The limbic brain: Continuing resolution - Semantic Scholar

Neuroscience and Biobehavioral Reviews 30 (2006) 119–125 www.elsevier.com/locate/neubiorev

Review

The limbic brain: Continuing resolution Peter J. Morganea,b, David J. Moklera,b,* b

a Center for Behavioral Development and Mental Retardation, Boston University School of Medicine, Boston, Massachusetts 02118, USA Department of Pharmacology, College of Osteopathic Medicine, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, USA

Abstract This paper presents an overview of the limbic brain and its distributed sub-systems. The extent of the limbic system has expanded in recent years. Among the brain areas that we now argue should be included in the extended limbic system are the medial prefrontal cortex, the insular cortex as well as the lower brainstem and spinal cord. In addition the limbic forebrain and limbic midbrain may be divided into medial and lateral divisions both anatomically and physiologically. This serves as an introduction to the papers that follow. q 2005 Elsevier Ltd. All rights reserved. Keywords: Limbic system; Limbic midbrain; Prefrontal cortex; Gudden’s nuclei

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction/Prećis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Some historical events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nauta—the true circumnavigator of the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limbic distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medial prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Johann Bernhard Alois Von Gudden’s Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lower brainstem and spinal cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central gray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The way ahead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction/Prećis Too much has been written about the limbic system and yet not nearly enough. The grand lobe limbique (Broca, 1878) continues to attract considerable scientific analysis and has seemed to some to be relatively inscrutable. Attempts at anatomical or functional ‘dissection’ using * Corresponding author. Address: Department of Pharmacology, College of Osteopathic Medicine, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, USA. Tel.: C1 207 283 0171; fax: C1 207 294 5931. E-mail address: [email protected] (D.J. Mokler).

0149-7634/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2005.04.020

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both lesion and stimulation (electrical or chemical) techniques and tract tracing have not provided sufficient insight into the functions of this system. As a large and diffuse extended system should we consider the limbic brain as an integrated functional complex or should we attempt to break it down into functional units? Do these approaches to explore the integrated system really work? Do they begin to reveal how the units talk to each other? Examining such functional units in a systems/network approach emphasizing chemical wiring diagrams, feedback, etc., have partially revealed some principles of organization and continue to represent, along with image analysis, the best long-term approaches to unraveling the distributed limbic brain. In this review, we will briefly outline the classic limbic forebrain-limbic midbrain circuit as a whole as well as the

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P.J. Morgane, D.J. Mokler / Neuroscience and Biobehavioral Reviews 30 (2006) 119–125

reciprocal ascending and descending components of the limbic midbrain-limbic forebrain. Accordingly, we have redefined the extended limbic system complex and attempted to present aspects of the functional make-up of the extended limbic brain (Morgane et al., 2005). Ascending brainstem projections are comprised of the biogenic amine systems and some components of the cholinergic ascending system (Hedou et al., 2000), while the descending system of the limbic forebrain-limbic midbrain is comprised largely of glutamatergic and cholinergic pathways descending from the basal forebrain to the brainstem. These ascending and descending loops provide inputs along their trajectory to the hypothalamus thus bringing into play an extensive system of autonomic regulation, comprising much of the major function of the limbic brain. This selective overview chapter presents some neglected areas of limbic biology in giving emphasis to the new distributed limbic brain. A selective bibliography gives some extensive details on the limbic brainstem and limbicspinal projections as well as summarizes medial prefrontal connection and functions.

2. Some historical events Two momentous events in limbic brain biology took place in 1937. First, Heinrich Klu¨ver and Paul Bucy carried out bilateral temporal lobectomies in the rhesus monkey publishing their immediate striking behavioral findings in abstract form (Klu¨ver and Bucy, 1937). These have been elaborated and widely published over ensuing years (Klu¨ver and Bucy, 1938, 1939; Nahm, 1997). Tameness, hypersexuality, visual agnosia, hyperphagia and, in general, changes in emotional behavior form the Klu¨ver-Bucy syndrome. Attempts at fractionating the Klu¨ver-Bucy syndrome in the 1950s have been only partially successful. Thus, Schreiner and Kling (1953) sought the role of the amygdaloid complex in the altered behavior. They found that following bilateral amygdalectomy in cats the animals were markedly

hypersexual showing significant increases in amount and varieties of sexual behavior. Morgane and Kosman (1957a, b) found obesity in cats following lesions in the amygdaloid complex. Klu¨ver and Bucy had not attempted to relate behavioral change to specific parts of the temporal lobes such as the hippocampal formation or amygdaloid complex. It was not until 1955 that the complete neuropathology of the Klu¨ver and Bucy monkey brains was completed (Bucy and Klu¨ver, 1955). The second landmark in limbic system biology was Papez’s (1937) theoretical paper which outlined a limbic forebrain circuit that has since been a general theme in limbic biology. The Papez circuit has been linked to emotional processes. Because the Papez circuit involves some of the same brain circuitry as damaged in the Klu¨ver-Bucy studies (i.e. fornix), it is important to consider these together. The works of Klu¨ver and Bucy, and Papez have been recently reviewed in detail by Morgane et al. (2005).

3. Nauta—the true circumnavigator of the limbic system Probably the most influential early papers laying out the limbic circuit(s) was the 1958 paper of Nauta (Nauta (1958); Nauta and Domesick (1976)). These silver degeneration studies revealed details of circuits not previously known. Strikingly, Nauta found the limbic forebrain to project widely to paramedian areas of the midbrain and termed the entire complex the limbic forebrain/limbic midbrain system. Nauta also noted that there are two descending medial forebrain-midbrain systems, one to the medial midbrain tegmentum and one to the lateral midbrain tegmentum. These appear to represent the continuation of the mid- and far lateral hypothalamus described by Morgane (1961, 1980a,b). These findings were followed in several, more recent studies providing details of these limbic sub-circuits and networks (Nauta, 1986). Both the medial and lateral midbrain tegmentum should be considered as parts of the extended limbic system (Fig. 1). The importance of Nauta’s

Fig. 1. Schema showing limbic forebrain structure and limbic midbrain formations and indicating projections to lower brainstem and spinal cord (spinal limbic system). The two main medial forebrain bundle divisions in midbrain are shown (medial and lateral tegmentum). The midbrain ‘hub’ refers to paramedian areas innervated by the medial tegmentum. Note medial and lateral divisions of limbic forebrain as it enters midbrain (see Nauta, 1958). Abbreviations: mPFC-medial prefrontal cortex; ANT-anterior thalamic nucleus, MD-mediodorsal thalamic nucleus, CC, corpus callosum, AM, amygdaloid complex; HIPP, hippocampus.


findings for later studies of the distributed limbic system cannot be overstated. It was the historic paper of Nauta (1958) that truly opened interest in lower brainstem structures as part of the limbic system as well as markedly increasing the territory of the limbic system. Working out the projections of the limbic forebrain to the paramedian structures of the midbrain was a marked achievement and gave the limbic brain the substance needed to move to the next level of analysis, i.e. projections to the lower brainstem and spinal cord, and projections into the prefrontal cortex. Thus, we were beginning to understand a whole system complex and its role as a substratum of emotions and motivations. An emotional brain cannot act unless it has ‘legs to stand on’ with the motor system of the striatum and the spinal brainstem. Nauta was also prescient enough in his paper with Domesick (Nauta and Domesick, 1976) to note that connections involving substantia nigra and striatum may represent the interface between motivation and movement.

4. Limbic distributions There is anatomical continuity between the limbic formations medially and the insular cortex and the orbital cortex laterally. Yakovlev (1959, 1968, 1972), using tectogenetic and architectonic criteria in studies of normal and pathologic human brain showed that the insula represents an extension of the limbic lobe into the lateral wall of the hemispheres (Fig. 2). The limbus or border of the cerebral hemispheres comprises the cingulate gyrus beginning in the parolfactory

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area of the brain and coursing around the corpus callosum to the uncus of the para-hippocampal gyrus. At this point the limbus, via the gyrus ambiens, joins the transverse gyrus of the insula. It then continues as the orbital limbus of the frontal lobe to return to the parolfactory area and thereby closes the so-called ‘limbic ring’. As Yakovlev et al. (1966) noted, we should include the orbito-insular sector in the definition of the limbus. The descriptive term limbic lobe cannot be ascribed to Broca since earlier studies as far back as the 1660s reference the limbic area as the limbus (White, 1965). The insula is now clearly defined as the lateral portion of the limbic lobe (Jacobs et al., 1984; Morgane et al., 2005). This lateral extension of the limbic lobe (Fig. 2) has been subjected to detailed analysis. In our early quantitative architectonic studies the insula showed its clear links to the limbic lobe both anteriorly and posteriorly (Jacobs et al., 1984). Recent work has associated the insular cortex to conditioned taste aversion (Bermudez-Rattoni and McGaugh, 1991; Cubero et al., 1999; Sewards, 2004). The insular cortex is a fascinating mix of sensory and motor cortex with strong links to the limbic system. Because of this mix of function and anatomy, the insular cortex may be part of the primary behavioral output system for the limbic system. Through the definitive boundaries of the limbic nervous system have appeared to be somewhat imprecise, studies over recent decades have now given these considerable additional substance and wholeness. The limbic nervous system now needs to be further reconceptualized anteriorly and posteriorly in the brain indicating, respectively, its relation with the prefrontal and other cortices and medial and lateral limbic midbrain fields and into lower brainstem and spinal cord. Much is owed to the studies of Nauta (1958), and Nauta and Domesick (1981), particularly relative to the caudal extensions of the limbic nervous system and the limbic telencephalon (medial prefrontal cortex and septal area). Balance needs to be brought using systems approaches and examining larger reciprocating circuits (limbic loops) in addition to the subcortical and cortical research attempting to resolve complex functional issues in localized, non-systems approaches.

5. Medial prefrontal cortex

Fig. 2. Orienting schema showing mediolateral relationships between the basic limbic lobe and insula. Note continuity between limbic lobe proper and insula (arrows).

The medial prefrontal cortex (mPFC) is a heterogeneous cortical area, which we consider part of the limbic telencephalon (Nauta, 1971). The functional organization of this cortex has, until recently, been largely a mystery. As ¨ ngu¨r and Price (2000), the region receives noted by O processed sensory afferents and provides cortical influence over visceral functions and also participates in cognitive and emotional processes. It provides a major cortical output to viscero-motor structures in the hypothalamus and lower brainstem. Its defining input is from the mediodorsal thalamus (Fig. 3) as is its output. It can be divided into

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Fig. 3. Schema of limbic thalamus (anterior nuclei (ANT) and mediodorsal thalamus (MD) projecting to cingulate area above corpus callosum (CC) and medial prefrontal cortex (mPFC), respectively).

numerous cortical areas, the cingulate cortex, prelimbic cortex and infralimbic cortex. Each area has strong relations with the mediodorsal thalamus, amygdaloid complex, hypothalamus, central gray and lower brainstem. An important output of the mPFC reflects a viscero-motor system (Holstege, 1992). There is little doubt that mPFC is involved in emotional ¨ ngu¨r and Price, 2000). It is related to fear and behavior (O reward related circuits through it relations with the amygdaloid complex and nucleus accumbens. In key papers relative to whether rats actually have a prefrontal cortex, Preuss (1995); Uylings et al. (2003) provide a wide variety of data confirming that rats do indeed have a mPFC. Preuss (1995) points out that from an evolutionary point of view no region of cerebral cortex has been more controversial that the prefrontal cortex. It has been widely acknowledged as a subject of higher cognitive function. In rats and primates the circuit that includes the mPFC is also characterized by strong inputs from the amygdaloid complex. The rat prefrontal cortex receives cortico-cortical inputs from motor, somatosensory, visual, auditory, gustatory and limbic cortices. Hence, rat prefrontal cortex is a model station or hub that is embedded in several parallel networks, such as reward and motivation. Overall, the mPFC is a complex brain region not easy to functionally dissect. It is clear that mPFC neurons integrate diverse information but there is still scanty information on major prefrontal functions (Miller, 2000). Sullivan and Brake (2003) point out that regulation of physiological and behavioral arousal is a major fundamental role of mPFC upon which ‘higher’ prefrontal functions are dependent or influenced. Recently Sullivan and Brake (2003) and others (Heidbreder and Groenewegen, 2003; Morgane et al., 2005) have emphasized a dorsal and ventral division of the mPFC. They emphasized that the ventral mPFC (especially infralimbic cortex) is regarded as a visceromotor output system. These ventromedial afferents appear to modulate many subcortical and brainstem areas controlling

autonomic and neuroendocrine activation as well as emotional expression (Terreberry and Neafsey, 1987; Sesack et al., 1989; Hurley et al., 1991). Stimulation of the ventral mPFC elicits a sympathetic response while dorsal mPFC stimulation (prelimbic and anterior cingulate) produces parasympathetic responses (Powell et al., 1994). Furthermore, while lesions of the ventral mPFC decrease stress-induced plasma corticosterone, lesions of dorsal mPFC result in increases in stress-induced plasma corticosterone (Sullivan and Brake, 2003). The functional significance of these findings will lead us to a better understanding of the role of the mPFC as a limbic system hub. A very detailed analysis of the medial prefrontal cortex showing evidence of a dorsal-ventral distinction in functional and anatomical characteristics were carried out by Heidbreder and Groenewegen (2003). Interestingly, limited connections between dorsal and ventral prefrontal cortex were found indicating perhaps that this is probably not a single functional unit. Strong reciprocal relations between the amygdaloid complex and both medial prefrontal areas (dorsal and ventral) abound. In the rat, the ventral mPFC extends projections to the spinal cord (Holstege, 1992; van Eden and Buijs, 2000; Holstege and Georgiadis, 2004). Dopamine fibers from the ventral tegmental area terminate in both areas of the mPFC with the ventral component receiving the heaviest innervation (Divac et al., 1978). In addition, there are important reciprocal connections between medial prefrontal cortex and the neurochemical systems of the median and dorsal raphe´ and locus coeruleus, parts of the medial and lateral tegmentum, respectively. Clearly the medial prefrontal cortex constitutes a limbic cortex and its activities and connections indicate it is a major anterior cortical limbic hub (area of convergence).

6. Johann Bernhard Alois Von Gudden’s Nuclei The dorsal and ventral nuclei of Gudden first came to prominence in Nauta’s studies (1958) within the context of the distributed limbic midbrain system. At that time the Gudden’s nuclei appeared to represent the termini of the limbic forebrain-limbic midbrain systems. To that end, our group, in 1962 and 1963, mapped out cholinergic REM sleep loci that followed the medial forebrain—medial midbrain paths extending from the anterior limbic forebrain to the dorsal nucleus of Gudden in the dorsal midbrain and central gray (Hernańdez-Peoń et al., 1962, 1963). At each brain locus, insertion of cholinergic crystals (carbachol) resulted in REM sleep within 6–8 min. As is well known, cholinergic sleep systems, both ascending and descending, extend across this entire anterior limbic territory (limbic cholinergic system). Petrovicky´ (Petrovicky´, 1971, 1973, 1985a) and others (Hayakawa and Zyo, 1983; Irle et al., 1984) have precisely identified the cytoarchitecture and connections of


these nuclei. Petrovicky´ (1971, 1973, 1985a,b) using anatomical approaches (comparative, cytoarchitectural and connectional) concluded that the two Gudden’s nuclei are not a functional unit. They found that very few fibers link the dorsal nuclei of Gudden to the ventral nuclei of Gudden. Irle et al. (1984) in HRP studies found that the ventral nucleus of Gudden serves as a midbrain core structure of the limbic system responsible for transfer of motion, sensory and autonomic information arising in the brainstem to limbic forebrain structures. Clearly, however, both the dorsal and ventral Gudden’s nuclei have reciprocal connections to the mamillary nuclei and thus access to the limbic forebrain. Functionally, Kocsis et al. (2001); Torterolo et al. (2002) in electrophysiologic studies showed these nuclei to serve as theta generators. Theta activity is an EEG rhythm that represents the ‘ready’ state of the hippocampal formation and other limbic forebrain structures. This state is seen in active waking and REM sleep and thus appears to be part of the extended vigilance complex.

7. Lower brainstem and spinal cord Holstege (1992); Holstege and Georgiadis (2004) have reviewed the extensive connections of the limbic forebrain and limbic midbrain to caudal brainstem and spinal cord thus considerably extending the limbic system. Holstege (1992) has termed this extension of the limbic system, the ‘emotional motor system’ which forms a major output for the limbic system. Such connections were not previously identified in the earlier studies of Nauta (1958). Fig. 1 illustrates the extension of the limbic system into the lower brainstem and spinal cord. The limbic midbrain can be divided into two extensions of the medial forebrain bundle. The medial division has been termed the medial tegmentum and consists of the raphe´ nuclei, the central gray and Gudden’s nuclei. This corresponds to the median paracore described by Nieuwenhuys (1985); Nieuwenhuys et al. (1988). The lateral tegmentum is the second division of the limbic midbrain. It is comprised of the ventral tegmental area, the locus coeruleus, the substantia nigra, the subcoeruleus, the nucleus ambiguus and the nucleus tractus solitarious. This, in turn, corresponds to the lateral paracore (Nieuwenhuys, 1985; Nieuwenhuys et al., 1988). Many aspects of emotional/visceral/autonomic activity are regulated through this system. Projections of the amygdaloid nuclei and the bed nucleus of the stria terminalis, as well as the lateral hypothalamus project directly to the PAG (central gray). Projections from the PAG through the lateral tegmentum form the output for the defense response (Holstege, 1992). In a similar manner, the insular cortex is sometimes referred to as the gustatory cortex because if its sensory and motor connections to the gut. This serves as an important link for the visceral

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response to emotion. In addition, stimulation of the insula leads to tachycardia and an increase in arterial blood pressure. The output from the insula involves the nucleus of the solitary tract and the PAG (Holstege, 1992). The stress system is a key subsystem of the limbic system (Morgane et al., 2005). The somatic output from the stress system also involves the medial tegmentum.

8. Central gray As indicated above, the central gray is part of the medial tegmentum and forms one of the key components of the limbic midbrain. While the original concept of the limbic system by Nauta had the termini of the limbic system in the Gudden’s nuclei, it is clear that the central gray and the raphe´ nuclei are key components of the limbic midbrain. While the median and dorsal raphe´ nuclei, which represent the serotonergic innervation of the limbic forebrain, have always been considered to be part of the limbic system, we should now include the caudal raphe´ nuclei. The raphe´ pallidus, raphe´ obscurus and raphe´ magnus are involved with the limbic system’s response to pain as well as other outputs from the limbic system. Likewise the interactions of the limbic system with the reticular activating system and the central gray have significant impact throughout the neuraxis, including the sensory and motor systems of the spinal cord.

9. The way ahead Hopefully, this special issue of Neuroscience and Biobehavioral Reviews will open new vistas on the limbic brain. We have attempted to bring together experts in the various dimensions of the limbic system to update and expand our knowledge of this important emotional system of the brain. The limbic brain cannot be adequately analyzed until its distributed networks are better understood. Its simple—the limbic brain is very complex. But its not a brain without borders!

Acknowledgements This work was supported by NIH grant HD 22539-15. We thank Dr Frank Willard for critically reviewing the paper.

References Bermudez-Rattoni, F., McGaugh, J.L., 1991. Insular cortex and amygdala lesions differentially affect acquisition on inhibitory avoidance and conditioned taste aversion. Brain Res. 549, 165–170.

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Broca, P., 1878. Anatomie comparee des circonvolutions cerebrales. Le grand lobe limbique et la scissure limbique dans la serie des mammife`res. Rev. Anthrop. 1, 385–498. Bucy, P.C., Klu¨ver, H., 1955. An anatomical investigation of the temproal lobe in the monkey (Macaca mulatta). J. Comp. Neurol. 103, 151–251. Cubero, I., Thiele, T.E., Bernstein, I.L., 1999. Insular cortex lesions and taste aversion learning: effects of conditioning method and timing of lesion. Brain Res. 839, 323–330. Divac, I., Bjorklund, A., Lindvall, O., Passinham, R.E., 1978. Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons to the neocortex in three species. J. Comp. Neurol. 180, 59–71. Hayakawa, T., Zyo, K., 1983. Comparative cytoarchitectonic study of Gudden’s tegmental nuclei in some mammals. J. Comp. Neurol. 216, 233–244. Hedou, G., Homberg, J., Martin, S., Wirth, K., Feldon, J., Heidbreder, C.A., 2000. Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex. Eur. J. Pharmacol. 390, 127–136. Heidbreder, C.A., Groenewegen, H.J., 2003. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci. Biobehav. Rev. 27, 555–579. Hernańdez-Peoń, R., Cha´vez-Ibarra, G., Morgane, P.J., Timo-Iaria, C., 1962. Cholinergic pathways for sleep, alertness and rage in the limbic midbrain circuit. Acta Neurol. Latinoam. 8, 93–96. Hernańdez-Peoń, R., Cha´vez-Ibarra, G., Morgane, P.J., Timo-Iaria, C., 1963. Limbic cholinergic pathways involved in sleep and emotional behavior. Exper. Neurol. 8, 93–111. Holstege, G., 1992. The emotional motor system. Eur. J. Morphol. 30, 67– 79. Holstege, G., Georgiadis, J., 2004. The emotional brain; neural correlates of cat sexual behavior and human male ejaculation. Prog. Brain Res. 143, 39–45. Hurley, K.M., Herbert, H., Moga, M.M., Saper, C.B., 1991. Efferent projections of the infralimbic cortex of the rat. J. Comp. Neurol. 308, 249–276. Irle, E., Sarter, M., Guldin, W.O., Markowitsch, H.J., 1984. Afferents to the ventral tegmental nucleus of Gudden in the mouse, rat and cat. J. Comp. Neurol. 228, 509–541. Jacobs, M.S., Galaburda, A.M., McFarland, W.L., Morgane, P.J., 1984. The insular formations of the dolphin brain: quantitative cytoarchitectonic studies of the insular component of the limbic lobe. J. Comp. Neurol. 225, 396–432. Klu¨ver, H., Bucy, P.C., 1937. ‘Psychic blindness’ and other symptoms following bilaterl temporal lobectomy in Rhesus monkeys. Am. J. Physiol. 119 (2), 352–353. Klu¨ver, H., Bucy, P.C., 1938. An analysis of certain effects of bilateral temporal lobectomy in the rhesus monkey, with special reference to ‘psychic blindness’. J. Physiol. (Lond.) 5, 33–54. Klu¨ver, H., Bucy, P.C., 1939. Preliminary analysis of functions of the temporal lobes in monkeys. Arch. Neurol. Psychiat. 42, 979–1000. Kocsis, B., Di Prisco, G.V., Vertes, R.P., 2001. Theta synchronization in the limbic system: the role of Gudden’s tegmental nuclei. Eur. J. Neurosci. 13, 381–388. Miller, E.K., 2000. The Prefrontal cortex: no simple matter. Neuroimage 11, 447–450. Morgane, P.J., 1961. Distinct ‘feeding’ and ‘hunger motivating ’systems in the lateral hypothalamus of the rat. Science 133, 887–888. Morgane, P.J., 1980. Concluding remarks on psychophysiology of motivation. Adv. Physiol. Sci. 17, 389–391. Morgane, P.J., 1980. Introduction to psychophysiology of motivation (organization of the cortico-limbic-reticular axis in regulating hypothalamic activity). Adv. Physiol. Sci. 17, 322–325. Morgane, P.J., Galler, J.R., Mokler, D.J., 2005. A review of systems and networks of the limbic forebrain/limbic midbrain. Prog. Neurobiol. 75, 143–160.

Morgane, P.J., Kosman, A.J., 1957. A rhinencephalic feeding center in the cat. Am. J. Physiol. 197, 158–162. Morgane, P.J., Kosman, A.J., 1957. Alterations in feline behaviour following bilateral amygdalectomy. Nature 180, 598–600. Nahm, F.K., 1997. Heinrich Kluver and the temporal lobe syndrome. J. Hist. Neurosci. 6, 193–208. Nauta, W.J.H., 1958. Hippocampal projections and related neuronal pathways to the mid-brain in the cat. Brain 81, 319–340. Nauta, W.J.H., 1971. The problem of the frontal lobe: a reinterpretation. J. Psychiat. Res. 8, 167–187. Nauta, W.J.H., 1986. Circuitous connections linking cerebral cortex, limbic system and corpus striatum. In: Doane, B.K., Livingston, K.E. (Eds.), Limbic System: Functional Organization and Clinical Disorders. Raven Press, New York, pp. 43–54. Nauta, W.J.H., Domesick, V.B., 1976. Crossroads of limbic and striatal circuitry: hypothalamo-nigral connections. In: Livingston, K.E., Hornykiewicz, O. (Eds.), Limbic Mechanisms. Plenum Press, New York, pp. 75–93. Nauta, W.J.H., Domesick, V.B., 1981. Ramifications of the limbic system. In: Matthysse, S. (Ed.), Psychiatry and the Biology of the Human Brain. Elsevier, New York, pp. 165–188. Nieuwenhuys, R., 1985. Chemoarchitecture of the Brain. Springer, New York. Nieuwenhuys, R., Veening, J.G., vanDomburg, P., 1988. Core and paracores; some new chemoarchitectural entities in the mammalian neuraxis. Acta Morphol. Neerl. Scand. 26, 131–163. ¨ ngu¨r, D., Price, J.L., 2000. The organization of networks within the orbital O and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219. Papez, J.W., 1937. A proposed mechanism for emotion. Arch. Neurol. Psychiat. 38, 725–743. Petrovicky´, P., 1971. Structure and incidence of Gudden’s tegmental nuclei in some mammals. Acta Anat. (Basel) 80, 273–286. Petrovicky´, P., 1973. Note on connections of Gudden’s tegmental nuclei. Acta Anat. (Basel) 86, 165–190. Petrovicky´, P., 1985. Gudden’s tegmental nuclei and their connections to the hypothalamus and the reticular formation I. An experimental study using retrograde labelling with HRP and iron-dextran in the rat. J. Hirnforsch. 26, 531–537. Petrovicky´, P., 1985. Gudden’s tegmental nuclei and their connections to the hypothalamus and the reticular formation II. An experimental study using retrograde double labelling with HRP and iron-dextran in the rat. J. Hirnforsch. 26, 539–545. Powell, D.A., Watson, K., Maxwell, B., 1994. Involvement of subdivisions of the medial prefrontal cortex in learned cardiac adjustments in rabbits. Behav. Neurosci. 108, 294–307. Preuss, T.M., 1995. Do rats have prefrontal cortex? The Rose-WoolseyAkert program reconsidered. J. Cogn. Neurosci. 7, 1–24. Schreiner, L., Kling, A., 1953. Behavioral changes following rhinencephalic injury in cat. J. Neurophysiol. 16, 643–659. Sesack, S.R., Deutch, A.Y., Roth, R.H., Bunney, B.S., 1989. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 290, 213–242. Sewards, T.V., 2004. Dual separate pathways for sensory and hedonic aspects of taste. Brain Res. Bull. 62, 271–283. Sullivan, R.M., Brake, W.G., 2003. What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function. Behav. Brain Res. 146, 43–55. Terreberry, R.R., Neafsey, E.F., 1987. The rat medial frontal cortex projects directly to autonomic regions of the brainstem. Brain Res. Bull. 19, 639–649. Torterolo, P., Sampogna, S., Morales, F.R., Chase, M.H., 2002. Gudden’s dorsal tegmental nucleus is activated in carbachol-induced active (REM) sleep and active wakefulness. Brain Res. 944, 184–189.

P.J. Morgane, D.J. Mokler / Neuroscience and Biobehavioral Reviews 30 (2006) 119–125 Uylings, H.B.M., Groenewegen, H.J., Kolb, B., 2003. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17. van Eden, C.G., Buijs, R.M., 2000. Functional neuroanatomy of the prefrontal cortex: autonomic interactions. Prog. Brain Res. 126, 49– 62. White Jr.., L.E., 1965. A morphologic concept of the limbic lobe. Int. J. Neurobiol. 8, 1–34. Yakovlev, P.I., 1959. Pathoarchitectonic studies of cerebral malformations III. Arrhinencephalies (holotelencephalies). J. Neuropathol. Exp. Neurol. 18, 22–55.

125

Yakovlev, P.I., 1968. Telencephalon ‘Impar’, ‘Semipar’ and ‘Totopar’ (Morphogenetic, tectogenetic and architectonic definitions). Int. J. Neurol. 6, 245–265. Yakovlev, P.I., 1972. A proposed definition of the limbic system. In: Hockman, C.H. (Ed.), Limbic System Mechanisms and Autonomic Function. Charles C.Thomas, Springfield, IL, pp. 241–283. Yakovlev, P.I., Locke, S., Angevine Jr.., J.B., 1966. The limbus of the cerebral hemisphere, limbic nuclei of the thalamus, and the cingulum bundle. In: Purpura, D., Yahr, M. (Eds.), Thalamic Integration of Sensory and Motor Activities. Columbia University Press, New York, pp. 77–97.