The anterior thalamic nuclei: core components of a tripartite episodic memory system.

Standard models of episodic memory focus on hippocampal-parahippocampal interactions, with the neocortex supplying sensory information and providing a final repository of mnemonic representations. However, recent advances have shown that other regions make distinct and equally critical contributions to memory. In particular, there is growing evidence that the anterior thalamic nuclei have a number of key cognitive functions that support episodic memory. In this article, we describe these findings and argue for a core, tripartite memory system, comprising a 'temporal lobe' stream (centred on the hippocampus) and a 'medial diencephalic' stream (centred on the anterior thalamic nuclei) that together act on shared cortical areas. We demonstrate how these distributed brain regions form complementary and necessary partnerships in episodic memory formation.

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory.

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.

Place cells in the claustrum remap under NMDA receptor control.

Place cells are cells that exhibit location-dependent responses; they have mostly been studied in the hippocampus. Place cells have also been reported in the rat claustrum, an underexplored paracortical region with extensive corto-cortical connectivity. It has been hypothesised that claustral neuronal responses are anchored to cortical visual inputs. We show rat claustral place cells remap when visual inputs are eliminated from the environment, and that this remapping is NMDA-receptor-dependent. Eliminating visual input decreases claustral delta-band oscillatory activity, increases theta-band oscillatory activity, and increases simultaneously recorded visual cortical activity. We conclude that, like the hippocampus, claustral place field remapping might be mediated by NMDA receptor activity, and is modulated by visual cortical inputs.

Collateral rostral thalamic projections to prelimbic, infralimbic, anterior cingulate and retrosplenial cortices in the rat brain.

As the functional properties of a cortical area partly reflect its thalamic inputs, the present study compared collateral projections arising from various rostral thalamic nuclei that terminate across prefrontal (including anterior cingulate) and retrosplenial areas in the rat brain. Two retrograde tracers, fast blue and cholera toxin B, were injected in pairs to different combinations of cortical areas. The research focused on the individual anterior thalamic nuclei, including the interanteromedial nucleus, nucleus reuniens and the laterodorsal nucleus. Of the principal anterior thalamic nuclei, only the anteromedial nucleus contained neurons reaching both the anterior cingulate cortex and adjacent cortical areas (prefrontal or retrosplenial), though the numbers were modest. For these same cortical pairings (medial prefrontal/anterior cingulate and anterior cingulate/retrosplenial), the interanteromedial nucleus and nucleus reuniens contained slightly higher proportions of bifurcating neurons (up to 11% of labelled cells). A contrasting picture was seen for collaterals reaching different areas within retrosplenial cortex. Here, the anterodorsal nucleus, typically provided the greatest proportion of bifurcating neurons (up to 15% of labelled cells). While individual neurons that terminate in different retrosplenial areas were also found in the other thalamic nuclei, they were infrequent. Consequently, these thalamo-cortical projections predominantly arise from separate populations of neurons with discrete cortical termination zones, consistent with the transmission of segregated information and influence. Overall, two contrasting medial-lateral patterns of collateral projections emerged, with more midline nuclei, for example, nucleus reuniens and the interoanteromedial nucleus innervating prefrontal areas, while more dorsal and lateral anterior thalamic collaterals innervated retrosplenial cortex.

Chemogenetics Reveal an Anterior Cingulate-Thalamic Pathway for Attending to Task-Relevant Information.

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.

Deconstructing the Direct Reciprocal Hippocampal-Anterior Thalamic Pathways for Spatial Learning.

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.

Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia.

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity.SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

Separate cortical and hippocampal cell populations target the rat nucleus reuniens and mammillary bodies.

Nucleus reuniens receives dense projections from both the hippocampus and the frontal cortices. Reflecting these connections, this nucleus is thought to enable executive functions, including those involving spatial learning. The mammillary bodies, which also support spatial learning, again receive dense hippocampal inputs, as well as lighter projections from medial frontal areas. The present study, therefore, compared the sources of these inputs to nucleus reuniens and the mammillary bodies. Retrograde tracer injections in rats showed how these two diencephalic sites receive projections from separate cell populations, often from adjacent layers in the same cortical areas. In the subiculum, which projects strongly to both sites, the mammillary body inputs originate from a homogenous pyramidal cell population in more superficial levels, while the cells that target nucleus reuniens most often originate from cells positioned at a deeper level. In these deeper levels, a more morphologically diverse set of subiculum cells contributes to the thalamic projection, especially at septal levels. While both diencephalic sites also receive medial frontal inputs, those to nucleus reuniens are especially dense. The densest inputs to the mammillary bodies appear to arise from the dorsal peduncular cortex, where the cells are mostly separate from deeper neurons that project to nucleus reuniens. Again, in those other cortical regions that innervate both nucleus reuniens and the mammillary bodies, there was no evidence of collateral projections. The findings support the notion that these diencephalic nuclei represent components of distinct, but complementary, systems that support different aspects of cognition.

Influences of photic stress on postsubicular head-directional processing.

The stress response serves vital adaptive functions. However, acute stress episodes often negatively impact cognitive processing. Here, we aimed to elucidate whether stress detrimentally affects the head-direction cells of the postsubiculum, which may in turn impair downstream spatial information processing. We recorded neurons in the rats' postsubiculum during a pellet-chasing task during baseline non-stress conditions and after a 30-min acute photic stress exposure. Based on their baseline firing rate, we identified a subpopulation of head-direction cells that drastically decreased its firing rate as a response to stress while preserving their head directionality. The remaining population of head-direction cells as well as other neurons recorded in the postsubiculum were unaffected. The observed altered activity in the subpopulation might be the basis for spatial processing deficits observed following acute stress episodes.

Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-α-induced depression model.

Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-α induced changes. In vitro radioligand receptor binding assays and the [35S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1ß and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression.

Fornical and nonfornical projections from the rat hippocampal formation to the anterior thalamic nuclei.

The hippocampal formation and anterior thalamic nuclei form part of an interconnected network thought to support memory. A central pathway in this mnemonic network comprises the direct projections from the hippocampal formation to the anterior thalamic nuclei, projections that, in the primate brain, originate in the subicular cortices to reach the anterior thalamic nuclei by way of the fornix. In the rat brain, additional pathways involving the internal capsule have been described, linking the dorsal subiculum to the anteromedial thalamic nucleus, as well as the postsubiculum to the anterodorsal thalamic nucleus. Confirming such pathways is essential in order to appreciate how information is transferred from the hippocampal formation to the anterior thalamus and how it may be disrupted by fornix pathology. Accordingly, in the present study, pathway tracers were injected into the anterior thalamic nuclei and the dorsal subiculum of rats with fornix lesions. Contrary to previous descriptions, projections from the subiculum to the anteromedial thalamic nucleus overwhelmingly relied on the fornix. Dorsal subiculum projections to the majority of the anteroventral nucleus also predominantly relied on the fornix, although postsubicular inputs to the lateral dorsal part of the anteroventral nucleus, as well as to the anterodorsal and laterodorsal thalamic nuclei, largely involved a nonfornical pathway, via the internal capsule.

The irregular firing properties of thalamic head direction cells mediate turn-specific modulation of the directional tuning curve.

Head direction cells encode an animal's heading in the horizontal plane. However, it is not clear why the directionality of a cell's mean firing rate differs for clockwise, compared with counterclockwise, head turns (this difference is known as the "separation angle") in anterior thalamus. Here we investigated in freely behaving rats whether intrinsic neuronal firing properties are linked to this phenomenon. We found a positive correlation between the separation angle and the spiking variability of thalamic head direction cells. To test whether this link is driven by hyperpolarization-inducing currents, we investigated the effect of thalamic reticular inhibition during high-voltage spindles on directional spiking. While the selective directional firing of thalamic neurons was preserved, we found no evidence for entrainment of thalamic head direction cells by high-voltage spindle oscillations. We then examined the role of depolarization-inducing currents in the formation of separation angle. Using a single-compartment Hodgkin-Huxley model, we show that modeled neurons fire with higher frequencies during the ascending phase of sinusoidal current injection (mimicking the head direction tuning curve) when simulated with higher high-threshold calcium channel conductance. These findings demonstrate that the turn-specific encoding of directional signal strongly depends on the ability of thalamic neurons to fire irregularly in response to sinusoidal excitatory activation. Another crucial factor for inducing phase lead to sinusoidal current injection was the presence of spike-frequency adaptation current in the modeled neurons. Our data support a model in which intrinsic biophysical properties of thalamic neurons mediate the physiological encoding of directional information.

Respiratory cycle entrainment of septal neurons mediates the fast coupling of sniffing rate and hippocampal theta rhythm.

Memory for odour information may result from temporal coupling between the olfactory and hippocampal systems. Respiration defines the frequency of olfactory perception, but how the respiratory rate affects hippocampal oscillations remains poorly understood. The afferent connectivity of the medial septum/diagonal band of Broca complex (MS/DB) proposes this region as a crossroads between respiratory and limbic pathways. Here we investigate if the firing rates of septal neurons integrate respiratory rate signals. We demonstrate that approximately 50% of MS/DB neurons are temporally correlated with sniffing frequency. Moreover, a group of slow-spiking septal neurons are phase-locked to the sniffing cycle. We show that inter-burst intervals of MS/DB theta cells relate to the sniff rate. Intranasal odour infusion evokes sniff phase preference for the activity of fast-spiking MS/DB neurons. Concurrently, the infusion augments the correlation between sniffing and limbic theta oscillations. During periods of sniffing-theta correlation, CA1 place cells fired preferentially during the inhalation phase, suggesting the theta cycle as a coherent time frame for central olfactory processing. Furthermore, injection of the GABAergic agonist muscimol into medial septum induces a parallel decrease of sniffing and theta frequencies. Our findings provide experimental evidence that MS/DB does not merely generate theta rhythm, but actively integrates sensorimotor stimuli that reflect sniffing rate. Such integration may provide temporal oscillatory synchronisation of MS/DB-innervated limbic structures with the sniffing cycle.

Whole-brain traumatic controlled cortical impact to the left frontal lobe: Magnetic resonance image-based texture analysis.

This research assesses the capability of texture analysis (TA) derived from high-resolution (HR) T2-weighted magnetic resonance imaging to identify primary sequelae following 1-5 hours of controlled cortical impact mild or severe traumatic brain injury (TBI) to the left frontal cortex (focal impact) and secondary (diffuse) sequelae in the right frontal cortex, bilateral corpus callosum, and hippocampus in rats. The TA technique comprised first-order (histogram-based) and second-order statistics (including gray-level co-occurrence matrix, gray-level run length matrix, and neighborhood gray-level difference matrix). Edema in the left frontal impact region developed within 1 hour and continued throughout the 5-hour assessments. The TA features from HR images confirmed the focal injury. There was no significant difference among radiomics features between the left and right corpus callosum or hippocampus from 1 to 5 hours following a mild or severe impact. The adjacent corpus callosum region and the distal hippocampus region (s), showed no diffuse injury 1-5 hours after mild or severe TBI. These results suggest that combining HR images with TA may enhance detection of early primary and secondary sequelae following TBI.

Hippocampal dynamics predict interindividual cognitive differences in rats.

There are important and sustained interindividual differences in cognition during aging. Here, we investigated hippocampal spatial representations in a rat model of cognitive aging characterized by individual differences in a mnemonic task. Individual cognitive capabilities in old rats were assessed in a delayed non-matching-to-position task. We recorded hippocampal CA1 place cells as the rats explored a familiar environment. Unlike the usual place cells commonly described in the literature, we found that a significant fraction of pyramidal neurons recorded in our study showed a substantial delayed onset of their place field activity. We established that this firing onset delay naturally occurs under basal conditions in old rats and is positively correlated with the remapping status of the animals. The lack of firing during the first few hundred seconds after the animals were introduced into a familiar environment was also associated with an increased locomotion in the remapping rats. This delayed activity is central to understanding the individual basis of age-related cognitive impairment and to resolving numerous discrepancies in the literature on the place cell contribution to the etiology of aged-related decline. Finally, we also found a positive correlation between the degree of firing variability of place cells ("overdispersion") and performance during the long delays in the delayed non-matching-to-position task. Place cell overdispersion might provide the functional basis for interindividual differences in behavior and cognition.

CREB selectively controls learning-induced structural remodeling of neurons.

The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons remains elusive. Using transgenic mice conditionally expressing a dominant-negative CREB (CREBS133A: mCREB) mutant, we found that inhibiting CREB function does not alter spine density, spine morphology, and levels of polymerized actin in naive CA1 neurons. CREB inhibition, however, impaired contextual fear conditioning and produced a learning-induced collapse of spines associated with a blockade of learning-dependent increase in actin polymerization. Blocking mCREB expression with doxycycline rescued memory and restored a normal pattern of learning-induced spines, demonstrating that CREB controls structural adaptations of neurons selectively involved in memory formation.

Converging diencephalic and hippocampal supports for episodic memory.

To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.

Theta-modulated head direction cells in the rat anterior thalamus.

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 that exhibit rhythmic spiking in the theta range. This class of units, termed HD-by-theta (head direction-by-theta) cells, discharged predominantly in spike trains at theta frequency (6-12 Hz). 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.

Neural, psychological, and social foundations of collective memory: Implications for common mnemonic processes, agency, and identity.

Recent advances in memory research within psychology and neuroscience have contributed to a shift from examining memory through an individualistic lens towards a growing recognition of potential social and collective influences on mnemonic processes. This shift is prominently illustrated by continuing research on collective memory. Through a scoping literature review, we identify three crucial components defining collective memory: memories held in common across individuals within a social group, which are centrally important to group identity, and which impact significantly on perceived group agency. This review attempts to distil and organize empirical evidence into (i) neural, (ii) psychological, and (iii) social foundations of collective memory, while considering the reflexive relationship between common memory, identity, and agency (CIA). We conceptualize collective memory as based on neuropsychological substrates, influenced by social processes, and extended to societal, historical, and political domains, driven by human sociality. To engage the complexity of, and shed light on, numerous remaining questions surrounding collective memory, future research should embrace a collaborative, interdisciplinary approach focused on issues of common memory, identity, and identity.

Time to retire the serial Papez circuit: Implications for space, memory, and attention.

After more than 80 years, Papez serial circuit remains a hugely influential concept, initially for emotion, but in more recent decades, for memory. Here, we show how this circuit is anatomically and mechanistically naïve as well as outdated. We argue that a new conceptualisation is necessitated by recent anatomical and functional findings that emphasize the more equal, working partnerships between the anterior thalamic nuclei and the hippocampal formation, along with their neocortical interactions in supporting, episodic memory. Furthermore, despite the importance of the anterior thalamic for mnemonic processing, there is growing evidence that these nuclei support multiple aspects of cognition, only some of which are directly associated with hippocampal function. By viewing the anterior thalamic nuclei as a multifunctional hub, a clearer picture emerges of extra-hippocampal regions supporting memory. The reformulation presented here underlines the need to retire Papez serially processing circuit.