Traumatic stress can cause long-lasting changes in cognition and affect, sometimes leading to diagnoses such as posttraumatic stress disorder (PTSD). The stress-enhanced fear learning (SEFL) model recapitulates understudied components of PTSD, such as trauma-induced sensitization of fear learning. The SEFL procedure entails exposing mice to footshock stress followed later by fear conditioning in a different context. When tested later for recall of fear conditioning, previously stressed mice exhibit enhanced freezing compared to non-stressed controls. Studies have shown that dorsal and ventral dentate gyrus (DG) generate neural ensemble representations of contextual fear, such that fear recall involves reactivation of a sparse set of "engram cells" that were active during fear memory acquisition. How stress affects these hippocampal ensemble representations is unknown. We used SEFL and activity-dependent neuronal tagging with FosTRAP2 mice to investigate effects of stress on fear memory ensembles in rostral and caudal hippocampal DG. FosTRAP2/Ai6 mice received footshock stress or equivalent context exposure without shock in Context A on day 1. Five days later, mice received 1-shock conditioning in Context B and immediately received an injection of 4-hydroxytamoxifen (4-OHT; 55 mg/kg) to tag fear acquisition neurons with the zsGreen reporter. One day later, mice were tested for fear recall in Context B and were perfused 90 min after testing. Confirming prior studies, stress potentiated 1-shock conditioning in Context B, with stressed mice displaying higher freezing in the Context B test session than nonstressed mice. At the level of neural activity, results showed stress had no effect on the number of zsGreen+ fear ensemble cells or the number of cfos+ recall-activated cells in rostral or caudal DG. However, stress increased reactivation (percentage of zsGreen+ cells expressing cfos) in the caudal but not rostral DG. The results suggest stress potentiates later fear learning by enhancing fear representations in caudal hippocampus, a region specialized for integrating emotional and motivational valence into memory.

The subiculum, a key component of the medial temporal lobe (MTL), has traditionally been viewed as a relay station for hippocampal output to cortical regions. However, its intricate afferent and efferent connections with diverse brain areas suggest a more independent role in memory and spatial navigation. This review argues that the subiculum encodes regularities in environmental structures (e.g., boundaries, corners, axes) and behavioral patterns imposed by task demands, integrating hippocampal information into schematic representations for goal-directed actions. In conditions where perceptual constraints are dominantly fostering predictable behaviors, subicular neurons exhibit invariant firing properties tied to environmental features, such as boundary vector and axis tuning. However, during task-guided behaviors, subicular firing is further shaped by task-relevant mnemonic constraints, as seen in theta-phase-specific fields that segment space into pre- and postchoice zones, encoding variables such as context and choice. Anatomical evidence, including convergent CA1 inputs and local recurrent connections within the subiculum, supports this function, with subicular outputs to regions like the medial prefrontal cortex facilitating rule-guided action generation. Ultimately, the subiculum transforms granular hippocampal codes into memory schemas, enabling efficient navigation and behavior in complex environments.

ABSTRACTThe hippocampal formation is a functional entity that includes the hippocampus, subicular complex, and the entorhinal cortex, and has an essential role in learning and memory, emotional processing, and spatial coding. The well‐defined structure of hippocampal fields and the segregation of the connections have made this structure a favorite candidate for functional models that rely on fundamental information such as the number of neurons populating the hippocampal fields. Existing models on the rat rely on neuronal populations obtained from single studies, so we aimed to obtain more representative estimates by analyzing all available data. We identified 89 studies using reliable methodology that provided 264 stereological estimates of principal neuron populations. The resulting averages for males showed 1,000,000 neurons for the granule cell layer (GCL); 50,000 for the hilus; 210,000 for CA3; ~30,000 for CA2; 350,000 for CA1; and 300,000 for the Subiculum. Entorhinal cortex (EC) averages for both sexes showed 108,000 neurons in layer II; 270,000 in layer III; and 340,000 in layer V/VI. Most of those estimates are significantly different from those traditionally used in hippocampal models (e.g., ~2‐fold difference in EC layer II), revealing an updated architecture of the rat hippocampal formation that might help build more realistic models of hippocampal connectivity and function. Comparisons by age or sex were not reliable given the scarce data available from adolescents or females, while comparisons by strain showed inconsistent results, with similar populations in most fields but significant differences in CA3/CA2. The reliability of this finding is discussed.

Memories are stored in a sparse population of neurons active at the time of an event, an engram ensemble, and reactivation of the engram ensemble drives memory recall. Although the amygdala is essential for fear memory encoding and recall, the precise spatial organization of engram neurons within amygdala nuclei remains an outstanding question. We hypothesized that the geometric architecture of an engram ensemble reflects its underlying function, thereby revealing novel organizational principles of memory coding. Using tissue clearing and light-sheet imaging, we mapped Arc-expressing neurons across the entire mouse amygdala in 3D to examine the spatial architecture of engram ensembles for aversive (shock) and valence-neutral (no shock) contextual memories during encoding and recall. At the meso-scale level, we identified distinct spatial "hotspots" of engram neuron density during that were differentially engaged during fear conditioning and fear memory retrieval across multiple amygdala nuclei. Notably, we also found shared spatial features during the retrieval of aversive and non-aversive contextual memories. At the micro-scale level, unsupervised clustering analyses showed that aversive learning and recall was associated with increased clustering of active neurons in the lateral (LA) and basal (BA) nuclei, and selectively in the central capsular nucleus (CeC) during aversive encoding. Network graphs derived from the spatial organization of active neurons revealed highly clustered and assortative local graph structures across conditions. Assortativity increased in the CeC during aversive learning, and hub nodes increased in the LA during aversive learning and recall, and in the CeC during aversive learning. Together, these results suggest that both meso- and micro-scale spatial signatures of neuronal activity differ across amygdala subregions and vary with memory valence and stage. Such structure may shape information flow through amygdala circuits, enhancing signal-to-noise and improving the fidelity of memory encoding and retrieval.

This manuscript covers my personal history on the search for the neural circuits supporting early developing memory in primates. A series of developmental neuropsychological studies is presented to follow the successive knowledge we gained over several decades on the timing of development of the hippocampus and hippocampal-dependent recognition memory functions in primates. The borrowing of an incidental recognition memory task measuring novelty preference to infer subjects' memory was central to assessing memory in young infant monkeys of only a few weeks old. Data revealed that the emergence of adult-like proficiency in visual recognition and spatial memory tasks sensitive to hippocampal dysfunction is a stepwise process. This progressive development was associated with the gradual maturation of different hippocampal intrinsic circuits (Entorhinal-CA1 and Entorhinal-Dentate Gyrus-CA fields) and their connections with other cortical structures (the perirhinal, parahippocampal, parietal, and prefrontal cortices). We also showed that a similar postnatal maturation of hippocampal-dependent memory is observed in human infants, suggesting important changes in the role of the hippocampus and medial temporal cortical areas in human memory development as well.

Visual exploration-where the eyes move and when-is guided by prior experiences. Memory-guided viewing behavior is altered in healthy aging and is further disrupted in amnestic mild cognitive impairment (aMCI), a condition in which there is accelerated structural and functional decline of the hippocampus and associated medial temporal lobe structures (HC/MTL). Computational modeling has demonstrated the potential for rapid information flow from the HC/MTL to regions responsible for the cognitive control of eye movements, such that visual exploration behavior could be impacted in the moment and on an ongoing fashion. It was predicted here, then, that older adults and individuals with aMCI would show changes in naturalistic viewing compared to younger adults, even in the absence of any memory task. Multivariate analyses revealed that viewing for younger adults was characterized by larger saccade amplitudes and a larger area of exploration; the opposite pattern was reliably expressed by individuals with aMCI. Viewing patterns of healthy older adults were associated with shorter gaze durations. The entropy of viewing in older adults was associated with overall cognitive status, as determined by the Montreal Cognitive Assessment, highlighting the top-down influence of cognitive function on active vision. Lower scores on the memory subtest were reliably associated with a pattern of viewing characterized by fewer fixations (with longer durations), saccades, regions explored, smaller area of exploration, and lower entropy, mimicking some of the viewing features of the aMCI group and suggesting that increasing HC/MTL decline results in less exploratory viewing patterns. These findings reveal the ongoing influence of the hippocampus and its extended system on moment-to-moment naturalistic viewing.

ABSTRACTNeural activity and bodily functions are inherently rhythmic and related to each other. The occurrence of hippocampal sharp‐wave ripples (SPW‐Rs) and dentate spikes (DSs) supporting memory consolidation is regulated by the overall state of the brain, and they also seem to aggregate to a certain phase of the breathing cycle in naturally sleeping mice. Further, SPW‐Rs and DSs synchronize to a variable degree between hemispheres, but how this is affected by the neural and bodily state is unclear. Here, we recorded dorsal hippocampal local‐field potentials, electrocardiogram, and respiration for several hours under urethane anesthesia in adult male Sprague–Dawley rats. For a subset of rats, we injected atropine (50 mg/kg, i.p.) halfway into the recording to decrease cholinergic and parasympathetic tone. We found variable relation of hippocampal oscillations to breathing phase and none to the cardiac cycle phase. A decrease in breathing rate implying increased parasympathetic tone preceded the start of SPW‐R bouts. Roughly 90% of DSs and half of SPW‐Rs were unilateral. In most rats, SPW‐Rs were more often bilateral during slow breathing compared to faster breathing. Atropine reduced the proportion of bilateral SPW‐Rs. Both nonrapid eye movement sleep‐like state and atropine increased the proportion of bilateral DSs under urethane anesthesia. Finally, in naturally sleeping rats, both DSs and SPW‐Rs were bilateral ~60% of the time. In sum, urethane seems to desynchronize DSs but not SPW‐Rs, and a low cholinergic and/or parasympathetic tone seems to dissociate SPW‐Rs and to synchronize DSs in the two hippocampi. Whether these findings have relevance in terms of memory consolidation and behavior should be investigated in the future.

ABSTRACT Neurons linked to spatial navigation and toroidal dynamics in the mouse medial entorhinal cortex (MEC) show unexpected minute‐scale (< 0.01 Hz) oscillatory sequences without neural organization or clear relation to behavior. However, the conditions sustaining these’ ultraslow' equences remain uncertain. Since dopaminergic modulation of spike‐timing‐dependent plasticity (STDP) enables infraslow (< 0.1 Hz) oscillations in sparse neural networks (SNN), we hypothesize that SNN might sustain minute‐scale (ultraslow) oscillatory sequences when bypassing the modulation. Using computational simulations through detailed numerical investigations, the conditions that enable the MEC‐like ultraslow rhythms are characterized in an Izhikevich's SNN with dopaminergic STDP modulation. To induce the ultraslow sequences, a few active neurons are defined at each simulation step following a toroid‐like trajectory. The results indicate that even when disrupting the dopamine‐based STDP learning, the ultraslow oscillations require a second‐scale resetting of the membrane potential to keep the sequential firing. Interestingly, separate oscillations on synapses that do not contribute to the firing rate at a specific time step (silent synaptic connections) are observed in the presence of the sequences. Since the mechanisms underlying the experimental finding are unknown, the present manuscript generates hypotheses on the conditions that sustain minute‐scale sequences, which will be relevant for the community studying population dynamics in the MEC.