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Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults.HighlightsAge-related inverted U-shaped curve of hippocampal myelin/neurite packingObesity-related reductions of hippocampal myelin/neurite packing and size/complexityAPOE modifies the effects of obesity on hippocampal size/complexityAge-related slowing of spatial navigationNo APOE, family history, or obesity effects on cognition

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily mediated through the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts are moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. We did, however, find subiculum complex-BNST tract microstructure associations with BMI, age, and sex. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer’s disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38–71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.

The hippocampus is essential for normal memory but does not act in isolation. The anterior thalamic nuclei may represent one vital partner. Using DREADDs, the behavioral consequences of transiently disrupting anterior thalamic function were examined, followed by inactivation of the dorsal subiculum. Next, the anterograde transport of an adeno-associated virus expressing DREADDs was paired with localized intracerebral infusions of a ligand to target specific input pathways. In this way, the direct projections from the anterior thalamic nuclei to the dorsal hippocampal formation were inhibited, followed by separate inhibition of the dorsal subiculum projections to the anterior thalamic nuclei. To assay spatial working memory, all animals performed a reinforced T-maze alternation task, then a more challenging version that nullifies intramaze cues. Across all four experiments, deficits emerged on the spatial alternation task that precluded the use of intramaze cues. Inhibiting dorsal subiculum projections to the anterior thalamic nuclei produced the severest spatial working memory deficit. This deficit revealed the key contribution of dorsal subiculum projections to the anteromedial and anteroventral thalamic nuclei for the processing of allocentric information, projections not associated with head-direction information. The overall pattern of results provides consistent causal evidence of the two-way functional significance of direct hippocampal-anterior thalamic interactions for spatial processing. At the same time, these findings are consistent with hypotheses that these same, reciprocal interactions underlie the common core symptoms of temporal lobe and diencephalic anterograde amnesia. SIGNIFICANCE STATEMENT It has long been conjectured that the anterior thalamic nuclei might be key partners with the hippocampal formation and that, respectively, they are principally responsible for diencephalic and temporal lobe amnesia. However, direct causal evidence for this functional relationship is lacking. Here, we examined the behavioral consequences of transiently silencing the direct reciprocal interconnections between these two brain regions on tests of spatial learning. Disrupting information flow from the hippocampal formation to the anterior thalamic nuclei and vice versa impaired performance on tests of spatial learning. By revealing the conjoint importance of hippocampal-anterior thalamic pathways, these findings help explain why pathology in either the medial diencephalon or the medial temporal lobes can result in profound anterograde amnesic syndromes.

Retrosplenial cortex contains two principal subdivisions, area 29 (granular) and area 30 (dysgranular). Their respective anatomical connections in the rat brain reveal that area 29 is the primary recipient of hippocampal and parahippocampal spatial and contextual information while area 30 is the primary interactor with current visual information. Lesion studies and measures of neuronal activity in rodents indicate that retrosplenial cortex helps to integrate space from different perspectives, e.g., egocentric and allocentric, providing landmark and heading cues for navigation and spatial learning. It provides a repository of scene information that, over time, becomes increasingly independent of the hippocampus. These processes, reflect the interactive actions between areas 29 and 30, along with their convergent influences on cortical and thalamic targets. Consequently, despite their differences, both areas 29 and 30 are necessary for an array of spatial and learning problems.

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology. SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.

Retrosplenial cortex (RSC) lies at the interface between perceptual and memory networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and connections, as a step towards understanding their functions. gRSC is more closely connected to the hippocampal system, in which theta-band local field potential oscillations are prominent. We therefore compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to examine whether differences in neural coding between RSC subregions might reflect differential inputs from the anterior thalamus, which is a prominent source of RSC afferents. We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC or both.HighlightsThe two retrosplenial cortex subregions, gRSC and dRSC, differ in their temporal firing characteristics and relation to theta oscillations.There are differential afferents from the anteroventral thalamic nucleus to gRSC and dRSC, with the dorsomedial subnucleus projecting selectively to gRSC.The anteroventral thalamus-retrosplenial cortex circuitry thus comprises two functionally and anatomically distinct but connected circuits, differentially connected to the hippocampal system, that may support the integration of cognitive and perceptual information.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38-71 years). Aging was associated with apparent glia but not neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa. Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.

In a changing environment, organisms need to decide when to select items that resemble previously rewarded stimuli and when it is best to switch to other stimulus types. Here, we used chemogenetic techniques to provide causal evidence that activity in the rodent anterior cingulate cortex and its efferents to the anterior thalamic nuclei modulate the ability to attend to reliable predictors of important outcomes. Rats completed an attentional set-shifting paradigm that first measures the ability to master serial discriminations involving a constant stimulus dimension that reliably predicts reinforcement (intradimensional-shift), followed by the ability to shift attention to a previously irrelevant class of stimuli when reinforcement contingencies change (extradimensional-shift). Chemogenetic disruption of the anterior cingulate cortex (Experiment 1) as well as selective disruption of anterior cingulate efferents to the anterior thalamic nuclei (Experiment 2) impaired intradimensional learning but facilitated 2 sets of extradimensional-shifts. This pattern of results signals the loss of a corticothalamic system for cognitive control that preferentially processes stimuli resembling those previously associated with reward. Previous studies highlight a separate medial prefrontal system that promotes the converse pattern, that is, switching to hitherto inconsistent predictors of reward when contingencies change. Competition between these 2 systems regulates cognitive flexibility and choice.

Large-scale simultaneous in vivo recordings of neurons in multiple brain regions raises the question of the probability of recording direct interactions of neurons within, and between, multiple brain regions. In turn, identifying inter-regional communication rules between neurons during behavioural tasks might be possible, assuming conjoint activity between neurons in connected brain regions can be detected. Using the hypergeometric distribution, and employing anatomically-tractable connection mapping between regions, we derive a method to calculate the probability distribution of ‘recordable’ connections between groups of neurons. This mathematically-derived distribution is validated by Monte Carlo simulations of directed graphs representing the underlying anatomical connectivity structure. We apply this method to simulated graphs with multiple neurons, based on counts in rat brain regions, and to connection matrices from the Blue Brain model of the mouse neocortex connectome. Overall, we find low probabilities of simultaneously-recording directly interacting neurons in vivo in anatomically-connected regions with standard (tetrode-based) approaches. We suggest alternative approaches, including new recording technologies and summing neuronal activity over larger scales, offer promise for testing hypothesised interregional communication and source transformation rules.

Appendix: Final 40 Research Priorities included in survey of psychological scientists is available at https://bpspsychub.onlinelibrary.wiley.com/doi/10.1111/bjop.12468#bjop12468-app-0001-title . Copyright © 2020 The Authors. The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) that has caused the coronavirus disease 2019 (COVID‐19) pandemic represents the greatest international biopsychosocial emergency the world has faced for a century, and psychological science has an integral role to offer in helping societies recover. The aim of this paper is to set out the shorter‐ and longer‐term priorities for research in psychological science that will (a) frame the breadth and scope of potential contributions from across the discipline; (b) enable researchers to focus their resources on gaps in knowledge; and (c) help funders and policymakers make informed decisions about future research priorities in order to best meet the needs of societies as they emerge from the acute phase of the pandemic. The research priorities were informed by an expert panel convened by the British Psychological Society that reflects the breadth of the discipline; a wider advisory panel with international input; and a survey of 539 psychological scientists conducted early in May 2020. The most pressing need is to research the negative biopsychosocial impacts of the COVID‐19 pandemic to facilitate immediate and longer‐term recovery, not only in relation to mental health, but also in relation to behaviour change and adherence, work, education, children and families, physical health and the brain, and social cohesion and connectedness. We call on psychological scientists to work collaboratively with other scientists and stakeholders, establish consortia, and develop innovative research methods while maintaining high‐quality, open, and rigorous research standards. Christopher Armitage's contribution is supported by the NIHR Manchester Biomedical Research Centre and the NIHR Greater Manchester Patient Safety Translational Research Centre. Til Wykes would like to acknowledge the support of her NIHR Senior Investigator Award.

Despite considerable interest in the properties of the cingulum bundle, descriptions of the composition of this major pathway in the rodent brain have not kept pace with advances in tract tracing. Using complementary approaches in rats and mice, this study examined the dense, reciprocal connections the anterior thalamic nuclei have with the cingulate and retrosplenial cortices, connections thought to be major contributors to the rodent cingulum bundle. The rat data came from a mixture of fluorescent and viral tracers, some injected directly into the bundle. The mouse data were collated from the Allen Mouse Brain Atlas. The projections from the three major anterior thalamic nuclei occupied much of the external medullary stratum of the cingulum bundle, where they were concentrated in its more medial portions. These anterior thalamic projections formed a rostral-reaching basket of efferents prior to joining the cingulum bundle, with anteromedial efferents taking the most rostral routes, often reaching the genu of the corpus callosum, while anterodorsal efferents took the least rostral route. In contrast, the return cortico-anterior thalamic projections frequently crossed directly through the bundle or briefly joined the internal stratum of the cingulum bundle, often entering the internal capsule before reaching the anterior thalamus. These analyses confirm that anterior thalamic connections comprise an important component of the rodent cingulum bundle, while also demonstrating the very different routes used by thalamo-cortical and cortico-thalamic projections. This information reveals how the composition of the cingulum bundle alters along its length.

Highlights • Despite overlapping cortical connectivity, different dorsal/ventral gradients. • Common domains of function but different contributions. • Primacy of anterior thalamic - retrosplenial interactions. • Primacy of nucleus reuniens - frontal interactions. • Contrasting patterns of hippocampal - thalamic interactivity., Two thalamic sites are of especial significance for understanding hippocampal – diencephalic interactions: the anterior thalamic nuclei and nucleus reuniens. Both nuclei have dense, direct interconnections with the hippocampal formation, and both are directly connected with many of the same cortical and subcortical areas. These two thalamic sites also contain neurons responsive to spatial stimuli while lesions within these two same areas can disrupt spatial learning tasks that are hippocampal dependent. Despite these many similarities, closer analysis reveals important differences in the details of their connectivity and the behavioural impact of lesions in these two thalamic sites. These nuclei play qualitatively different roles that largely reflect the contrasting relative importance of their medial frontal cortex interactions (nucleus reuniens) compared with their retrosplenial, cingulate, and mammillary body interactions (anterior thalamic nuclei). While the anterior thalamic nuclei are critical for multiple aspects of hippocampal spatial encoding and performance, nucleus reuniens contributes, as required, to aid cognitive control and help select correct from competing memories.

SummaryHippocampal function relies on the anterior thalamic nuclei, but the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded subicular cells in rats with either permanent (N-methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. Bayesian and other statistical analyses underscored the notable absence of the diverse spatial signals normally found in the subiculum, including place cells, following permanent anterior thalamic lesions. Likewise, there was marked disruption of these diverse spatial signals during transient lesions. By contrast, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Anterior thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance, while leaving a non-spatial recognition memory task unaffected. These findings, which help explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of subiculum function and reveal its dependence on anterior thalamic signalling.Graphical Abstract

Summary Hippocampal function relies on the anterior thalamic nuclei, yet the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded subiculum cells in rats with either permanent ( N -methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. The diverse spatial signals normally found in the subiculum, including place cells, disappeared following permanent thalamic lesions and showed marked disruption during transient lesions. Meanwhile, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance levels, while leaving a non-spatial recognition memory task unaffected. These findings, which help to explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of subiculum function, and reveal its dependence on anterior thalamic signalling.

The fornix is a key tract of the hippocampal formation, whose status is presumed to contribute to age-related cognitive decline. The precommissural and postcommissural fornix subdivisions form respective basal forebrain/frontal and diencephalic networks that may differentially affect aging and cognition. We employed multi-parametric magnetic resonance imaging (MRI) including neurite orientation density and dispersion imaging, quantitative magnetization transfer (qMT), and T1-relaxometry MRI to investigate the microstructural properties of these fornix subdivisions and their relationship with aging and cognition in 149 asymptomatic participants (38–71 years). Aging was associated with increased free water signal and reductions in myelin-sensitive R1and qMT indices but no apparent axon density differences in both precommissural and postcommissural fibers. Precommissural relative to postcommissural fibers showed a distinct microstructural pattern characterised by larger free water signal and axon orientation dispersion, with lower apparent myelin and axon density. Furthermore, differences in postcommissural microstructure were related to performance differences in object-location paired-associate learning. These results provide novel in vivo neuroimaging evidence for distinct microstructural properties of precommissural and postcommissural fibers that are consistent with their anatomy as found in axonal tracer studies, as well as for a contribution of postcommissural fibers to the learning of spatial configurations.

There is a dearth of freely-available, standardised open source analysis tools available for the analysis of neuronal signals recorded in vivo in the freely-behaving animal. In response, we have developed a freely-available, open-source toolbox, NeuroChaT (Neuron Characterisation Toolbox), specifically addressing this lacuna. Although we have particularly emphasised single unit analyses for spatial coding, NeuroChaT also characterises rhythmic properties of units and their dynamics associated with local field potential signals. NeuroChaT was developed using Python and facilitates a complete pipeline from automation of analysis to producing and managing publication-quality figures. Additionally, we have adopted a platform-independent format (Hierarchical Data Format version 5) for storing recorded and analysed data. By providing an easy-to-use software package, we aim to simplify the adoption of standardised analyses for behavioural neurophysiology and facilitate open data sharing and collaboration between laboratories.

Both nucleus reuniens and the anterior thalamic nuclei are densely interconnected with medial cortical and hippocampal areas, connections that reflect their respective contributions to learning and memory. To better appreciate their comparative roles, pairs of different retrograde tracers were placed in these two thalamic sites in adult rats. Both thalamic sites receive modest cortical inputs from layer V that contrasted with much denser projections from layer VI. Despite frequent overlap in layer VI, ventral prefrontal and anterior cingulate inputs to nucleus reuniens were concentrated in the deepest sublayer (VIb). Meanwhile, inputs to the anterior thalamic nuclei originated more evenly from both sublayers VIa and VIb, with the result that they were often located more superficially than the projections to nucleus reuniens. Again, while the many hippocampal (subiculum) neurons projecting to nucleus reuniens and the anterior thalamic nuclei were partially intermingled within the deep cellular parts of the subiculum, cells projecting to nucleus reuniens consistently tended to lie even deeper, i.e., immediately adjacent to the alveus. Variable numbers of double-labelled cells were present in those cortical and subicular portions where the two cell populations intermingled, though they remained in a minority. Our data also show how projections to these two thalamic sites are organized in opposing dorsal/ventral and rostral/caudal gradients across both the cortex and hippocampal formation. While the anterior thalamic nuclei are preferentially innervated by dorsal cortical sites, more ventral frontal sites preferentially reach nucleus reuniens. These anatomical differences may underpin the complementary cognitive functions of these two thalamic areas. Significance statement Both nucleus reuniens and the anterior thalamic nuclei link frontal cortical areas with the hippocampal formation. We show that the cortical and hippocampal projections to these thalamic sites show intermingled but opposing gradients of origin across the cerebral cortex (anterior thalamic – more dorsal, nucleus reuniens – more ventral), with their respective afferents typically arising from different neurons. There is also a repeated tendency across cortical areas for nucleus reuniens inputs to arise from the very deepest layer (VIb), while anterior thalamic inputs are often slightly more superficial, located across VIb and VIa. A similar depth distinction is again seen in the subiculum. These patterns indicate a separation of information reaching these two thalamic sites, alongside functional divisions within cortical layer VI.

Altres ajuts: This work was supported by a Biotechnology and Biological Sciences Research Council research grant awarded to JA, AN, SV and FS (BB/L021005/1), a Sêr Cymru fellowship (80762-CU-080) to AR, a Wellcome Trust Strategic Award (100202/z/12/z) to Michael J. Owen, J.H., Lawrence Wilkinson, Adrian Harwood, Meng Li, David Linden, John Aggleton, Vincenzo Crunelli, and Derek Jones, and a Wellcome Trust ISSF Seedcorn Award (105613/Z/14/Z) to A.R. S.V. is funded by a Wellcome Trust Senior Research Fellowship (212273/Z/18/Z). The rodent retrosplenial cortex (RSC) functions as an integrative hub for sensory and motor signals, serving roles in both navigation and memory. While RSC is reciprocally connected with the sensory cortex, the form in which sensory information is represented in the RSC and how it interacts with motor feedback is unclear and likely to be critical to computations involved in navigation such as path integration. Here, we used 2-photon cellular imaging of neural activity of putative excitatory (CaMKII expressing) and inhibitory (parvalbumin expressing) neurons to measure visual and locomotion evoked activity in RSC and compare it to primary visual cortex (V1). We observed stimulus position and orientation tuning, and a retinotopic organization. Locomotion modulation of activity of single neurons, both in darkness and light, was more pronounced in RSC than V1, and while locomotion modulation was strongest in RSC parvalbumin-positive neurons, visual-locomotion integration was found to be more supralinear in CaMKII neurons. Longitudinal measurements showed that response properties were stably maintained over many weeks. These data provide evidence for stable representations of visual cues in RSC that are spatially selective. These may provide sensory data to contribute to the formation of memories of spatial information.

Memory research remains focused on just a few brain structures-in particular, the hippocampal formation (the hippocampus and entorhinal cortex). Three key discoveries promote this continued focus: the striking demonstrations of enduring anterograde amnesia after bilateral hippocampal damage; the realization that synapses in the hippocampal formation are plastic e.g., when responding to short bursts of patterned stimulation ("long-term potentiation" or LTP); and the discovery of a panoply of spatially-tuned cells, principally surveyed in the hippocampal formation (place cells coding for position; head-direction cells, providing compass-like information; and grid cells, providing a metric for 3D space). Recent anatomical, behavioral, and electrophysiological work extends this picture to a growing network of subcortical brain structures, including the anterior thalamic nuclei, rostral midline thalamic nuclei, and the claustrum. There are, for example, spatially-tuned cells in all of these regions, including cells with properties similar to place cells of the hippocampus proper. These findings add new perspectives to what had been originally been proposed-but often overlooked-half a century ago: that damage to an extended network of structures connected to the hippocampal formation results in diencephalic amnesia. We suggest these new findings extend spatial signaling in the brain far beyond the hippocampal formation, with profound implications for theories of the neural bases of spatial and mnemonic functions.

The claustrum is a subcortical nucleus that exhibits dense connectivity across the neocortex. Considerable recent progress has been made in establishing its genetic and anatomical characteristics, however a core, contentious issue that regularly presents in the literature pertains to the rostral extent of its anatomical boundary. The present study addressed this issue in the rat brain.Using a combination of immunohistochemistry and neuronal tract tracing, we have examined the expression profiles of several genes that have previously been identified as exhibiting a differential expression profile in the claustrum relative to the surrounding cortex. The expression profiles of parvalbumin, crystallin mu (Crym), and guanine nucleotide binding protein (G protein), gamma 2 (Gng2) were assessed immunohistochemically alongside, or in combination with cortical anterograde, or retrograde tracer injections. Retrograde neuronal tracer injections into various thalamic nuclei were used to further establish the rostral border of the claustrum.Expression of all three markers delineated a nuclear boundary that extended considerably (~500 μm) beyond the anterior horn of the neostriatum. Cortical retrograde and anterograde neuronal tracer injections, respectively, revealed distributions of cortically-projecting claustral neurons and cortical efferent inputs to the claustrum that overlapped with the gene marker-derived claustrum boundary. Finally, retrograde tracer injections centred in nucleus reuniens, whilst including the rhomboid, mediodorsal and centromedial nuclei, revealed that insular cortico-thalamic projections encapsulated a claustral area, with strongly diminished cell label, that corresponded to the claustrum.

Perimeters are an important part of the environment, delimiting its geometry. Here, we investigated how perimeters (vertical walls; vertical drops) affect neuronal responses in the rostral thalamus (the anteromedial and parataenial nuclei in particular). We found neurons whose firing patterns reflected the presence of walls and drops, irrespective of arena shape. Their firing patterns were stable across multiple sleep-wake cycles and were independent of ambient lighting conditions. Thus, rostral thalamic nuclei may participate in spatial representation by encoding the perimeters of environments.

The integrative memory model contains multiple subsystems. In this commentary, the processes within these subsystems are questioned. First, the assumption that familiarity largely reflects perceptual fluency is examined. Next, the distinction between “process” and “representational” models of temporal lobe function is challenged. Finally, the “relational representation core system” (or “extended hippocampal system”), which is central to the model, is especially sketchy. Here, I highlight key questions to be addressed in order to understand this system's role in trace formation.

Rodents will spontaneously learn the location of an individual object, an ability captured by the object-in-place test. This review considers the network of structures supporting this behavioural test, as well as some potential confounds that may affect interpretation. A hierarchical approach is adopted, as we first consider those brain regions necessary for two simpler, ‘precursor’ tests (object recognition and object location). It is evident that performing the object-in-place test requires an array of areas additional to those required for object recognition or object location. These additional areas include the rodent medial prefrontal cortex and two thalamic nuclei (nucleus reuniens and the medial dorsal nucleus), both densely interconnected with prefrontal areas. Consequently, despite the need for object and location information to be integrated for the object-in-place test, for example, via the hippocampus, other contributions are necessary. These contributions stem from how object-in-place is a test of associative recognition, as none of the individual elements in the test phase are novel. Parallels between the structures required for object-in-place and for recency discriminations, along with a re-examination of the demands of the object-in-place test, signal the integration of temporal information within what is usually regarded as a spatial-object test.

The rodent retrosplenial cortex is known to be vital for spatial cognition, but evidence has also pointed to a role in processing nonspatial information. It has been suggested that the retrosplenial cortex may serve as a site of integration of incoming sensory information. To examine this proposal, the current set of experiments assessed the impact of excitotoxic lesions in the retrosplenial cortex on two behavioral tasks that tax animals' ability to process multiple and overlapping environmental stimuli. In Experiment 1, rats with retrosplenial lesions acquired a negative patterning discrimination, a form of configural learning that can be solved only by learning the conjunction of cues. Subsequent transfer tests confirmed that both the lesion and control animals had solved the task by using configural representations. Furthermore, in Experiment 2, a 2nd cohort of retrosplenial lesion animals successfully acquired conditioned inhibition. Nevertheless, the same animals failed a subsequent summation test that assesses the ability to transfer what has been learned about one stimulus to another stimulus in the absence of reinforcement. Taken together, these results suggest that in the nonspatial domain, the retrosplenial cortex is not required for forming associations between multiple or overlapping environmental stimuli and, consequently, retrosplenial engagement in such processes is more selective than was previously envisaged. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Aging leads to gray and white matter decline but their causation remains unclear. We explored two broad classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative multi-modal MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38 - 71 years). Aging was associated with apparent glia but not axon density damage in the fornix. Mediation analysis unambiguously supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlation between age and hippocampal damage disappears, but not vice versa. Fornix and hippocampal tissue loss were both associated with reductions in episodic memory performance. The implications of these findings for neuroglia and neurodegenerative models of aging and late onset dementia are discussed.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides inter-hemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted MRI (DW-MRI) and white matter tractography to reconstruct the DHC across both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived Diffusion Tensor MRI (DT-MRI) metrics from the DHC in a large sample of human subjects to investigate whether inter-individual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC was correlated with performance in a standardised episodic memory task; an effect that was not reproduced in a comparison commissure tract – the anterior commissure. These findings highlight a role for the DHC in episodic memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Perirhinal cortex lesions in rats consistently impair object recognition memory, as shown by the failure to spend more time exploring a novel object in preference to a familiar object in a spontaneous object recognition task. Nevertheless, these same lesioned rats show normal levels of object exploration during the initial ‘Sample Phase’, when first familiarized to a novel object. This consistent finding is surprising as it indicates an intact ability to detect novelty. This apparent paradox was examined in greater detail using the ‘Bow-Tie maze’, which allows multiple, continuous trials within the same session. Experiments using this apparatus revealed that rats with perirhinal lesions show normal levels of object exploration when presented with just novel or just familiar objects to explore, i.e., when presented separately. Preference deficits reappear when novel and familiar objects are presented simultaneously. These results, which reveal novelty detection mechanisms outside perirhinal cortex, highlight how much is unknown about the mnemonic processes taxed by spontaneous object recognition tasks, despite their apparent simplicity. The results also reveal how the particular test procedure can lead to seemingly different findings.

The projections from the amygdala and hippocampus (including subiculum and presubiculum) to prefrontal cortex were compared using anterograde tracers injected into macaque monkeys (Macaca fascicularis, Macaca mulatta). Almost all prefrontal areas were found to receive some amygdala inputs. These connections, which predominantly arose from the intermediate and magnocellular basal nucleus, were particularly dense in parts of the medial and orbital prefrontal cortex. Contralateral inputs were not, however, observed. The hippocampal projections to prefrontal areas were far more restricted, being confined to the ipsilateral medial and orbital prefrontal cortex (within areas 11, 13, 14, 24a, 32, and 25). These hippocampal projections principally arose from the subiculum, with the fornix providing the sole route. Thus, while the lateral prefrontal cortex essentially receives only amygdala inputs, the orbital prefrontal cortex receives both amygdala and hippocampal inputs, though these typically target different areas. Only in medial prefrontal cortex do direct inputs from both structures terminate in common sites. But, even when convergence occurs within an area, the projections predominantly terminate in different lamina (hippocampal inputs to layer III and amygdala inputs to layers I, II, and VI). The resulting segregation of prefrontal inputs could enable the parallel processing of different information types in prefrontal cortex.

Many brain structures project to both the anteroventral thalamic nucleus and the anteromedial thalamic nucleus. In the present study, pairs of different tracers were placed into these two thalamic sites in the same rats to determine the extent to which these nuclei receive segregated inputs. Only inputs from the laterodorsal tegmental nucleus, the principal extrinsic cholinergic source for these thalamic nuclei, showed a marked degree of collateralization, with approximately 13% of all cells labeled in this tegmental area projecting to both nuclei. Elsewhere, double-labeled cells were very scarce, making up ∼1% of all labeled cells. Three general patterns of anterior thalamic innervation were detected in these other areas. In some sites, e.g., prelimbic cortex, anterior cingulate cortex, and secondary motor area, cells projecting to the anteromedial and anteroventral thalamic nuclei were closely intermingled, with often only subtle distribution differences. These same projections were also often intermingled with inputs to the mediodorsal thalamic nucleus, but again there was little or no collateralization. In other sites, e.g., the subiculum and retrosplenial cortex, there was often less overlap of cells projecting to the two anterior thalamic nuclei. A third pattern related to the dense inputs from the medial mammillary nucleus, where well-defined topographies ensured little intermingling of the neurons that innervate the two thalamic nuclei. The finding that a very small minority of cortical and limbic inputs bifurcates to innervate both anterior thalamic nuclei highlights the potential for parallel information streams to control their functions, despite arising from common regions.

The anterior thalamic nuclei form part of a network for episodic memory in humans. The importance of these nuclei for recognition and recency judgments remains, however, unclear. Rats with anterior thalamic nuclei lesions and their controls were tested on object recognition, along with two types of recency judgment. The spontaneous discrimination of a novel object or a novel odor from a familiar counterpart (recognition memory) was not affected by anterior thalamic lesions when tested after retention delays of 1 and 60 min. To measure recency memory, rats were shown two familiar objects, one of which had been explored more recently. In one condition, rats were presented with two lists (List A, List B) of objects separated by a delay, thereby creating two distinct blocks of stimuli. After an additional delay, rats were presented with pairs of objects, one from List A and one from List B (between-block recency). No lesion-induced deficit was apparent for recency discriminations between objects from different lists, despite using three different levels of task difficulty. In contrast, rats with anterior thalamic lesions were significantly impaired when presented with a continuous list of objects and then tested on their ability to distinguish between those items early and late in the same list (within-block recency). The contrasting effects on recognition and recency support the notion that interlinked hippocampal–anterior thalamic interconnections support aspects of both spatial and nonspatial learning, although the role of the anterior thalamic nuclei may be restricted to a subclass of recency judgments (within-block).

In humans recognition memory deficits, a typical feature of diencephalic amnesia, have been tentatively linked to mediodorsal thalamic nucleus (MD) damage. Animal studies have occasionally investigated the role of the MD in single-item recognition, but have not systematically analyzed its involvement in other recognition memory processes. In Experiment 1 rats with bilateral excitotoxic lesions in the MD or the medial prefrontal cortex (mPFC) were tested in tasks that assessed single-item recognition (novel object preference), associative recognition memory (object-in-place), and recency discrimination (recency memory task). Experiment 2 examined the functional importance of the interactions between the MD and mPFC using disconnection techniques. Unilateral excitotoxic lesions were placed in both the MD and the mPFC in either the same (MD + mPFC Ipsi) or opposite hemispheres (MD + mPFC Contra group). Bilateral lesions in the MD or mPFC impaired object-in-place and recency memory tasks, but had no effect on novel object preference. In Experiment 2 the MD + mPFC Contra group was significantly impaired in the object-in-place and recency memory tasks compared with the MD + mPFC Ipsi group, but novel object preference was intact. Thus, connections between the MD and mPFC are critical for recognition memory when the discriminations involve associative or recency information. However, the rodent MD is not necessary for single-item recognition memory.

Cognitive control, an important facet of human cognition, provides flexibility in response to varying behavioral demands. Previous work has focused on the role of prefrontal cortex, notably the anterior cingulate cortex. However, it is now clear that this is one node of a distributed cognitive network. In this emerging network view, structural connections are inherent elements, but their role has not been emphasized. Furthermore, lesion and functional imaging studies have contributed little knowledge about anatomical segregation, functional specialization, and behavioral importance of white matter connections. The relationship between cognitive control and microstructure of connections within the cingulum, a major white matter tract and conduit of projections to prefrontal sites, was probedin vivoin humans with diffusion MRI. Twenty healthy controls and 25 individuals with amnestic mild cognitive impairment (MCI), an early stage of age-associated cognitive deterioration, underwent cognitive testing, including several measures of cognitive control. For each individual, the anterior, middle, posterior, and parahippocampal portions of the cingulum bundle were reconstructed separately using deterministic tractography and anatomical landmarks. Microstructural variation in the left anterior cingulum was closely related to interindividual control based on verbal or symbolic rules. Errors in a task that involved maintenance of spatial rules were largely restricted to patients with MCI and were related, additionally, to right anterior cingulum microstructure. Cognitive control in MCI was also independently related to posterior parahippocampal connections. These results show how specific subpopulations of connections are critical in cognitive control and illustrate fine-grained anatomical specializations in the white matter infrastructure of this network.

Recognition memory, the discrimination of a novel from a familiar event, can be classified into item recognition and associative recognition. Item recognition concerns the identification of novel individual stimuli, while associative recognition concerns the detection of novelty that arises when familiar items are reconfigured in a novel manner. Experiments in rodents that have mapped the expression of immediate-early genes, e.g., c-fos, highlight key differences between these two forms of recognition memory. Visual item novelty is consistently linked to increased c-fos activity in just two brain sites, the perirhinal cortex and the adjacent visual association area Te2. Typically there are no hippocampal c-fos changes. In contrast, visual associative recognition is consistently linked to c-fos activity changes in the hippocampus, but not the perirhinal cortex. The lack of a c-fos perirhinal change with associative recognition presumably reflects the fact that the individual items in an array remain familiar, even though their combinations are unique. Those exceptions, when item recognition is associated with hippocampal c-fos changes, occur when rats actively explore novel objects. The increased engagement with objects will involve multisensory stimulus processing and potentially create conditions in which rats can readily learn stimulus attributes such as object location or object order, i.e., attributes involved in associative recognition. Correlations based on levels of immediate-early gene expression in the temporal lobe indicate that actively exploring novel stimuli switches patterns of entorhinal-hippocampal functional connectivity to emphasise direct entorhinal-dentate gyrus processing. These gene activity findings help to distinguish models of medial temporal lobe function.

The anterior/posterior (AP) positions of three subcortical regions; the amygdala, supra-optic nucleus of the hypothalamus and mammillary bodies, were estimated with respect to the skull in 35 rhesus monkeys (Macaca mulatta). The distances from the external auditory meatus, from which stereotaxic coordinates are typically derived, to these subcortical nuclei were found to be highly variable. In contrast the posterior tip of the sphenoid bone, which was visualized on lateral radiographs, provided a landmark at a remarkably constant AP distance from these nuclei. This landmark was used to guide a series of a amygdaloid lesions and injections. The accuracy of these operations strongly suggested that the posterior tip of the sphenoid bone could be used to predict not only the AP but also the height of the amygdala. It is proposed that this radiographic technique could be applied to other hypothalamic and basal forebrain regions.

Rats with electrolytic lesions placed in either the basolateral or corticomedial divisions of the amygdala acquired a conditioned taste aversion to sucrose. Comparisons with a surgical control group indicated that damage to the corticomedial amygdala did not alter the animals' performance, while damage in the basolateral nuclei resulted in a small but significant attenuation of the aversion. Furthermore, these amygdaloid lesions did not alter the acceptability of two quinine hydrochloride solutions (0.01% and 0.001%). The daily drinking behavior of the rats with basolateral amygdaloid lesions appeared consistent with the hypothesis that this lesion affected the animals' appreciation of the novelty of the sucrose solution, and hence attenuated the subsequent aversion.

A review of medial temporal lobe connections reveals three distinct groupings of hippocampal efferents. These efferent systems and their putative memory functions are: (1) The 'extended-hippocampal system' for episodic memory, which involves the anterior thalamic nuclei, mammillary bodies and retrosplenial cortex, originates in the subicular cortices, and has a largely laminar organisation; (2) The 'rostral hippocampal system' for affective and social learning, which involves prefrontal cortex, amygdala and nucleus accumbens, has a columnar organisation, and originates from rostral CA1 and subiculum; (3) The 'reciprocal hippocampal-parahippocampal system' for sensory processing and integration, which originates from the length of CA1 and the subiculum, and is characterised by columnar, connections with reciprocal topographies. A fourth system, the 'parahippocampal-prefrontal system' that supports familiarity signalling and retrieval processing, has more widespread prefrontal connections than those of the hippocampus, along with different thalamic inputs. Despite many interactions between these four systems, they may retain different roles in memory which when combined explain the importance of the medial temporal lobe for the formation of declarative memories.

The projections to the retrosplenial cortex (areas 29 and 30) from the hippocampal formation, the entorhinal cortex, perirhinal cortex, and amygdala were examined in two species of macaque monkey by tracking the anterograde transport of amino acids. Hippocampal projections arose from the subiculum and presubiculum to terminate principally in area 29. Label was found in layer I and layer III(IV), the former seemingly reflecting both fibers of passage and termination. While the rostral subiculum mainly projects to the ventral retrosplenial cortex, mid and caudal levels of the subiculum have denser projections to both the caudal and dorsal retrosplenial cortex. Appreciable projections to dorsal area 30 [layer III(IV)] were only seen following an extensive injection involving both the caudal subiculum and presubiculum. This same case provided the only example of a light projection from the hippocampal formation to posterior cingulate area 23 (layer III). Anterograde label from the entorhinal cortex injections was typically concentrated in layer I of 29a–c, though the very caudal entorhinal cortex appeared to provide more widespread retrosplenial projections. In this study, neither the amygdala nor the perirhinal cortex were found to have appreciable projections to the retrosplenial cortex, although injections in either medial temporal region revealed efferent fibers that pass very close or even within this cortical area. Finally, light projections to area 30V, which is adjacent to the calcarine sulcus, were seen in those cases with rostral subiculum and entorhinal injections. The results reveal a particular affinity between the hippocampal formation and the retrosplenial cortex, and so distinguish areas 29 and 30 from area 23 within the posterior cingulate region. The findings also suggest further functional differences within retrosplenial subregions as area 29 received the large majority of efferents from the subiculum. © 2012 Wiley Periodicals, Inc.

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water-maze, T-maze, and radial-arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation-mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay.

A major tool in understanding how the brain processes information is the analysis of neuronal output at each hierarchical level along the pathway of signal propagation. Theta rhythm and head directionality are the two main signals found across all levels of Papez’s circuit, which supports episodic memory formation. Here, we provide evidence that the functional interaction between both signals occurs at a subcortical level. We show that there is population of head-direction cells (39%) in rat anteroventral thalamic nucleus which exhibit rhythmic spiking in the theta range. This class of units, termed head-direction by theta (HD-by-theta) cells, discharged predominantly in spike trains at theta frequency (6-12Hz). The highest degree of theta rhythmicity was evident when the animal was heading/facing in the preferred direction, expressed by the Gaussian peak of the directional tuning curve. The theta-rhythmic mode of spiking was closely related to the firing activity of local theta-bursting cells. We also found that 32% of anteroventral theta-bursting cells displayed a head-directional modulation of their spiking. This crossover between theta and head-directional signals indicates that anterior thalamus integrates information related to heading and movement, and may therefore actively modulate hippocampo-dencephalic information processing.

The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms.

The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (alpha 7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive. The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (alpha 7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive.

Both clinical investigations and studies with animals reveal nuclei within the diencephalon that are vital for recognition memory (the judgment of prior occurrence). This review seeks to identify these nuclei and to consider why they might be important for recognition memory. Despite the lack of clinical cases with circumscribed pathology within the diencephalon and apparent species differences, convergent evidence from a variety of sources implicates a subgroup of medial diencephalic nuclei. It is supposed that the key functional interactions of this subgroup of diencephalic nuclei are with the medial temporal lobe, the prefrontal cortex, and with cingulate regions. In addition, some of the clinical evidence most readily supports dual-process models of recognition, which assume two independent cognitive processes (recollective-based and familiarity-based) that combine to direct recognition judgments. From this array of information a “multi-effect multi-nuclei” model is proposed, in which the mammillary bodies and the anterior thalamic nuclei are of preeminent importance for recollective-based recognition. The medial dorsal thalamic nucleus is thought to contribute to familiarity-based recognition, but this nucleus, along with various midline and intralaminar thalamic nuclei, is also assumed to have broader, indirect effects upon both recollective-based and familiarity-based recognition.

A mouse model of amyloid pathology was used to first examine using a cross sectional design changes in retrosplenial cortex activity in transgenic mice aged 5, 11, 17, and 23 months. Attention focused on: (1) overt amyloid labeled with β-amyloid((1-42)) and Congo Red staining, (2) metabolic function assessed by the enzyme, cytochrome oxidase, and (3) neuronal activity as assessed indirectly by the immediate-early gene (IEG), c-Fos. Changes in cytochrome oxidase and c-Fos activity were observed in the retrosplenial cortex in Tg2576 mice as early as 5 months of age, long before evidence of plaque formation. Subsequent analyses concentrating on this early dysfunction revealed at 5 months pervasive, amyloid precursor protein (APP)-derived peptide accumulation in the retrosplenial cortex and selective afferents (anterior thalamus, hippocampus), which was associated with the observed c-Fos hyporeactivity. These findings indicate that retrosplenial cortex dysfunction occurs during early stages of amyloid production in Tg2576 mice and may contribute to cognitive dysfunction.

Sequence learning and spatial alternation were examined in rats with anterior thalamic lesions or sham surgeries. There was a lesion-induced deficit in spatial alternation but not in sequence learning. During sequence learning, rats discriminated between six different sequentially presented compounds (e.g., reinforce A before B, but not B before A), composed of audio-visual elements. The solution required rats to learn both specific stimulus sequences and the reward contingencies associated with these specific temporal relationships. The failure of anterior thalamic lesions to affect the acquisition of this sequential configural task complements the recent finding that anterior thalamic lesions also spare the acquisition of a configural task involving specific stimulus pairings and their spatial relationships. These findings suggest that such “structural” learning is more reliant on cortico-hippocampal than thalamo-hippocampal interactions.

There is growing evidence that lesions of the anterior thalamic nuclei cause long-lasting intrinsic changes to retrosplenial cortex, with the potential to alter its functional properties. The present study had two goals. The first was to identify the pattern of changes in eight markers, as measured by in-situ hydridisation, in the granular retrosplenial cortex (area Rgb) following anterior thalamic lesions. The second was to use retrograde trans-neuronal tracing methods to identify the potential repercussions of intrinsic changes within granular retrosplenial cortex. In Experiment 1, adult rats received unilateral lesions of the anterior thalamic nuclei and were perfused four weeks later. Of the eight markers, four (c-fos, zif268, 5ht2rc, kcnab2) showed a very similar pattern of change, with decreased levels in superficial retrosplenial cortex (lamina II) in the ipsilateral hemisphere but little or no change in deeper layers (lamina V). A fifth marker (cox6b) showed a shift in activity levels in the opposite direction to the previous four markers. Three other markers (cox6a1, CD74, ncs-1) did not appear to change activity levels after surgery. The predominant pattern of change, a decrease in superficial cortical activity, points to potential alterations in plasticity and metabolism. In Experiment 2, wheat germ agglutin (WGA) was injected into the anterior thalamic nuclei in rats given different survival times, sometimes in combination with the retrograde, fluorescent tracer, Fast Blue. Dense aggregations of retrogradely labeled cells were always found in lamina VI of granular retrosplenial cortex, but additional labeled cells in lamina II were only found: 1) in WGA cases, i.e. never after Fast Blue injections, and 2) after longer WGA survival times (three days). These layer II Rgb cells are likely to have been trans-neuronally labeled, revealing a pathway from lamina II of Rgb to those deeper retrosplenial cells that project directly to the anterior thalamic nuclei.

Bilateral damage in the posterior cingulate region can induce anterograde amnesia. Identifying the potential contributions of the various areas within this heterogeneous region has, however, largely depended on animal research. Within the posterior cingulate region the retrosplenial cortex stands out by virtue of its dense interconnections with the hippocampal formation and anterior thalamic nuclei. Consistent with these connections is the finding from lesion studies in animals that the retrosplenial cortex is necessary for navigation and spatial learning, and that these functions occur in close conjunction with the hippocampal formation and anterior thalamus. Suggested functions include the creation and maintenance of scenes, linked to the switching between scenes based on different frameworks (e.g. egocentric versus allocentric). More fine-grain analyses suggest that there are functional distinctions between the subregions within the retrosplenial cortex, though these subregions are likely to then act as a coordinated unit. Other studies reveal that the retrosplenial cortex is highly sensitive to damage in distal sites, including damage to sites that do not have direct retrosplenial connections. The resultant retrosplenial dysfunctions, which include decreases in metabolic activity and a loss of plasticity, may contribute both to diencephalic and temporal lobe amnesias as well as to Alzheimer's disease.