What does the retrosplenial cortex do?

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What does the retrosplenial cortex do? Seralynne D. Vann*, John P. Aggleton* and Eleanor A. Maguire‡

Abstract | The past decade has seen a transformation in research on the retrosplenial cortex (RSC). This cortical area has emerged as a key member of a core network of brain regions that underpins a range of cognitive functions, including episodic memory, navigation, imagination and planning for the future. It is now also evident that the RSC is consistently compromised in the most common neurological disorders that impair memory. Here we review advances on multiple fronts, most notably in neuroanatomy, animal studies and neuroimaging, that have highlighted the importance of the RSC for cognition, and consider why specifying its precise functions remains problematic.

*School of Psychology, Cardiff University, Tower Building, Park Place, Cardiff, CF10 3AT, UK. ‡ Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, WC1N 3BG, UK. Correspondence to S.D.V. e-mail: [email protected] doi:10.1038/nrn2733 Published online 8 October 2009

It is 100 years since Brodmann delineated the human RSC (areas 29 and 30) within the posterior cingulate region1. Regrettably, so few advances in our understanding of the human RSC seemed to have occurred over the next 90 years that Vogt et al. stated ‘nothing is known about its function’2. Early views of RSC function focused on its potential role in brain systems that regulate emotion. The most famous example of these is the Papez circuit 3, in which projections from the anterior thalamic nuclei to the cingulate cortex and from there to other cortical regions emotionally colour our psychic processes. MacLean’s concept of the ‘visceral brain’4 endorsed Papez’ ideas, citing evidence that stimulation of the cingulate cortices can evoke autonomic changes that are linked with emotion. This past focus on emotion and autonomic regulation may, however, have deflected attention away from the potential importance of this region for other cognitive functions. This Review first considers RSC neuroanatomy, then focuses on evidence that the RSC contributes to memory and navigation, and finally considers how these roles fit with its more recently revealed involvement in other aspects of cognition.

Location, terminology and appearance For RSC research, location is everything. The term ‘retrosplenial’ defines the RSC’s position immediately behind the splenium, the most caudal part of the corpus callosum. Consequently, the primate RSC is located deep in the midline, much of it hidden from the medial surface of the brain. The RSC forms part of the posterior cingulate region, the other components of the primate posterior cingulate region being areas 23 and 31 (FIG. 1). Area 31 is

sometimes considered to belong to both the posterior cingulate and the precuneate cortices5,6, but it is agreed that area 23 separates the RSC from the precuneate region. The importance of distinguishing the RSC from other parts of the posterior cingulate region is underlined by the many morphological and connectivity differences that areas 29 and 30 have from area 23 (ReFs 7,8). The RSC is regarded as an ‘intermediate’ cortex as it has a transitional pattern of lamination that reaches a clearly defined pattern of six layers only in the adjacent area 23. Consequently, progressing in a lateral to medial direction around the callosal sulcus above the splenium in the primate brain (both human and monkey), lamination increases from the induseum griseum to Brodmann’s area 26 (not present in the monkey), to lateral area 29 (four layers) to medial area 29 (four or five layers, depending on the authority) to the dysgranular area 30 (six layers but a poorly defined, dysgranular layer IV) and finally to area 23 (six distinct layers)8–11. When referring to the monkey brain in this article, we use the RSC boundaries and terminology of Kobayashi and Amaral8, as their nomenclature accompanies the most detailed analyses of primate RSC connectivity to date (FIG. 1). The rat posterior cingulate region differs substantially from the primate RSC as it has no direct counterparts to areas 23 and 31, so the entire region is designated the RSC12,13. The term posterior cingulate for the rodent brain is, therefore, potentially misleading. As in the primate, the rat RSC can be separated into dysgranular (area 30) and granular (area 29) regions, and the latter area has been divided into either two13 or three12 subregions, depending on the authority. In this Review we refer to the regions and subregions as described by Van

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REVIEWS Groen and Wyss13–15 — that is, dysgranular (Rdg), granular a (Rga) and granular b (Rgb) regions — because some connectivity studies and all studies of selective lesions in areas 29 and 30 have used this terminology. A striking feature of the rat RSC is its size — it extends over half the length of the entire cerebrum, making it one of the largest cortical regions in this species.

Anatomical connections If little else was known about RSC function, its connections would immediately point to a role in memory. Axonal tracing studies in monkeys (FIG. 1) have revealed reciprocal connections with three notable regions: the hippocampal formation (subiculum, presubiculum a

and parasubiculum), the parahippocampal region (the entorhinal cortex and areas TH and TF) and select thalamic nuclei (the anterior and lateral dorsal nuclei). Pathology in all three regions has been repeatedly implicated in amnesic syndromes. Furthermore, the densities of the hippocampal and anterior thalamic connections with areas 29 and 30 are much higher than the densities of these connections to the adjacent posterior cingulate area 23 (ReFs 7,16,17), suggesting that within the posterior cingulate region the RSC is most likely to be involved in hippocampus-dependent functions. other notable connections include reciprocal retrosplenial pathways to parts of the prefrontal cortex (areas 46, 9, 10 and 11), which provide an indirect route for

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Figure 1 | Retrosplenial neuroanatomy. Location and principal connections of the retrosplenial cortex (RSC). a | Medial Reviews | Neuroscience surface of a human brain showing the position of the RSC (Brodmann’s areas 29 and 30) (blue)Nature and the remaining posterior cingulate cortex (areas 23 and 31) (green). b | How the RSC can help to integrate information in cortical sensory and prefrontal sites (upper half of the schematic) with subcortical sites required for memory (lower half). c | Principal connections of the macaque (Macaca fascicularis) RSC. The darker arrows indicate denser projections (bicoloured arrows indicate denser projections in the direction indicated by the darker colour)7,16. d | Location and principal connections of the rat RSC; d indicates the dysgranular cortex (area 30); a and b respectively indicate divisions Rga and Rgb within the granular cortex (area 29)12–14. The arrowheads in area 29 do not distinguish between Rga and Rgb. e | A series of coronal sections depicting the location of areas 29 and 30 (the RSC, blue) and area 23 (green) in the posterior cingulate region of M. fascicularis8. Numbers prefixed by ‘A’ indicate the distance (in millimetres) anterior to the auditory meatus8. All other numbers refer to area designations. AD, anterior dorsal thalamic nucleus; AM, anterior medial thalamic nucleus; AV, anterior ventral thalamic nucleus; Caud, caudate nucleus; Clau, claustrum; HF, hippocampal formation; LD, laterodorsal thalamic nucleus; LP, lateroposterior thalamic nucleus; MPulv, medial pulvinar; ParaS, parasubiculum; PH, parahippocampal cortex; Post, postsubiculum; PR, perirhinal cortex; PreS, presubiculum; STSd, dorsal superior temporal sulcus; Sub, subiculum; V4, visual area 4. Part a is modified, with permission, from ReF. 142 © (2001) Elsevier. Part c is modified, with permission, from ReF. 16 © (2007) Wiley. Part d is modified, with permission, from ReF. 12 © (1981) Wiley. Part e is modified, with permission, from ReF. 8 © (2000) Wiley. nATuRE REVIEWS | NeuRoscieNce

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REVIEWS

Head-direction cells Cells that can distinguish, by altering their firing rate, the direction that an animal is facing.

Executive function The planning and sequencing of future actions, selected from multiple options.

Immediate-early genes Genes that encode transcription factors that are induced within minutes of raised neuronal activity without requiring a protein signal. Immediate-early gene activation is, therefore, used as an indirect marker of neuronal activation.

Working memory In animal research this term refers to information that is required within a trial but may well prove to be misleading across trials or sessions.

Ideothetic information Internal feedback information that can be used to monitor progress and, hence, position in space.

Path integration The continuous integration of self-movement (ideothetic) cues to update representations of current position (and so plot a direct path back to the start of a journey). Also known as ‘dead reckoning’.

hippocampal influences on the dorsolateral prefrontal cortex (areas 46 and 9) and vice versa18. There are also reciprocal links with the dorsal superior temporal sulcus, area V4 and cingulate areas 23 and 24. The dense intracingulate connections suggest that interactions between different parts of the cingulate cortex might form additional sets of segregated networks7,19. The pathways for these cortico-cortical and cortico-thalamic connections contribute to the cingulum bundle17. The rat RSC is dominated by its reciprocal connections with the anterior thalamic nuclei, the lateral dorsal thalamic nucleus and the hippocampal formation13–15. The hippocampal inputs originate in the postsubiculum, the subiculum and the presubiculum. The granular regions (area 29) in the RSC (Rga and Rgb) are distinguished by reciprocal connections with sites (the lateral dorsal and anterior dorsal thalamic nuclei and the postsubiculum) that contain ‘head-direction’ cells, whereas the dysgranular cortex (area 30) in the RSC (Rdg) is more interconnected with visual areas through reciprocal connections with areas 18b and 17 (ReF. 20). As in the primate, there are reciprocal connections with the anterior cingulate cortex 15,19. Subcortical inputs to the rat RSC include projections from the raphe nuclei, the locus coeruleus and the diagonal band21. It is striking that in both the rodent and the monkey brain the RSC provides reciprocal, indirect routes between the hippocampal formation and the anterior thalamic nuclei, even though these same regions are also linked by dense direct connections (FIG. 1b). The functional importance of these indirect routes is highlighted by disconnection studies (see next section) showing that the anterior thalamic nuclei, the RSC and the hippocampus require each other to support spatial learning 22,23. These considerations raise the important issue of identifying those RSC connections that are not shared by either the hippocampal formation or the anterior thalamic nuclei, so as to obtain clues to the unique mnemonic contributions of the RSC. Candidate RSC connections not shared with either the hippocampus or the anterior thalamus include reciprocal connections with areas 46 and 9 in the dorsolateral prefrontal cortex 18, which could provide important routes between the hippocampus and cortical regions involved in executive function. In addition, the principal extrinsic cholinergic inputs to the RSC, the hippocampus and the anterior thalamic nuclei originate from different sources (the basal nucleus of Meynert, the medial septum and vertical limb of the diagonal band, and the laterodorsal tegmental nucleus, respectively). Perhaps most importantly, the RSC receives more early-processed sensory information than either the hippocampus or the anterior thalamic nuclei. The direct inputs from V2 and V4, along with afferents from the claustrum and the lateroposterior thalamic nuclei, could provide visual information21, but additional sensory information might be conveyed through direct parietal cortex (area 7) projections to the RSC. In addition, the parietal cortex (area 7a, area 7b, area LIP (lateral intraparietal cortex) and area DP (dorsal prelunate cortex)) has particularly dense projections to posterior cingulate area 23 (ReF. 7),

which in turn projects heavily to the RSC. Thus, areas 29 and 30 could be vital conduits for sensory (parietal and occipital) information reaching both the hippocampal formation and the anterior thalamic nuclei.

Animal studies of RSC function The inaccessibility of the RSC in the human brain has promoted research in other animals, which has predominantly used lesion techniques and electrophysiology. RSC lesions — method and extent. Prompted by the connectivity of the RSC with the hippocampal formation, most RSC lesion studies have focused on cognitive abilities attributed to hippocampal activity. Despite some initial controversy, there is now a general consensus that RSC lesions in rodents impair spatial memory 24,25. Many of the earlier disparities can be traced to differences in lesion extent and surgical method26: although the RSC reaches the caudal limit of the rat cerebrum, many lesion studies targeted more rostral parts of the RSC. The importance of the spared caudal retrosplenial tissue for spatial memory has been demonstrated using immediate-early gene mapping 27 and electrophysiology 28 and by directly comparing the behavioural impact of different size RSC lesions29. Lesion size also interacts with lesioning method, as traditional surgical techniques (electrolytic and aspiration) are prone to damaging the underlying cingulum bundle and so potentially disconnecting much of the entire cingulate cortex. A further factor is that the extent of pre-surgical and post-surgical training can alter the impact of RSC lesions30. Different types of RSC lesion-induced impairments. Most rodent lesion studies have focused on spatial memory and navigation. RSC lesions impair performance on standard spatial memory tasks, including learning the fixed22,31–34 or daily-changing22,32,33,35 location of a platform in a water maze, and performance on working memory tasks in a radial-arm maze31,36. These tasks involve the use of distal visual cues (‘allocentric’ tasks), but lesion-induced impairments have also been reported on tasks designed to tax the use of directional information37 (requiring rats to alternate their position around a fixed direction) or the use of ideothetic information for path integration34. Inactivation studies (using tetracaine injection) have shown that the RSC is necessary for correct performance in a radial-arm maze task under normal light conditions and for radial-arm maze performance and path integration in the dark38–40. In rats, although the RSC is not required for the detection of novel objects31, it seems to be important for the detection of novel spatial arrangements of objects (‘object-inplace’ detection)31. This wide array of RSC lesion-induced spatial deficits on tasks that rely on different spatial strategies (involving both visual and somatosensory feedback) is consistent with the multiple sources of afferent sensory information to the RSC (FIG. 1). The RSC supports spatial memory in conjunction with at least two other sites, the hippocampus and the anterior thalamic nuclei (FIG. 1). This conclusion is bolstered by findings from spatial working memory tasks in which rats use familiar spatial cues27 or novel



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Visuospatial conditional tasks Tasks in which animals are required to learn fixed associations between visual stimuli or spatial contexts and either spatial locations or objects to gain a reward.

Compound-feature negative-discrimination task A task in which animals are given two types of trial: one in which a stimulus (for example, a tone) is followed by a reward and a second in which the same stimulus is presented with another stimulus (for example, a light) but no reward. Control animals learn to respond to the tone only but not the tone and light combinations.

Contextual fear conditioning When animals learn to associate a specific context or environment with the administration of an aversive stimulus, for example a shock. When re-exposed to the same context or environment control animals will demonstrate a fear response, for example freezing.

Active avoidance in a two-way shuttle box When animals avoid a shock that they have learnt — through prior conditioning — is associated with a stimulus by entering the compartment in which they know they will not be shocked.

configurations of spatial cues41 and show immediateearly gene activation in all three brain structures. The relationships between these three regions were tested more formally in a disconnection study in which unilateral lesions were made in the RSC and in either the contralateral hippocampus or the anterior thalamic nuclei. Both lesion combinations impaired learning the position of a fixed platform in a water maze task22 (BOX 1). By contrast, learning in visuospatial conditional tasks is spared in rats with lesions of the RSC36,42. Interestingly, performance on this class of task is sensitive to lesions of the hippocampus and the anterior thalamic nuclei36 but not of other structures known to be necessary for spatial memory — the mammillary bodies43 and fornix 44. It is possible that the extensive training required for animals to acquire these conditional discriminations36,44 masks the contribution of some of these brain structures. The magnitude of the spatial deficits after lesioning of the RSC is typically smaller than the magnitude of the deficits associated with either anterior thalamic or hippocampal damage, which presumably reflects some compensation across structures mediated by their parallel interconnections (FIG. 1b). The full impact of RSC lesions often emerges only when animals are forced to shift modes of spatial learning — for example, from light to dark38 or from local to distal cues29,37 — indicating that rats with lesions of the RSC cannot switch or integrate parallel modes of task performance. A striking, robust example is when radial-arm maze training

changes so that intra-maze cues are placed in conflict with extra-maze cues29,35,37. RSC function in rodents is not limited to spatial memory. Recent findings highlight the importance of the RSC for the simultaneous processing of multiple stimuli, with RSC lesions disrupting performance on a compound-feature negative-discrimination task45, contextual fear conditioning46 and the acquisition of active avoidance in a two-way shuttle box47. In addition, RSC lesions severely impair the ability of rabbits to learn how to avoid an electric shock when they hear an acoustic signal48. Although these impairments do not seem to reflect general impairments in the processing of fear-evoking stimuli47, they reveal that RSC function might extend to include learning that is associated with affective stimuli. Selective subregion lesions. Based on the connectivity of RSC subregions, and recent immediate-early gene studies49, it might be supposed that the dysgranular RSC is more important for visually guided spatial memory and navigation, whereas the granular RSC has a greater involvement in internally directed navigation. To date only two studies in rodents have targeted the individual RSC subregions. one study found that lesions of the Rgb, but not the Rga, disrupted delayed matching to position in a water maze50. The other study 51 found that selective Rdg lesions impaired the use of visual allocentric cues in the radial-arm maze, consistent with the predominance of visual inputs to

Box 1 | The retrosplenial cortex as a site of covert pathology? The retrosplenial cortex (RSC) is unusually sensitive to Control MTT lesion deafferentation. As noted in BOX 2, RSC hypometabolism is found in patients with Alzheimer’s disease and mild cognitive impairment — conditions that are associated with atrophy in sites that project to the RSC, for example the hippocampal RSC formation and the anterior thalamic nuclei. Studies in rats using immediate-early gene activity as a marker of neuronal activity found that lesions in the anterior thalamic nuclei and hippocampus both produce marked RSC dysfunction119,120. The loss of immediate-early gene (for example, Fos and Egr1) expression in the RSC is striking and seems to be far greater than in comparison sites121. Even indirect disconnections can produce dramatic RSC hypoactivity, for example after mammillothalamic tract (MTT) lesions122 (see the figure: the ACC upper right panel shows loss of Fos expression in the RSC after MTT lesion, whereas the lower right panel shows normal Fos expression in the anterior cingulate cortex (ACC)). Complementary microarray studies revealed a swathe of 100 µm altered gene activity in the RSC following anterior thalamic lesions, particularly for genes involved in metabolism123.These Nature Reviews | Neuroscience same limbic lesions have little or no effect on RSC cell numbers120,124. These findings suggest that the functional impact of some limbic lesions could be exacerbated by distal dysfunctions in the RSC. A direct test of this possibility125 showed that RSC brain slices from rats with anterior thalamic lesions fail to show normal synaptic plasticity. This result is persuasive as the slice preparation ensures that the RSC tissue is stimulated as per normal, but owing to a distal thalamic lesion — made weeks previously — it is not possible to induce long-term depression in the RSC125. This implies that anterior thalamic lesions induce ‘covert pathology’ in the RSC — that is, a seemingly intact cytoarchitecture combined with a persistent functional abnormality. To date, no studies have examined possible effects of RSC lesions on immediate-early gene activation in the hippocampus and anterior thalamic nuclei but, given the apparent interdependence of these structures and the effects of RSC lesions on anterior dorsal thalamic head-direction cells28 and hippocampal place cells40, it would be predicted that other functional measures would also be affected by RSC lesions and potentially contribute to subsequent behavioural impairments. Figure is reproduced, with permission, from ReF. 122 © (2009) Wiley.

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REVIEWS Box 2 | Retrosplenial hypoactivity and memory loss Primary lesions involving the retrosplenial cortex (RSC) can be caused by tumours, arteriovenous malformations, infarction and haemorrhage. Pathological changes in this region can also occur in conditions such as schizophrenia126, bipolar disorder127, post-traumatic stress disorder128, dyslexia129 and fibromyalgia81. More subtle changes, specifically reduced RSC activity, have been found in patients with temporal lobe or diencephalic amnesia130,131. Especially striking is the discovery that the earliest metabolic decline in Alzheimer’s disease, as measured using [18F]-fluorodeoxyglucose positron emission tomography, is centred on the RSC132,133. This finding has been shown in people with mild cognitive impairment (MCI), which is often a prodromal stage of Alzheimer’s disease. Such results are consistent with the link between retrosplenial hypoactivity and memory loss in patients with early Alzheimer’s disease110. There are currently two explanations for this RSC hypoactivity. The first is that it is a secondary response to atrophy in other brain sites that are known to undergo pathological damage in early Alzheimer’s disease and that have direct RSC inputs133, such as the hippocampus, the entorhinal cortex and the anterior thalamic nuclei (FIG. 1). The second account, which is not mutually exclusive with the first, is that the RSC may itself atrophy in early Alzheimer’s disease134,135. Of particular relevance is an MRI analysis of patients with MCI who subsequently developed Alzheimer’s disease135. These incipient Alzheimer’s cases showed volume decreases in both the RSC and the adjacent posterior cingulate area 23 that were comparable to their hippocampal atrophy135. These findings show that RSC dysfunction is likely to be a major contributor to the cognitive deficits associated with MCI and Alzheimer’s disease133.

the Rdg. Whether the two major RSC subregions can be functionally dissociated on the same task, and in the same study, remains to be determined.

Place cells Cells that fire differentially depending on the animal’s location in an environment.

Grid cells Neurons that fire strongly when an animal is at one of several specific locations in an environment and that are organized in a grid-like fashion.

Episodic memory The recollection of events with a specific spatial and temporal context, such as personal experiences. Often referred to as autobiographical memory.

Electrophysiology. Recording studies directly implicate the rodent RSC in navigation. Approximately 10% of RSC cells in the rat are ‘head-direction’ cells52. Such cells, along with ‘place cells’ and ‘grid cells’, form part of the triumvirate of the spatial navigation system. Headdirection cells are equally distributed across the granular and dysgranular RSC52. In the granular, but not the dysgranular, RSC the spatial tuning of some of these cells is modulated by aspects of behaviour such as the velocity of locomotion52. In addition, some RSC cells fire in response to particular combinations of location, direction and movement 53, although actual place cells have not been detected in the RSC. Head-direction cells are also found in other brain structures, including the postsubiculum and the anterior dorsal and lateral dorsal thalamic nuclei. Although these regions are reciprocally connected with the RSC, the RSC is not thought to be crucial for the generation of the headdirection signal28. nevertheless, lesions that include the caudal Rdg can disrupt anterior dorsal thalamic headdirection cells such that their preferred firing direction becomes less stable and likely to drift over time28. It is likely that the Rdg contributes visual information to the headdirection circuit, a view that is consistent with its anatomical connections and the impact of selective Rdg lesions51. A similar situation may hold for the place cell circuit, as temporary inactivation of the RSC can transiently change the spatial tuning of hippocampal place cells while leaving other electrophysiological properties intact40. Rhythmical slow-wave (theta) activity has been recorded in the RSC; it is locally generated and, unlike hippocampal theta activity, is only partially dependent on septal inputs54,55. Although RSC theta activity

is independent of hippocampal theta activity 55, some aspects of hippocampal rhythmical slow activity (in the 8–12 Hz frequency range) are mediated by the RSC (and/ or the underlying cingulum bundle)56. Cells in the RSC also respond differentially to different types of reward, and many RSC cells fire exclusively when animals make a physical response to acquire rewards (not during the presentation of conditioned stimuli)57. Finally, electrophysiological studies have found that RSC activity increases with the progression of learning an auditory avoidance conditioning task48. Parallel studies on the anterior thalamic nuclei led to the proposal that these regions work together to support both training-induced increases in attention to significant cues (for example, the conditioned stimulus) and subsequent cue-based retrieval48. Together, findings from animal studies highlight the importance of the RSC for various behavioural tasks, in particular those that tax spatial memory or require the integration of different types of stimuli. The importance of the RSC to the latter is most apparent when animals are required to shift spatial strategies. It is also apparent that the RSC is closely interlinked with the hippocampus and the anterior thalamic nuclei.

Human neuropsychological studies Human studies also provide evidence for a role for the RSC in navigation and spatial memory. In addition, they have allowed investigations into topics that are less amenable to study in animals, such as episodic memory. As early as 1929, reports linked RSC pathology to memory disorders and spatial disorientation58, findings that have since been confirmed59–66. unsurprisingly, it has been difficult to exclude the possibility that neighbouring posterior cingulate areas61, the fornix 60 or the hippocampus62 also contribute to these symptoms, and this caveat remains. It has also emerged that RSC dysfunction might contribute to Alzheimer’s disease from its earliest stages (BOX 2). Patients with damage involving the RSC consistently show difficulty acquiring new information presented verbally or visually 61. In addition to these learning deficits, patients generally have problems retrieving memories of recent but not of very remote autobiographical events59,61,63,65,66. However, the extent of the retrograde amnesia varies from less than 1 year 59 to 10 years62. Damage involving the RSC can also cause a selective deficit in spatial orientation61,64,67–72. In most of these cases, patients can recognize neighbourhood landmarks but fail to navigate effectively in familiar environments, indicating that they are unable to derive directional information from landmark cues. RSC damage can also compromise learning to navigate in new environments61. Patients with hippocampal lesions are also impaired at navigating in familiar and novel environments (for example, see ReF. 73) but, unlike patients with RSC lesions, they are usually able to orient in familiar environments and can have a preserved sense of direction73,74. In patients with unilateral RSC damage, the spatial deficit can resolve after several months61,68, and a neuroimaging study of such a patient suggests that this recovery is supported by the remaining RSC tissue64. Verbal and visual memory deficits are often, but not



REVIEWS always, consistent with the side of the lesion; for example, there is a preponderance of right-sided RSC pathology in patients with selective spatial disorientation61, but left-sided lesions have also been reported64,70,72,75,76. This indicates that interpreting the cause of such deficits is difficult owing to the rarity of selective RSC lesions and, consequently, the possibility of undetected bilateral pathology. The type of spatial deficit in patients (and animals) with RSC pathology, along with the anatomical connectivity of the RSC, has fostered the idea that the RSC has a ‘translational’ function61,67–69,77,78. It has been proposed that the RSC transforms allocentric representations into egocentric representations and vice versa. In other words, the RSC helps to switch between egocentric, viewpoint-dependent (mediated by the posterior parietal cortex) and allocentric, viewpoint-independent (mediated by the medial temporal lobe) frames of reference61,67,68,77,78. Based on a computational model, Burgess and colleagues77,78 proposed that the RSC uses headdirection information from the anterior thalamic nuclei to compensate for the rotational offset between egocentric and allocentric coordinates. This proposal has been extended to episodic and autobiographical memory 77,78, according to which the hippocampus indexes the location that is embodied in an autobiographical memory, scene or imagined event and the RSC then translates this information into an egocentric representation so that the memory, scene or imagined event can be viewed from a specific viewpoint. For instance, a scene or event is constructed in a person’s hippocampus and medial temporal lobe. This is in an allocentric framework (for example, it is built in relation to a landmark 10 metres north, where north is relative to the environmental cues driving the head-direction system). This representation has to be translated into egocentric directions to enable a person to act, such as left or right from the current (or imagined) direction of view (for example, a landmark 10 metres ahead if the viewpoint is north or 10 metres to the left if the viewpoint is east). In this model77,78 the RSC is involved in the translation process, possibly by acting as a short-term buffer for the representations as they are being translated77,78.

Rotational offset subtraction of the allocentric heading direction from the allocentric direction of an environmental landmark.

Neuroimaging in humans Memory and spatial navigation. The location of the RSC poses severe challenges to techniques like magnetoencephalography and transcranial magnetic stimulation. By contrast, functional MRI (fMRI) has been so successful that activity in the RSC region has been reported to be modulated by a bewildering array of tasks or processes, ranging from basic speech production and comprehension79 to motivation80 and pain81. Most striking, however, is its almost ubiquitous engagement in studies of spatial navigation61,68 and episodic memory 82,83, in which it is often the brightest ‘blob’ on the brain activation maps. For example, in a recent meta-analysis82 the RSC emerged as one of a number of brain regions that consistently showed significant activation during autobiographical memory retrieval. This meta-analysis also highlights a recurrent limitation on ascertaining the function of the RSC from

imaging studies, as the authors82 placed studies showing RSC activation and studies showing activation of other posterior cingulate regions into one category. Despite this generalization, plots of activation peaks from the studies they surveyed clearly implicate the right and left RSC in numerous studies82. In some instances, greater RSC activity has been observed during the retrieval of recent versus remote autobiographical experiences84–86. This pattern accords with neuropsychological studies in which damage involving the RSC seemed to disproportionately affect the retrieval of recent events59,61,63,65,66. However, in general, the RSC is active during retrieval of any kind of past autobiographical experience, be it recent or remote, emotional87 or neutral82,83. The RSC is also consistently engaged by spatial navigation tasks61,68,74,88–90. These include passive viewing of navigation footage, mental navigation and interactive navigation in virtual-reality environments. The RSC is also active during learning of new environments, navigation in recently learned environments and navigation in very familiar environments. Indeed, it is hard to find a navigation or topographical memory task in which the RSC is not activated (for example, see ReF. 91). Importantly, however, some studies have a rather liberal interpretation about what constitutes the RSC2: activation in posterior cingulate areas 23 and 31 (ReFs 92,93), in the parietal-occipital sulcus and in the anterior calcarine region92 has been misattributed to the RSC. In an effort to determine when during navigation different brain areas are engaged, Spiers and Maguire90 scanned participants navigating through a highly realistic virtual-reality simulation of central London. The analysis revealed a complex choreography of neural dynamics: they were both focal and distributed, and both transient and sustained. Activity in the RSC increased specifically when topographical representations needed to be updated, integrated or manipulated for route planning, or when new topographical information was acquired90. Thus, RSC processing is not tonically maintained during navigation in familiar environments; rather, its activity alters depending on specific circumstances and priorities. This could relate to the proposal that the RSC acts as a short-term buffer for translating between representations77,78, as outlined above. There has also been considerable interest in the RSC’s role in processing scenes68,94. Bar suggested that rather than supporting spatial navigation and orientation, the RSC (and other ‘scene areas’ like the parahippocampal cortex) might process scene-relevant relationships between objects and their contexts94. In support of this hypothesis, one study 95 found that the RSC was engaged by viewing objects strongly associated with a specific context more so than by viewing objects that were weakly associated with a context. Recently, Henderson et al.96 directly examined whether the RSC was engaged by three-dimensional geometric structure in scenes (which might underpin its role in navigation) and contrasted this with its purported role in contextual associations. Their findings were not compatible with the contextualassociations hypothesis93 but were consistent with the idea that the RSC supports spatial navigation.



REVIEWS Imagination and thinking about the future. In recent years a new theme has emerged in memory research, based on two observations. First, Hassabis et al. 97 reported that patients with bilateral hippocampal damage not only are unable to recollect past experiences but also are impaired at imagining fictitious and future experiences. Second, recalling past experiences was found to activate many of the same brain regions as imagining plausible personal future98–102 and fictitious103 experiences. These areas included the hippocampus and the RSC99,101–103. Moreover, these brain areas were also active during spatial navigation (see above), theory of mind tasks104, daydreaming 105 and when the brain is in a ‘resting state’ (BOX 3). A meta-analysis106 of studies from a number of these domains confirmed that the RSC is part of a common ‘core network’ that subserves a range of cognitive functions. This implies that the hippocampus and the RSC are engaged in a type of processing that may not be purely mnemonic in nature but that is Box 3 | The retrosplenial cortex and the default mode network

When participants are not performing tasks during functional neuroimaging, they show a characteristic pattern of brain activity involving the medial frontal and medial temporal lobe regions, lateral and medial parietal areas and the retrosplenial cortex (RSC)136. The areas that are active in this ‘resting brain state’ are together also known as the ‘default mode network’137. Although some default mode network areas show a decrease in activity once a participant engages in a cognitive task136, the RSC response during tests of spatial navigation and autobiographical memory retrieval is significantly above the resting-state baseline, reflecting its true engagement during such tasks61,68,82,83. There are temporal correlations in functional MRI (fMRI) signals between areas in the default mode network138, which might reflect the interconnectivity between regions such as the RSC and the hippocampus. There might also be subsystems in the default mode network that converge on two main hubs — one consisting of posterior cingulate cortex (PCC) areas 23 and 31 and the RSC, and the other lying in the medial prefrontal cortex139. Interestingly, although the default mode network changes across age groups, PCC and RSC involvement is observed consistently, even in 2-week-old infants140, suggesting that the PCC and RSC together are the main hub of the default mode network. Greicius et al.141 combined resting state fMRI and diffusion tensor imaging (DTI) to assess whether resting-state functional connectivity maps reflect neural connectivity. Using seed regions from functional connectivity maps, DTI revealed robust structural connections (orange fibres in the figure) between the RSC and the medial temporal lobes (green and purple areas), whereas tracts from the medial prefrontal cortex (yellow area) contact the PCC just rostral to the RSC (blue fibres). Fibre tracts connecting the RSC and the medial temporal lobes have previously been identified in macaque tracer studies (see the main text) but have not been shown in humans. Combining fMRI with DTI might, therefore, prove useful for characterizing normal RSC connectivity in humans and for assessing the impact of pathologies such as Alzheimer’s disease (BOX 2). Figure is reproduced, with permission, from ReF. 141 © (2009) Oxford Journals.

nevertheless crucial for memory. Several theories have been advanced to account for the functions of this ‘core network’104,107,108. For example, Hassabis and Maguire107 suggested that this network supports ‘scene construction’ — the process of mentally generating and maintaining a complex and coherent scene or event — which they believe underpins functions such as autobiographical memory, navigation and thinking about the future. Linking memory and navigation with imagination and thinking about the future, and placing them in the wider context of cognition, opens up new perspectives for understanding the role of the RSC. For example, a recent study used fMRI to examine brain activation during retrieval of autobiographical events, of episodes from a movie and of real news clips, as well as previously imagined events of all three types109 (FIG. 2). Crucially, activation patterns in the RSC differed from those in posterior cingulate areas 23 and 31: parts of areas 23 and 31 were more active during retrieval of real events than during retrieval of imagined events across all categories, which suggests that re-experiencing real events modulates activity in this area (FIG. 2). By contrast, the ventral portion of the parietal-occipital sulcus, extending into the left and right RSC, was activated specifically by real and imagined autobiographical events that involved the participant personally. It is possible that the recollection of (real or imagined) autobiographical events requires participants to constantly update their first-person perspective relative to the changing spatial context of the environment as they progress through the unfolding event. By contrast, the detached, observer perspective from which movie and most news events are recalled requires less self-referencing to specific spatial contexts. This interpretation fits with the proposed function of the RSC in spatial updating and translating between egocentric and allocentric frames of reference outlined above.

Conclusions and future directions Early studies characterized the memory impairments following RSC damage as disconnection effects resulting from the interruption of pathways from the hippocampus to either the anterior thalamic nuclei59 or the frontal cortex 18. Although anatomical studies give some credence to this view, they also highlight its shortcomings. As illustrated in FIG. 1, some key mnemonic structures link through the RSC, but they also have direct interconnections. Consequently, the focus has shifted to the contributions that the RSC per se makes to memory. This shift is important given the growing evidence of pervasive RSC dysfunction in conditions like Alzheimer’s disease (BOX 2); such dysfunction might contribute to the cognitive deficits from the earliest stages of this disease110,111. Determining the relationship between RSC dysfunction and symptoms in Alzheimer’s disease is complicated by the potential for ‘covert’ pathology in the RSC (BOX 1). Both functional neuroimaging and clinical studies suggest that the RSC is involved in a range of cognitive functions, although there is a continued need for greater anatomical precision in these studies. Indeed, the propensity for RSC activation in fMRI studies makes it all the more difficult to determine its precise functions.



REVIEWS a

Day 1

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Day 15 (fMRI)

Experience Recall the Recall the autobiographical events autobiographical events autobiographical events Real events

Watch a movie

Recall events from the movie

Recall the events from the movie

Watch news clips

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b

Left hemisphere Self > non-self Real > imagined

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RS > IS Film > news

Self > non-self and RS > IS All 6 event types

Figure 2 | segregating the specific contributions of the retrosplenial cortex Nature Reviews | Neuroscience using functional MRi. a | Two weeks before scanning, participants experienced autobiographical events, viewed a movie and watched recent news clips. One week later they recalled events of all three types and also imagined additional events: autobiographical events that had not happened but could happen, events that could have happened in the movie but did not and news events that were plausible but had never occurred. The following week, participants recalled the six event types during functional MRI. Using this design it was possible to divide posterior medial midline regions into functionally separable areas. b | The retrosplenial cortex was particularly responsive to any experiences (real or imagined) that personally involved the participant (red). By contrast, a more dorsal posterior cingulate region (areas 23 and 31) was engaged by real self-related (RS) events and much less so by imagined self-related (IS) events (yellow). In fact, activity in this region was higher whenever real events (whether autobiographical, from the movie or from the news) were recalled than when imagined events were recalled (blue), even when vividness, accuracy of recall and task difficulty were matched. Part b is reproduced, with permission, from ReF. 109 © (2009) Elsevier.

Therefore, fMRI studies should be complemented by more comprehensive neuropsychological investigations of patients with RSC damage. For instance, little is known about the RSC’s role in semantic versus episodic memory, in recollection versus familiarity or in recognition versus recall, despite predictions112 that RSC damage will preferentially disrupt episodic memory, recollection and recollection-based recognition. neuroimaging data have provided some support for these predictions, but they implicate both the RSC and adjacent parietal areas and the evidence thus remains inconclusive113. Furthermore, although impairments in autobiographical memory have been described in some patients with damage involving the RSC59,62, they have not been tested with the same

degree of rigor as impairments associated with hippocampal pathology 114–116, and nothing is known about how the RSC contributes to the detail, vividness or spatial context of memory for past experiences. The potential value of more detailed analyses of autobiographical memory is underlined by evidence from mouse studies which suggests that a dynamic reorganization of remote spatial memory involves complementary activity of the hippocampus and the RSC117. It does, however, seem incontrovertible that the RSC is important for spatial navigation. one prominent hypothesis purports that the RSC is involved in translating information between allocentric (world-centred) and egocentric (self-centred) reference frames61,67,68,77,78. This class of model (FIG. 3) accommodates many anatomical and behavioural findings. For example, patients with RSC damage fail to use directional information, and studies of RSC lesions in rats reveal its involvement in a range of spatial tasks, including some that involve direction problems. The relatively modest spatial deficits in rats with RSC lesions do, however, indicate that other regions can compensate for RSC removal. Meanwhile, its direct visual and proprioceptive inputs, together with findings from fMRI studies in humans90, suggest that the RSC might be of particular importance when different spatial strategies are integrated or updated, for example when mnemonic information is combined with path integration39. A resulting prediction, which is supported by findings from recent animal studies 29,37,118, is that RSC lesion effects consistently emerge when there are conflicting spatial cues that require an animal to switch attention to just one of them (for example, dark versus light, local versus distal cues or allocentric versus egocentric (head direction) information). This switching between spatial codes can be seen as a forerunner of the role in translating between viewpoint-dependent and viewpoint-independent frames of reference. Perhaps the biggest challenge lies in linking the RSC’s role in navigation with its involvement in episodic memory, imagination and thinking about the future while being precise about its specific contributions. A version of the RSC ‘translation model’ has been extended to a number of these domains77,78 through the suggestion that the RSC uses information about current heading direction to translate allocentric (hippocampal) representations into egocentric (parietal cortical) representations — this would be required to reconstruct a scene or memory or to imagine a new perspective. However, this model and its assumptions remain essentially untested. For instance, does RSC damage specifically disrupt translations between hippocampal and parietal codes? If so, does this occur because of degradations in both egocentric and allocentric representations, or is the deficit selective to the actual process of changing perspectives? If the RSC does not perform translations, might it store its own distinct representations of the environment 68,74? Could its core function be related to scene processing 68,94–96 and, if so, how might this fit with theories such as scene construction107? These



REVIEWS ATN Head direction, theta Prefrontal cortex Executive, scene manipulation

Parietal cortex Body-oriented information

Egocentric framework

Retrosplenial cortex Scene translation

Perirhinal cortex Object-based information Occipital cortex Visual information Hippocampus Event within a scene, scene construction

Parahippocampal Scene-based information Allocentric framework

Figure 3 | The key anatomical and functional relationships of the retrosplenial cortex. Effective episodic Nature Reviews | Neuroscience memory, navigation and future thinking all require the ability to integrate and manipulate different frameworks of information, for example egocentric (self-centred) and allocentric (world-centred) frameworks. By virtue of its principal connections, the retrosplenial cortex is uniquely placed to enable translation within these domains. ATN, anterior thalamic nuclei.

key questions could be addressed by assessing patients with RSC damage on their ability to imagine fictitious and future experiences and on how they process scenes, and by using fMRI studies with task designs that specifically target the RSC. The RSC has too long 1. 2.

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Acknowledgements

The authors would like to thank A. Perrotin, N. Burgess, M. Greicius and L. Woods. E.A.M. is supported by the Wellcome Trust. S.D.V. is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) David Phillips Research Fellowship. S.D.V. and J.P.A.’s contributions have also been supported by a BBSRC grant (BB/D002001/1).

DATABASES Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene Egr1 | Fos

FURTHER INFORMATION Seralynne D. Vann’s homepage: http://www.cardiff.ac.uk/psych/vann John P. Aggleton’s homepage: http://www.cardiff.ac.uk/psych/aggleton Eleanor A. Maguire’s homepage: http://www.fil.ion.ucl.ac.uk/Maguire All liNks ARe AcTive iN The oNliNe pdf


o n l I n E o n ly ToC Blurb

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What does the retrosplenial cortex do? Seralynne D. Vann, John P. Aggleton and Eleanor A. Maguire Vann and colleagues review anatomical, lesion and imaging studies suggesting that the retrosplenial cortex is involved in navigation and memory. They propose that it achieves this function through a key role in scene construction by translating between different perspectives of the environment.

At a glance • The main connectional properties of the retrosplenial cortex (RSC) (Brodmann areas 29 and 30) are conserved across mammalian species. Key features include reciprocal links with the hippocampal formation, the parahippocampal region, the limbic thalamus and the parietal cortex. • Functional studies of the RSC of rodents consistently point to a role in learning and navigation. These roles are thought to be acted out in concert with the hippocampal formation and the limbic thalamus. • neuropsychological studies of the human RSC remain problematic owing to difficulties in isolating this area. nevertheless, studies of patients with unilateral retrosplenial damage suggest an important contribution to navigation, whereas bilateral retrosplenial damage is often associated with anterograde and varying degrees of retrograde amnesia. • There is consistent evidence that the RSC suffers very early pathological changes in the progression of mild cognitive impairment and Alzheimer’s disease. These pathological changes are reflected by a decrease in metabolic activity. • Functional neuroimaging studies of healthy volunteers suggest broad involvement of the RSC in an array of cognitive abilities, with an almost ubiquitous engagement by tests of spatial navigation and episodic (autobiographical) memory. • These patterns of retrosplenial activity might relate to a key role in scene construction — the process of mentally generating and manipulating a complex or coherent scene. This process may underpin functions such as autobiographical memory, navigation and thinking about the future. • one specific hypothesis relating to the retrosplenial cortex is that it translates between different perspectives of the external world, namely viewpoint-dependent and viewpoint-independent frames of reference.

Institutes of Health (Bethesda, Maryland). Through a combination of anatomical, behavioural and clinical investigations he has studied the brain systems that support episodic memory in humans and spatial memory in rodents. His particular focus is on the functional interactions between the temporal lobe and the medial diencephalon. Eleanor A. Maguire is a Wellcome Trust Senior Research Fellow and Professor of Cognitive neuroscience at the Wellcome Trust Centre for neuroimaging, university College London, uK. She heads the Memory and Space research laboratory at the Centre, where her team seeks to understand how spatial and episodic memories are formed, represented and recollected by the human brain.

Bios Seralynne Vann obtained her B.Sc. in experimental psychology from the university of Sussex, uK, and was subsequently awarded her Ph.D. in behavioural neuroscience from Cardiff university, uK. Her research focuses on the neural basis of learning and memory and on how the limbic midbrain, medial diencephalon, medial temporal lobe and related cortical structures interact to support memory. Key interests are the mammillary bodies, and her research on this structure is currently supported by a fellowship from the Biotechnology and Biological Sciences Research Council, uK. John Patrick Aggleton has been Professor of Cognitive neuroscience at Cardiff university since 1994. Prior to that he was a Lecturer and Senior Lecturer at Durham university and before that a Fellow at the Laboratory of neuropsychology at the uS national

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What does the retrosplenial cortex do?

What does the retrosplenial cortex do?

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