfactory center closely associated with the stria


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terminalis and thereby with the hypothalamus (Ramon y Cajal, 1911; Johnston, 1923; Kappers et al., 1967). Weiskrantz (1956) was the first to demonstrate that the dramatic emotional deficits that follow bilateral lesions of the temporal lobe in primates (known as Klüver–Bucy syndrome) were due to bilateral damage to the amygdala, a view that contrasted with its supposed olfactory nature. In the early 1970s, several studies pointed to the involvement of the amygdala in a variety of behaviors with strong emotional valence such as those related to reproduction and aggression (see Klingler and Gloor, 1960 and Kaada, 1972 for a review of the literature available at that time). In spite of these data, the amygdala was not considered an important center in the emotional system until the last decades of the twentieth-century (LeDoux, 1996). p0775 Three main reasons explain why the roles of the amygdala in the expression of emotions were neglected for so long. First, the influential limbic system theory (MacLean, 1949, 1952, 1970) situated the hippocampus at the core of the emotional brain and did not consider the amygdala as a relevant structure for emotion. Second, the association of the amygdala with the olfactory (Cowan et al., 1965; Powell et al., 1965) and vomeronasal systems (Winans and Scalia, 1970; Scalia and Winans, 1975) argued in favor of a role of the amygdala in chemosensory perception. And third, the outcomes of amygdala manipulations indicated that it was involved in a variety of functions and behaviors, ranging from the autonomic control and sexual behavior to stress responses and associative learning (see Price et al., 1987). This led to the suggestion, still prevalent to some extent today, that the amygdala is not involved in a unique function, but individual anatomical subdivisions of the amygdala play different roles in different aspects of behavior and physiology (Kaada, 1972; Swanson and Petrovich, 1998), thus the name of amygdaloid complex. p0780 In the last 20 years of the twentieth-century, by using Pavlovian fear conditioning, the works of several groups yielded abundant evidence suggesting that the main function of the amygdala is to endow sensory stimuli with an appropriate emotional label (Aggleton, 2000; LeDoux, 2000), a view put forward by Weiskrantz (1956): “the effect of amygdalectomy ... is to make it difficult for reinforcing stimuli, whether positive or negative, to become established or to be recognized as such.” In this section, we review the evidence supporting a role of the amygdala in emotional behavior in rats and other rodents, in the context of appetitive or aversive learning paradigms. In addition, we review the data on the involvement of the amygdala in emotional behavior expressed towards conspecifics (which include a variety of socio-sexual responses), or toward individuals of other species (mainly defensive

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responses against predators). Finally, we discuss the question of whether the amygdala is a functional system or a collection of structures with no functional relation among them.

The Role of the Amygdala in Fear and Aversion: Data from Standard Laboratory Paradigms

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s0360 Fear Acquisition and Fear Expression During the 1980s and 1990s, several groups demon- p0785 strated a major role of the amygdala in fear conditioning, a specific kind of emotional learning (Maren and Fanselow, 1996). In summary, this paradigm consists of the acquisition of fear to a previously neutral stimulus (e.g., a monotonal sound) by means of its Pavlovian association with unconditioned fear-eliciting stimuli (such as a footshock). Usually, fear is assessed by measuring diverse behavioral responses, such as freezing (fear-elicited immobility) or the startle reflex to a loud, unexpected sound, which is potentiated by fear. THE ROLE OF THE LATERAL AND CENTRAL NUCLEI OF THE AMYGDALA IN FEAR CONDITIONING

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Numerous studies, using mainly rats as the experi- p0790 mental species, have not only identified the amygdala as the key brain center mediating the association of neutral and unconditioned aversive stimuli (LeDoux, 2000), but also described the intra- and extra-amygdaloid circuits (Fig. 18) and the mechanisms mediating such process. In auditory fear conditioning, the information regarding the tone reaches the lateral amygdala from the medial geniculate and posterior intralaminar thalamus either directly or through the associative auditory cortex (LeDoux et al., 1990b; Doron and LeDoux, 1999). Footshock-derived somatosensory information also reaches the lateral nucleus directly from the posterior intralaminar thalamus (LeDoux et al., 1987; Lanuza et al., 2004) and other pathways through the posterior insular cortex (Shi and Davis, 1999). Therefore, tone and footshock information converge onto the lateral nucleus. In fact, lesions of this structure abolish auditory fear conditioning (LeDoux et al., 1990a), thus indicating that the lateral amygdala is part of the circuit subserving this kind of emotional learning. Lesions of the auditory thalamus completely suppressed learning (LeDoux et al., 1984), whereas lesions of the temporal auditory cortex had no effect (Romanski and LeDoux, 1992a), although the cortico-amygdaloid route can mediate fear conditioning in the absence of the direct thalamo-amygdaloid pathway (Romanski and LeDoux, 1992b). In Pavlovian models of fear learning, the synaptic p0795 potentiation leading to this kind of association takes place in the lateral nucleus of the amygdala (Davis, 1992; Maren, 1999; LeDoux, 2000; Maren and Quirk,


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FIGURE 18 The amygdaloid circuit for auditory fear conditioning. The conditioned (tone) and unconditioned (footshock) stimuli can reach the amygdala using direct thalamo-amygdaloid pathways or indirect thalamo-corticoamygdaloid projections. Both stimuli converge in the lateral amygdala, where long-term synaptic plasticity mediates emotional learning. A complex intrinsic circuitry connects the La with the central amygdala, mainly via the BM and BL. The descending projections from the central amygdala (in fact from the whole central extended amygdala) mediate the different components of fear response. In addition, direct efferents from the BL to the striatum might subserve complex instrumental responses leading to avoidance and escape from the fear-eliciting stimuli. f0095

2004; Fanselow and Poulos, 2005; Pape and Pare, 2010). This nucleus sends direct and indirect (through the basomedial nucleus) projections to the central nucleus, which in turn mediate the behavioral responses usually measured as an index of fear (Fig. 18), such as freezing and potentiated startle (LeDoux et al., 1988; Hitchcock and Davis, 1991). Recent evidence indicates that plasticity in the central nucleus is also important in fear learning (Wilensky et al., 2006). s0370 IS THE REST OF THE AMYGDALA INVOLVED IN FEAR CONDITIONING? p0800

The data reviewed above suggest that only two amygdaloid nuclei, the lateral and central nuclei, are responsible of what is usually seen as the major role of the amygdala, fear learning. In fact, lesions of the basolateral, basomedial, or medial amygdaloid nuclei have no effect on the acquisition of auditory fear conditioning in rats (Nader et al., 2001). Although these results may be interpreted as evidence of functional heterogeneity (Swanson and Petrovich, 1998), recent data indicates that the basolateral nucleus is actually necessary in fear conditioning when, instead of freezing, other fear responses occur, such as fear-motivated instrumental learning in which the animal has the possibility to terminate the fear-inducing conditioned stimuli by stepping into an adjoining chamber (Amorapanth et al., 2000). Moreover, the medial amygdala has been shown to mediate unconditioned neuroendocrine responses to stressors (Dayas et al., 1999), and is necessary in the acquisition of fear conditioning when olfactory cues are used as conditioned stimuli (Cousens et al., 2012). In addition, as stated below (see Role of the Amygdala in Ethologically Relevant

Fear and Aversive Responses), the medial amygdala is involved in unconditioned and conditioned fear to predators and, therefore, cannot be considered alien to the fear conditioning circuit. Regarding the basomedial nucleus, Canteras et al. (2001) hypothesized that it may be involved in fear responses to live predators (see below). The observed interconnections of the basomedial nucleus with the lateral and central nuclei (Pitkänen et al., 1997) make a functional relation of this nucleus with fear and fear learning feasible. The role of cortical amygdala in fear learning has not p0805 been proven. However, it may contribute to emotional learning about aversive situations when chemical stimuli are involved in close functional integration with the remaining amygdala, either as conditioned or unconditioned (predator-derived) stimuli. In this respect, the cortical amygdala, especially its posterior part, shows important projections to the basomedial and lateral amygdaloid nuclei, as well as to the amygdalo-piriform area, which indicate a functional interdependence of these structures (Majak and Pitkänen, 2003) and may suggest a role of the cortical amygdala in learned or innate fear to olfactory or vomeronasal stimuli. In conclusion, although the lateral and central nuclei p0810 of the amygdala are key centers in the acquisition and expression of fear conditioning, other areas of the amygdala might be involved in different aspects of fear learning. s0375 Conditioned Taste Aversion The amygdala is also involved in a different type p0815 of aversive learning, the conditioned taste aversion (CTA). In this behavioral paradigm, a particular food item or liquid (conditioned stimulus, CS) is paired


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with an emetic agent (LiCl, unconditioned stimulus, US). This protocol elicits in the animals a subsequent avoidance of the CS (Lamprecht and Dudai, 2000). Lesion studies in rats suggest that the basolateral nucleus (lesions often encompassing part of the lateral nucleus; Aggleton et al., 1981; Shimai and Hoshishima, 1982; Sakai and Yamamoto, 1999) but not the central amygdala (Yamamoto et al., 1995; Morris et al., 1999) is involved in the acquisition of CTA. In contrast to these lesion studies, pharmacological inhibition of protein synthesis (also in rats) in the central amygdala blocks acquisition but not extinction of CTA; whereas a similar intervention in the basolateral nucleus blocks extinction but not acquisition (Bahar et al., 2003). Therefore, the specific role of these amygdaloid nuclei in CTA remains unclear. It has been hypothesized that the effects of basolateral amygdala lesions are actually related to a deficit in neophobia (Reilly and Bornovalova, 2005), since the gustatory stimulus used as CS in the CTA paradigm should be a novel one— otherwise its efficacy is greatly diminished due to a phenomenon known as latent inhibition (De la Casa and Lubow, 1995). Neophobia is attenuated in animals bearing lesions of the basolateral amygdala (Rolls and Rolls, 1973; Lin et al., 2009), so an impaired novelty perception can explain the attenuation observed in CTA acquisition. p0820 Taken together, these data suggest that fear conditioning and CTA share parts of a neural circuit that includes the central amygdala. s0380 p0825

Role of the Amygdala in Ethologically Relevant Fear and Aversive Responses The fear responses elicited by a footshock are used as a non-naturalistic laboratory model of the innate fear responses that animals show in the wild in response to life-threatening stimuli (Blanchard et al., 2007). Among these, the most frequent danger is the encounter with a predator. A number of studies in the rat have examined the role of the amygdala in the fear response to predators or predator-derived odors (Apfelbach et al., 2005; Takahashi et al., 2005, 2008). In rats, cat odor—apparently detected through the accessory olfactory system (Staples et al., 2008; Papes et al., 2010)—has been shown to elicit unconditioned fear responses (Dielenberg et al., 2001) and to activate a defensive circuit that includes the posteroventral part of the medial amygdala and the basolateral amygdala (Staples et al., 2008). Consistently, lesions of the medial (but not the central) amygdala block unconditioned freezing induced by cat odor (Li et al., 2004) and both lesions of the medial and the basolateral amygdala significantly reduce conditioned fear induced by cat

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odors in rats (Takahashi et al., 2007). In addition, exposure to a cat (but not to cat odor) induced c-fos activation in the posterior basomedial amygdala (Canteras et al., 2001), suggesting that this nucleus might be involved in the generation of fear and/or defensive responses to live predators elicited by non-chemical stimuli. A different substance that apparently works as a p0830 predator signal for rats is trimethylthiazoline (TMT), an odorous substance found in fox feces (Wallace and Rosen, 2000). TMT is detected by the main (but not the accessory) olfactory system (Staples et al., 2008), and elicits unconditioned fear responses (Wallace and Rosen, 2000; Rosen et al., 2008). Although there is some debate on the real fear-inducing characteristics of TMT (McGregor et al., 2002; Fendt and Endres, 2008; Fortes-Marco et al., 2013), TMT also activates the medial amygdala (Day et al., 2004), as reported for cat odor. Consistently, inactivation of the medial amygdala blocks freezing induced by TMT (Muller and Fendt, 2006). TMT also activates the central amygdala (Day et al., 2004; Staples et al., 2008), but pharmacological inactivation of the central amygdala has no effect on the unconditioned freezing response to TMT (Wallace and Rosen, 2001; Fendt et al., 2003). In contrast, TMT-induced freezing depends on the anterior part of the ST (Fendt et al., 2003), and a similar role of the ST has recently been reported in fear responses of rats to cat urine (Xu et al., 2012). Since the anterior ST receives important projections from the medial amygdala (Canteras et al., 1995), it is tempting to suggest that the unconditioned fear responses to predator odors depend on the main (for TMT) or the accessory (for cat odor) input to the medial amygdala (Scalia and Winans, 1975; Pro-Sistiaga et al., 2007), and from this structure to the anterior ST, which in turn gives rise to important projections to the brainstem centers controlling freezing, such as the periaqueductal gray (Walker et al., 2009), and other fear responses (see Outputs From the Amygdala above). The amygdala has been involved in fear responses p0835 to suffocation danger in mice. The activation of the amygdala is due to the extracellular acidosis generated by the increase in the inhalation of carbon dioxide (Ziemann et al., 2009), and has been shown to depend on the acid-sensing ion channel-1a, which is expressed in the amygdala and in other brain regions involved in fear expression (Wemmie et al., 2003).

The Amygdala and Appetitive Responses: Reward and Motivated Behavior

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Available experimental data strongly suggest that p0840 aversive emotional learning is not the only role of the


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amygdala as a whole. The implication of the amygdala in reward learning is becoming increasingly clear (Baxter and Murray, 2002). However, experiments using appetitive conditioning have yielded contradictory results. Studies in rats and monkeys showed that electrolytic lesions of the amygdala impaired several aspects of reward learning (Henke and Maxwell, 1973; Spiegler and Mishkin, 1981; Gaffan and Harrison, 1987). In contrast, other works revealed that rats with excitotoxic lesions of the amygdala display no deficits in acquiring simple appetitively motivated conditioned responses, while similar lesions seriously impaired aversive conditioning (Cahill and McGaugh, 1990). Subsequent studies using excitotoxic lesions of the amygdala restricted the role of the basolateral amygdala to behavioral paradigms involving secondorder conditioning or devaluation of the reinforcer (Cador et al., 1989; Everitt et al., 1989, 1991, 2003; see also Baxter and Murray, 2002; Murray, 2007), while the central amygdala is necessary for Pavlovian components of the conditioned response, such as the conditioned approach and the Pavlovian-to-instrumental transfer (Everitt et al., 2000). In parallel to these data derived from behavioral studies, electrophysiological experiments carried out in rats and monkeys (Ono et al., 1995) suggested that the role of the amygdala is very similar in the association of neutral stimuli with either positive or negative experiences. Currently, it is generally accepted that the role of the amygdala involves updating the stimulus-reward association when the reward value is modified (Murray, 2007). In fact, it is thought that the reciprocal projection of the basolateral amygdala with the orbital frontal cortex is crucial in updating the value of stimulus-reward associations (Gallagher and Holland, 1992; Schoenbaum et al., 1999; Holland and Gallagher, 2004) and the projections of the basolateral amygdala to the limbic part of the basal ganglia (including the nucleus accumbens) are considered the main pathways mediating the integration of reward information with instrumental components of emotional responses (Everitt and Robbins, 1992). The anatomical relationship between the amygdala and the nucleus accumbens is well known in rats, mice and primates (Novejarque et al., 2011; MartínezGarcía et al., 2012). s0390

Emotional Behaviors Elicited by Conspecifics: Sociosexual Behavior

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The role of the amygdala in intraspecific aggression in rats is suggested by c-Fos (Veening et al., 2005) and fMRI data (Ferris et al., 2008) showing the activation of the medial and cortical amygdala during male–male

aggressive encounters. Similar results have been obtained using the expression of immediate early genes in hamsters and prairie voles (Knapska et al., 2007). Lesion studies in rats have yielded contradictory results: while some reports have indicated that amygdala lesions did not affect agonistic behavior (Busch and Barfield, 1974; McGregor and Herbert, 1992; Oakes and Coover, 1997), others showed that lesions, especially those centered in the cortical amygdala, reduced or suppressed aggressive behavior (Miczek et al., 1974). These contradictions might be attributed to differences in the extent of lesions (Luiten et al., 1985), the test of aggressive behavior used in each case, or the implication of social learning (previous experience) in the behavioral tests (Bolhuis et al., 1984). Noteworthy, medial amygdala lesions reduced offensive aggression in experienced but not inexperienced rats (Vochteloo and Koolhaas, 1987), suggesting that, as a result of previous experience, the corticomedial amygdala controlled this aggressive behavior. The data reviewed above have been obtained in stud- p0850 ies of intermale aggression, usually by means of the resident–intruder paradigm. Female rats are usually non-aggressive, but display a strong aggressive behavior against intruders during the lactation period (Lonstein and Gammie, 2002). Maternal aggression requires olfactory processing and apparently little involvement of the vomeronasal input (Kolunie and Stern, 1995). Both lesions (De Almeida and Lucion, 1997) and c-fos expression experiments performed in mice (Gammie and Nelson, 2001) indicate that the corticomedial amygdala is part of the neural circuits underlying maternal aggression. The amygdala is also involved in another agonistic p0855 behavioral response, namely defensive behavior induced in response to alarm cues produced by stressed conspecifics (Kiyokawa et al., 2006). The alarm pheromone is released by the perianal region of footshocked male rats, and is apparently detected by the vomeronasal organ (Kiyokawa et al., 2007). Consistently, the anterior medial nucleus (part of the vomeronasal amygdala) is activated in rats exposed to this alarm pheromone (Kiyokawa et al., 2005). In summary, in all three cases of agonistic interactions p0860 (intermale aggression, maternal aggression, and defensive behavior) induced by alarm pheromones, the corticomedial amygdala apparently plays a relevant role. s0400 The Amygdala and Sexual Behavior In most mammals, including rodents, sexual behav- p0865 ior can be envisaged as a two-step process. The first stage is a search for the mate, what is induced by attraction to key stimuli, such as sexual pheromones or courtship displays. The second step is mating itself, consisting of paracopulatory and copulatory behavior


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IS THE AMYGDALA A FUNCTIONAL SYSTEM?

(Blaustein and Erskine, 2002). There is evidence that the amygdala is involved in mate search as well as in facilitation of paracopulatory and copulatory behavior under appropriate hormonal conditions (Swann et al., 2009). s0405 SEXUAL MOTIVATION AND MATE ATTRACTION p0870

Chemical signals detected by the main and the accessory olfactory systems are relevant stimuli involved in intersexual attraction in rats (Carr et al., 1965; Larsson, 1971; Edwards and Davis, 1997), and therefore it is not surprising that both the olfactory and the vomeronasal amygdala are involved in the control of the behavioral responses to possible mates (Hull et al., 2006; Swann et al., 2009). In fact, several nuclei of the chemosensory amygdala are considered part of the network of ventral forebrain structures sensitive to gonadal steroids known to regulate mating behavior (Newman, 1999). Several pieces of evidence, mainly obtained in hamsters (Lehman et al., 1980; Maras and Petrulis, 2006) and rats (Everitt, 1990; Romero et al., 1990), indicate that the amygdala is involved in sexual motivation. The corticomedial amygdala plays a role in sexual attraction, which is consistent with its direct chemosensory input; in addition, the basolateral amygdala is involved in conditioned sexual arousal. In line with this interpretation, lesions of the medial preoptic area in male rats seriously affected copulatory behavior but spared different signs of sexual motivation, such as vigorous investigation of the female and (failed) mounting attempts (Everitt, 1990). In fact, lesions of the medial preoptic area affected neither the motivation to press a lever that gave access (under a second-order schedule of reinforcement) to a receptive female (Everitt and Stacey, 1987), nor acquisition of conditioned place preference using sexual interaction with a female as a reward (Hughes et al., 1990). Quite the opposite, lesions of the basolateral nucleus of the amygdala abolished the lever press responses under a second-order schedule of sexual reinforcement, leaving intact the ability to perform copulatory behavior (Everitt et al., 1989). These results suggest that the basolateral nucleus of the amygdala plays a role in conditioned sexual motivation. This role of the basolateral nucleus of the amygdala has been interpreted as not being specific for sexual motivation but general for conditioned incentive motivation towards different types of natural rewards (Everitt, 1990).

s0410 ROLE OF THE AMYGDALA IN MATING p0875

The studies revised above indicate that the amygdala is more involved in motivational aspects (sexual attraction and precopulatory behavior) than in performance of mating behavior. However, some studies in rats and hamsters indicate that the chemosensory amygdala

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plays a role in copulatory behavior as well. These studies indicate that mating deficits are specifically observed in males (in the number of mounts, intromissions and ejaculations) following lesions of the medial amygdaloid nucleus (for a review, see Swann et al., 2009) or the functional disconnection between the medial amygdala and the medial preoptic area (Kondo and Arai, 1995; Been and Petrulis, 2012). Notably, only complete bilateral lesions of the medial amygdala are effective (Kondo and Sachs, 2002). It remains to be evaluated to what extent the copulatory deficits resulting in these lesions of the medial amygdala derive from the inability to process sexually relevant chemical signals. Relevant to this issue, the infusion of a dopamine agonist into the medial preoptic area restored copulatory ability in male rats with excitotoxic bilateral lesions of the medial amygdala (Dominguez et al., 2001), thus suggesting that the medial amygdala has a facilitatory role of copulatory behavior mediated by dopamine signaling in the medial preoptic area, probably in response to the appropriate chemical signals. The role of the chemosensory amygdala in the p0880 female copulatory behavior seems less relevant than that in males, since lesions of the medial amygdala only attenuate lordosis (Rajendren and Moss, 1993) and leave intact paced mating behavior (Guarraci et al., 2004).

IS THE AMYGDALA A FUNCTIONAL SYSTEM?

s0415

The information provided in the previous sections p0885 make it clear that the amygdala is involved in many different and complex behaviors in rats; however, all of them are performed with a high degree of motivation, and therefore have an important emotional value, which can be either positive (sexual behavior) or negative (antipredator, agonistic). Clearly, different territories can be recognized within the amygdala from a developmental approach (see Development and Territories in the Rat Amygdala above) and an important heterogeneity also appears from a functional point of view (Swanson and Petrovich, 1998). However, these functional divisions can be reinter- p0890 preted from the point of view of the role they play in the emotional evaluation of different sensory inputs (chemosensory, visual, auditory, somatosensory, viscerosensory). Intra-amygdaloid connections allow further processing, learning about these emotionally-laden incoming stimuli, and finally initiating the appropriate response (Fig. 19). In conclusion, the amygdala of mammals which, p0895 structurally, is notably similar to that of other vertebrates,


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f0100 FIGURE 19 The amygdala as a functional system. Schematic diagram of the main inputs and outputs of the amygdala organized to show how it may work as a functional system for the expression of emotional behaviors, including species-specific behavioral responses with a strong emotional component. The pallial amygdala receives every kind of sensory inputs and gives rise to projections to the central and medial extended amygdala, which in turn control fear/anxiety and socio-sexual behaviors respectively, via differential projections to the hypothalamus and brainstem. Both systems are interconnected through projections of parts of the pallial amygdala to both the cEA and mEA, and by means of the direct connections from the mEA to the cEA. In addition, the pallial amygdala gives rise to direct projections to the ventral striato-pallidal system, which allow controlling the expression of motivated behaviors. Therefore, this complex circuitry subserves the expression of appropriate emotional responses (fear, anxiety, or aversion versus reward, motivation, or attraction) associated to agonistic or sexual behaviors elicited by conspecifics or to aversive or appetitive stimuli not related to conspecifics, such as anti-predator defensive behaviors.

controls aversive and appetitive emotional behaviors that, in presence of other individuals of the same species, consist of the repertoire of the species-specific sociosexual behaviors. s0420

SP SS TH VGlutT2

Substance P Somatostatin Tyrosine hydroxilase Vesicular glutamate transporter 2

p0975 p0980 p0985 p0990

Acknowledgments

Abbreviation List

p0900

(Not used in the atlas. For the rest of the abbreviations, see Paxinos and Watson, 2004)

p0905 p0910 p0915 p0920 p0925 p0930 p0935 p0940 p0945 p0950 p0955 p0960 p0965 p0970

AHi AVP CB CCK CGRP CR CRF ENK GAD65 GAL NADPHd NPY NT PV

Amygdalohippocampal area Arginine-vasopressin Calbindin Cholecystokinin Calcitonin gene-related peptide Calretinin Corticotropin-releasing factor Enkephalin Glutamate decarboxylase Galanin NADPH diaphorase Neuropeptide Y Neurotensin Parvalbumin

This work has been funded by the Spanish Ministry of Science-FEDER p0010 (BFU2010-16656/BFI). The authors would like to thank Hugo SalaisLópez for his help with the reference list and the rest of the lab members for their suggestions and support.

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10018-PAXINOS-9780123742452

PAXINOS: 18 Non-Print Items

Abstract The amygdala is considered a key center in managing emotional information and its dysfunction is at the base of disorders ranging through anxiety, depression, PTSD and autism. However, the amygdala seems heterogeneous both structurally (with pallial and supallial components) and functionally. Thus, whereas cortical and thalamic multimodal sensory inputs enter the basolateral complex, the corticomedial amygdala is dominated by olfactory and vomeronasal inputs. Intrinsic amygdaloid circuitry, connects these two amygdaloid divisions and convey processed information to the main amygdala outputs. The pallial amygdala is the main source for telencephalic outputs to associative cortical areas (e.g., frontal lobe and hippocampus) and to the ventral striatum. The two subdivisions of the extended amygdala, central and medial, originate descending projections to the hypothalamus and brainstem centers for emotional responses and behavioral control. The amygdala is the key node of the neural network where sensory information acquires emotional value through Pavlovian associations and where fear memories may be extinguished. It is also a fundamental piece of the neural machinery controlling socio-sexual and defensive behaviors. Keywords: Aggression; Anxiety; Emotion; Extinction; Fear; Learning; Reward; Sociosexual behaviour; Conditioned taste aversion.

Chapter 18 - Amygdala: Structure and Function

Chapter 18 - Amygdala: Structure and Function

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