Hippocampus

Adult-born hippocampal neurons are highly plastic but there remains uncertainty about the magnitude of neurogenesis and its long-term functional consequences. Theoretical predictions indicate that adult neurogenesis should lead to substantial growth of the dentate gyrus (DG) granule cell population. However, in practice, most studies find no changes in total cell number across adulthood. This discrepancy may partly be a sensitivity issue, where small sample sizes and the examination of older age windows (when neurogenesis is reduced) have prevented detection. However, neurogenic growth could also be masked by the turnover of developmentally-born DG neurons, which are known to die off in normal aging. To address the question of how neuronal birth and loss impacts DG population dynamics, here we quantified numbers of developmentally-born neurons, proliferating Ki67+ cells (as a proxy for adult-born neurons), and total DG neurons from 2-18 months of age in the rat. We estimate that over this timeframe 670,000 adult-born neurons are added (30% of the total population). Consistent with neurogenic growth, the total number of DG neurons increased across adulthood. However, net growth was only 385,000 cells, which is less than predicted by adult neurogenesis alone. Indeed, 20% of developmentally-born neurons were lost over the same interval, and so we propose that the difference is explained by neuronal turnover. Neuronal persistence and turnover may be relevant for theories of hippocampal long-term memory, as well as for understanding psychiatric conditions that are characterized by hippocampal plasticity and atrophy.

Cajal-Retzius neurons (CRs) are a transient cell type that populates the postnatal hippocampus. To test how the persistence of CRs shapes the maturation of hippocampal function, we used a CRs-specific transgenic mouse line combined with targeted viral delivery to selectively ablate CRs in the postnatal hippocampus. Single cell sequencing revealed that gene networks in superficial CA1 pyramidal cells were more strongly perturbed compared to deep CA1 pyramidal cells. To test if these two subpopulations were also distinctly affected in their function, we performed in vivo recordings from spatially modulated cells in CA1. Our analysis showed an impaired spatial representation specifically in superficial CA1 pyramidal cells. Additionally, we observed an increased CA3 to CA1 excitatory drive, as indicated by increased gamma oscillations, and alterations of intrinsic firing properties in superficial CA1 pyramidal neurons confirmed by in vitro electrophysiological recordings. Together, these results indicate a crucial role for CRs in the maturation of hippocampal subcircuits.

The hippocampus routes information to the striatum through at least four polysynaptic circuits. Striatal projection neurons are organized into two tissue compartments, the matrix and striosome, which differ in their embryologic origins, relative abundance, intra-striate location, and afferent and efferent connectivity. These compartments are embedded in distinct functional networks and are activated by different tasks. Consequently, hippocampal inputs that route preferentially through the striosome may underpin different functions and engage with different remote networks than inputs that route through the matrix. It was unknown whether striosome-bound and matrix-bound projections from the hippocampus followed different polysynaptic circuits. We assessed hippocampo-striate projections in living humans using probabilistic diffusion tractography by first parcellating the striatum into voxels with striosome-like and matrix-like structural connectivity. We then quantified structural connectivity between hippocampal efferents (CA1) to each set of compartment-like voxels. CA1 projections to striosome-like voxels in the dorsal striatum (caudate and putamen) were 3.1-fold more abundant than those to matrix-like voxels, particularly in caudo-lateral CA1. This striosome-favoring bias was similar in three segregated hippocampo-striate circuits, in streamlines routing through the subiculum, lateral septum, or medial prefrontal cortex. However, a small region in rostro-medial CA1 preferentially targeted matrix-like voxels. Functional connectivity between CA1 and compartment-like voxels matched this segregated pattern: CA1 activation was correlated with striosome-like voxels but anti-correlated with matrix-like voxels. Additionally, streamlines from CA1 to nucleus accumbens exhibited hemispheric asymmetries, with the left hemisphere biased towards matrix and the right towards striosome. These findings suggest that hippocampo-striate projections are spatially segregated into compartment-specific circuits.

Accurate and efficient memory processing is essential for survival. Recent work in human subjects and animal models has suggested that memory processing may differ in meaningful ways between males and females. In mice, contextual fear memory (CFM) encoding, consolidation, and recall have been well studied, and the mouse hippocampus and amygdala have been implicated in these processes. The present study addresses how the specific contribution of these brain regions to each stage CFM processing in female vs. male mice. We find that male and female mice show no differences in CFM recall, nor in sleep behavior in the hours following single-trial contextual fear conditioning (CFC), which is essential for CFM consolidation. However, females - but not males - show significantly increased expression of cFos in dorsal hippocampal CA1 and CA2 neurons during CFM encoding. On the other hand, males - but not females - show increased cFos expression among DG granule cells during CFM consolidation. These findings highlight the fact that the neurobiological underpinnings of memory processing may differ between males and females, even when recall performance is identical. Scope statementHistorically, research on the neurobiological basis of memory processing has been carried out mainly in male subjects. Thus, our understanding of these mechanisms is biased towards male brain neurophysiology. Recent studies have variously reported performance differences for episodic memory tasks, in which male subjects perform better, worse, or the same as females. Here, we find that male and female mice perform similarly on a well-studied experimental memory task but nonetheless have differences in the relative activity of different brain structures during sequential stages of memory processing. This emphasizes the importance of including both males and females in memory studies, due to potential sex differences in the neurobiological substrates of memory.

ContextGrid cells in the medial entorhinal cortex (MEC) of head-fixed mice exhibit ultraslow (<0.01 Hz) oscillations (USO) during walking in a 1D running wheel in darkness. It was proposed that these oscillations may have a connection with navigational behavior. ProblemThere is no clear link between the functional role of these oscillations and path integration, a fundamental navigation strategy used by animals to calculate their current position and orientation by continuously summing self-motion cues. HypothesisGiven the synaptic projections from MEC to the hippocampus, we hypothesized that ultraslow oscillations have a role in linking spatiotemporal memories acquired during navigation. MethodologyA realistic computational model of entorhinal-grid with ultraslow oscillations and hippocampal-place cells is proposed using synaptic plasticity between cell types, sustaining path integration of a rodent-like simulated animal. ResultsUltraslow oscillations induced persistent changes in the grid cell dynamics, represented as a positional drift of grid fields. Such drift resulted in position estimation errors but generated new grid-place cell associations when combined with synaptic plasticity. >DiscussionsUltraslow entorhinal oscillations were found to shape spatial memory through grid cell drifting, which could serve as a mechanism for flexibly accessing different spatial memories during navigation. HIGHLIGHTSO_LIPath integration dynamics hide ultraslow oscillations despite coexistence. C_LIO_LIUltraslow oscillations significantly degrade position estimation in path integration. C_LIO_LIGrid and place fields drift after the effect of ultraslow oscillations. C_LIO_LINew spatial memories were created as a result of the ultraslow oscillation drift. C_LIO_LIUltraslow oscillations enable dynamic access of different spatial memories C_LI

Hippocampal dentate granule cells receive multisensory information from the entorhinal cortex in a laminated and functionally segregated manner. We previously reported that brief periods of voluntary exercise in mice increased EPSCs and dendritic spines for inputs from the lateral, but not the medial, entorhinal cortex. Here we asked whether laminar specificity was due to molecular changes specific to distal granule cell dendrites or rather was dependent on upstream drive from the entorhinal cortex. Selective chemogenetic stimulation of either lateral entorhinal cortex (LEC) or the medial entorhinal cortex (MEC) increased granule cell dendritic spine density in the selected pathway. However, the preponderance of exercise-activated cells originated from LEC based on expression of an activity-dependent retrograde virus in Fos-TRAP mice. Our results indicate that the preferential activation by exercise reflects the drive of locomotor-related inputs from the lateral entorhinal cortex rather than selective molecular mechanisms in distal dendrites of dentate granule cells. How this activation pattern affects other salient stimuli involving contextual or spatial cues may underlie the benefits of exercise on learning and memory.

BackgroundFlexibility and robustness of neuronal function are closely linked to degeneracy, the ability of distinct structural or parametric configurations to produce similar functional outcomes. At the cellular level, this often manifests as ion-channel degeneracy, in which multiple combinations of intrinsic conductances yield comparable electrophysiological phenotypes. MethodologyWe used a population-based, data-driven modelling framework to generate large ensembles of biophysically detailed CA1 pyramidal neuron models constrained by somatic electrophysiological features extracted from patch-clamp recordings in acute slices from early-birth rats. 10 reconstructed morphologies were incorporated, and model populations were analyzed using parameter correlation analysis, principal component analysis, and generalization tests to assess robustness, degeneracy, and morphology dependence of intrinsic properties. ConclusionsAcross the model population, similar somatic firing behaviours emerged from widely different combinations of intrinsic parameters, demonstrating robust two-level ion channel degeneracy both within and across morphologies. Each morphology occupied a distinct region of parameter space, indicating morphology-specific compensatory effects, while weak pairwise parameter correlations suggested distributed compensation rather than tight parameter dependencies. Even with a fixed morphology, multiple parameter subspaces supported comparable electrophysiological phenotypes. Generalization across morphologies was structure-dependent and non-reciprocal, with successful parameter similarity occurring preferentially between structurally similar neurons. Interestingly, to accurately simulate spike-frequency adaptation, it was important to retain some kinetic properties of the ion channel models as free parameters during optimization. Together, these findings show that dendrite morphology shapes the valid parameter space, and similar electrophysiology of CA1 pyramidal neurons arises from the interplay between structural variability and ion-channel diversity. This work highlights the importance of population-based modelling for capturing biological variability and provides insights into how neuronal robustness might be maintained despite substantial heterogeneity, and offers a scalable pipeline for generating biophysically realistic CA1 neuron populations for use in network simulations. Author summaryNeurons must reliably process information even though their internal components, such as ion channels and cellular shape, can vary widely from cell to cell. How stable behaviour emerges from such variability is a fundamental question in neuroscience. In this study, we explored this problem using detailed computer models of early-birth rat hippocampal CA1 pyramidal neurons, a cell type that plays a central role in learning and memory. Instead of building a single "average" neuron model, we created large populations of models that all reproduced key experimental recordings but differed in their internal parameters. We found that neurons with different shapes and different combinations of ion channels could nevertheless generate similar electrical activity. This phenomenon, known as ion channel degeneracy, allows neurons to remain functional despite biological variability or perturbations. Our results show that neuronal shape strongly influences which parameter combinations are viable, but that multiple solutions exist even for the same morphology. The population of models we provide offers a resource for future studies of early-birth CA1 pyramidal cell function and dysfunction.

BackgroundHippocampal place cells (PCs) undergo representational drift, i.e., a gradual change in their place fields despite unaltered behavior. While Ca2+ imaging enables long-term tracking of PC populations, distinct PC detection methods have been shown to yield different subpopulations of PCs, with only a few systematic comparisons between methods, especially in open arenas. New MethodWe provide an analysis protocol for one-photon PC data obtained during free foraging in two-dimensional arenas that allows us to compare two widely used PC detection methods, significance of spatial information (SI), and split-half correlation (SHC), and their effect on representational drift. The analysis is demonstrated on previously published Ca2+ data from dorsal CA1 of freely foraging mice, with cells tracked for 10 consecutive days. ResultsBoth criteria, SI and SHC, yielded proportions of approx. 17% PCs with only 40% overlap. SI-identified PCs demonstrated higher stability, higher rate map correlations, and a slower rate of representational drift than SHC-PCs. Comparison with existing methodsPrevious studies comparing SI and SHC PC detection methods in Ca2+ data did not focus on either open field behavior or representational drift. ConclusionOur results indicate that the choice of PC detection method significantly affects the estimate of representational drift in Ca2+ imaging studies.

The hippocampus is widely viewed as a spatial mapping system because many CA1 neurons show location-specific activity during exploration. However, the hippocampus is also required for non-spatial learning, including trace eye-blink conditioning. Because most prior reports of non-spatial signals were obtained in immobile animals, it has been proposed that the hippocampus encodes space during locomotion and non-spatial variables during immobility. To test this directly, we used calcium imaging to record thousands of CA1 neurons while rats performed trace eye-blink conditioning during free exploration of an open field. Across more than 6,000 neurons from five rats, mean firing rates during trace-conditioning periods were [~]1.5-fold higher than during non-trial periods, and this difference persisted after controlling for locomotor speed. At the single-cell level, task-related modulation was widespread and strongly biased toward increased firing. Task-enhanced neurons outnumbered spatially selective neurons by more than threefold, indicating that trace coding predominated over place coding. Although trace-conditioning events occurred at random spatial locations and during continuous locomotion, trace-related activity remained robust at both single-cell and population levels. In contrast, spatial coding was reduced during trace periods, with lower spatial information and decreased similarity between task and non-task rate maps. These findings show that during active behavior, trace coding dominates and disrupts place coding, challenging the view that the hippocampus functions primarily as a stable spatial map.

Granule cells of the hippocampal dentate gyrus fire at exceptionally low rates in order to maintain sparse neural codes. Despite the need for granule cells to remain in such relative quiescence, the mechanisms that regulate their firing rates have not received much attention. We investigated the potential of family of mechanisms, homeostatic downscaling, that could theoretically maintain granule cell firing at preferential levels following chronically elevated activity. Surprisingly, we found no evidence of reduced synaptic input or intrinsic excitability in granule cells even after prolonged exposure to GABAA receptor blockade. In fact, we found that mini excitatory postsynaptic current frequency was elevated in granule cells after prolonged exposure to GABAA antagonists. This effect was consistent across blockers or when cell firing was driven by elevated extracellular K+, and did not rely on NMDA receptors, L-type voltage gated Ca2+ channels or thrombospondin-driven synaptogenesis. However, the magnitude of long-term potentiation was reduced at synapses onto granule cells after prolonged exposure to a GABAA antagonist in vivo. We conclude that granule cells are the first known cell type that do not display homeostatic downscaling. Instead, these cells rely on other mechanisms, including metaplasticity, to maintain their activity within optimal bounds.

Despite decades of animal and human intracranial work highlighting the critical role theta oscillations (4-12 Hz) play in memory encoding and recall stage during navigation, the link between scalp recorded human theta oscillations and spatial encoding and recall is lacking. In the present study, we used right posterior theta (RPT) - a scalp-level theta signal believed to be generated in the medial temporal cortex - to examine spatial encoding and recall during virtual spatial navigation. In particular, we recorded EEG from 27 healthy subjects performing a novel virtual Linear Track Memory (LTM) task. During the encoding stage of the task, a reward cue was presented at one of five pillar locations along a linear track. During the recall stage, subjects were presented with images of the five pillars and five new pillars, and were asked to press a button when the rewarded target pillar location appeared. If correct, subjects received 5 cents for that trial. Memory performance was assessed using reaction time, d-prime (d), and response bias ({beta}), and RPT was measured following the onset of the reward cue at bilateral scalp electrodes P7 and P8. Consistent with previous work, RPT peaked approximately 170-300 ms over the right hemisphere (P8) after cue onset, which was significantly increased for reward cues during the encoding stage and for the target pillar during the recall stage. Importantly, general linear model regressions revealed that peak RPT power during the encoding stage significantly predicted higher d and {beta} scores during recall, supporting the relationship between RPT peak power and memory performance. Together, these findings support the proposal that RPT activity reflects the encoding of salient information for the purpose of spatial navigation and a promising candidate biomarker for memory-related functioning in health and disease (e.g., Alzheimers disease).

Episodic memory depends on neural representations encoded in the hippocampus. Experimental and computational evidence suggests that the hippocampus encodes pattern-separated representations that support later recall of episodic event elements. While extant data in humans predominantly focus on assaying the relationship between the similarity of spatial neural patterns at encoding and later memory performance, similarity of neural patterns in the temporal domain may also reveal encoding computations predictive of future memory. To examine how the similarity among temporal patterns of hippocampal activity during encoding relates to later episodic retrieval (associative cued recall and recognition memory), hippocampal activity was recorded from human participants (n=7) with implanted intracranial electrodes while they encoded arbitrary (A-B) paired-associates. Subsequent memory analyses first revealed that hippocampal high-frequency broadband power (HFB; 70-180Hz) was linked to a graded increase in memory strength; HFB power was greater during the encoding of pairs later correctly recalled relative to events later recognized and was lowest for events later forgotten. Second, and critically, subsequent memory analyses further revealed that more distinctive temporal patterns in the hippocampus during encoding -- indexed by the similarity of the HFB timeseries elicited by a given event to that elicited by other events -- were associated with superior subsequent memory performance. Finally, exploratory analyses revealed stimulus category effects on hippocampal HFB power during encoding and retrieval cuing. These results indicate that the temporal distinctiveness of hippocampal traces during encoding is important for subsequent retrieval of episodic event elements, consistent with theories that posit that pattern separation facilitates future remembering.

The hippocampal CA1 subregion supports learning, memory formation, and spatial navigation. Although its three-layered architecture has been described in ex-vivo investigations, the in-vivo microstructural profile of CA1 and its relation to individual variations in memory performance remain poorly characterized. In this study, we used ultra-high field structural MRI at 7 Tesla to investigate the depth-dependent myelination patterns (measured by quantitative T1) of CA1 in younger adults, their relation to the local arterial architecture, and their association with individual differences in cognitive functions, specifically memory performance. Results show that left and right CA1 present depth-dependent patterns of myelination, with the outer and inner compartments showing higher myelination than the middle compartment. No significant relationship between layer-specific myelination of CA1 and distance to the nearest artery was observed. Right CA1 was found to be more myelinated than left CA1. Pairwise correlations and regression models showed that higher left CA1 myelination is linked to higher accuracy in object localization. Together, our data demonstrates the feasibility of describing the three layered myelin architecture of CA1 in vivo, and provides information on how alterations in the architecture of CA1 may relate to alterations in cognitive performance in younger adults.

The ventral hippocampus contributes to food intake regulation and a range of motivational and memory processes, and its dysfunction is associated with several cognitive and behavioral disorders. However, its circuit-level organization remains incompletely understood. Ventral CA1 (CA1v) neurons send projections to several regions involved in motivational control. Here we focus on three major forebrain targets: the nucleus accumbens shell (ACBsh), medial prefrontal cortex (mPFC), and lateral hypothalamic area (LHA). We mapped the upstream and downstream circuitry of CA1v neurons defined by their projections to these target regions in rats using complementary transsynaptic anterograde and retrograde viral tracing approaches. Monosynaptic outputs to ACBsh, mPFC, and LHA were targeted using ATLAS, a novel transsynaptic anterograde viral approach that drives Cre recombinase in neurons receiving glutamatergic synaptic transmission from the CA1v. Second-order projections arising from these defined pathways were then mapped using a Cre-dependent anterograde viral tracing strategy. In parallel, upstream inputs to CA1v neurons projecting to each downstream target were mapped using a conditional retrograde glycoprotein-deleted rabies viral approach. Anterograde tracing revealed both shared and pathway-specific second-order targets, including bidirectional CA1v projections. Retrograde tracing confirmed expected inputs (e.g., CA3) and uncovered previously unrecognized cortical sources that differed across downstream projection-defined CA1v subpopulations. Together, these findings delineate pathway-specific, multinode circuits linking CA1v neurons to key motivational systems that may inform future therapeutic strategies for disorders involving ventral hippocampal dysfunction.

Retrieval training (i.e., cued recall) is theorised to induce rapid memory consolidation, similarly to sleep. Across consolidation, related neural representations become increasingly similar; yet, this representational change has never been directly compared between sleep and retrieval training. In this study, 30 subjects (27F, 18-34, M=22.17) completed four separate sessions in which they (1) learnt object-word pairs, followed by (2) immediate recognition testing, (3) one of four 120-min interventions (retrieval training, restudy, sleep, or wake), and (4) delayed recognition testing. We compared EEG phase similarity between similar and different objects to assess the time, frequency, and anatomical distribution of representational similarity across encoding (learning to immediate recognition), and each intervention (immediate to delayed recognition). We hypothesised that EEG phase patterns for similar objects would become more similar (i.e., representational merging) across retrieval training and sleep interventions, and predict a greater endorsement of similar-object lures. Indeed, we found increased representational similarity between similar objects across the encoding shift in the theta-band and occipital sources. Crucially, additional representational merging was only observed across the retrieval training intervention, in the alpha-band and parieto-occipital sources. Despite retrieval training leading to reduced performance in discriminating similar-objects lures, greater representational merging across retrieval training predicted greater discrimination of similar-object lures. Together, these findings suggest that sleep and retrieval training induce different memory transformations across the same timescale. Retrieval training may generally provoke rapid gist extraction, with greater neocortical integration supporting episodic discrimination. Conversely, sleep may selectively maintain task-relevant episodic and semantic details in the short-term.

Traumatic stress can cause long-lasting changes in cognition and affect, sometimes leading to diagnoses such as post-traumatic stress disorder (PTSD). The stress-enhanced fear learning (SEFL) model recapitulates understudied components of PTSD, such as stress-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) generates 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-OHT (55mg/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 minutes after testing. Confirming prior studies, prior stress potentiated 1-shock conditioning in Context B, with stressed mice displaying higher freezing in the Context B test session than non-stressed 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 of the hippocampus specialized for integrating emotional and motivational valence into memory.

Current evidence suggests that older adults perform worse at tasks involving spatial memory and navigation, yet the underlying reasons remain unclear. Here, we tested the hypothesis that age-related declines in spatial memory stem from difficulties in recognizing spatial environments from rotated perspectives. Young and older adults underwent fMRI as they encoded virtual scenes which were later viewed either from the same or rotated perspective. Older adults were worse at identifying changes in these scenes, although the age effect was equally robust across perspective conditions. Neural specificity of scene representations was examined with the phenomenon of fMRI repetition adaptation. We predicted that young adults would show significant fMRI adaptation to the same but not rotated perspective, indicative of intact viewpoint specificity, while older adults show would adaptation effects to both. While analyses of raw fMRI BOLD produced results consistent with these predictions, follow-up analyses revealed a general attenuation of activity in older adults across both perspective conditions. Additionally, although older adults showed both lower fMRI BOLD and worse spatial memory, lower trial-wise BOLD was associated with better performance independent of age. This suggests that the variance associated with fMRI adaptation is reflective of two independent sources of variance: age and cognition. Our results suggest that age differences in spatial memory may manifest due to cognitive and neural factors that are shared across same and rotated perspectives, and thus they cannot be explained by a selective deficit in allocentric (viewpoint-independent) processing. Significance StatementIncreasing age is often associated with reduced spatial memory and navigation. Prior research suggests that age differences in spatial memory could be exacerbated by changes in perspective, possibly due to increased difficulties in the ability to construct allocentric (viewpoint-independent) representations from previously encoded egocentric perspectives. Here, we demonstrate that older adults are equally disadvantaged when recognizing layouts across same and rotated perspectives. FMRI analyses indicate that older age is associated with reduced fMRI BOLD in higher-level visual cortex across both perspective conditions, as opposed to altered specificity of perspective coding. Consequently, the present study challenges the notion that aging is associated with a selective decline in allocentric spatial memory and instead supports a more general age-related difficulty with scene processing.

Phagocytosis is a key function performed by microglia to maintain tissue homeostasis. The degree of microglial phagocytic activity differs across ages and between gross anatomical brain regions, dictated by the local environment. Here, we asked whether microglial phagocytic phenotype exhibits subregion-scale tuning by circuit-specific features within a brain region. To address this, we took advantage of the highly stereotyped architecture of the hippocampus. We examined three adjacent synaptic subregions, the CA1 stratum radiatum (SR), stratum lacunosum moleculare (SLM) and dentate gyrus molecular layer (DGML). These three subregions provide an ideal system for examining local microglia heterogeneity, as each subregion contains distinct neuropil features, creating three adjacent unique micro-environments to which the microglia are exposed. We measured the phagocytic activity and morphological properties of over 1,000 individual microglia at two developmental points, mid-postnatal (P16) and early adulthood (P60) in the CA1 SR, SLM and DGML. We found that microglial phenotype diversified with development into early adulthood. At the mid-postnatal age, phagocytic activity and morphology were homogeneous across subregions. Conversely, in young adulthood, microglia in the CA1 SR and DGML exhibited a reduction in phagocytic activity, while microglia in the CA1 SLM maintained a highly phagocytic phenotype reminiscent of an immature-like state. These findings uncover a fine-scale tuning of microglia activity that emerges during maturation and is dictated at the sub-region level of the hippocampus, uncovering a distinct population of microglia in the CA1 SLM that exhibit a persistent immature phenotype under physiological conditions. Understanding the target(s) of this phagocytosis and consequences for CA1 SLM function will provide new insight into the role of local tuning of microglia properties for circuit-specific needs in both health and disease.

Grid cells in medial entorhinal cortex (MEC) support spatial navigation by responding to multiple variables, including position, speed, and head direction. While tuning curves for each of these variables have been examined individually at the level of single-cells, less is known about the conjunctive coding of grid cells for these properties. To investigate this, we analyzed neural recordings of freely foraging rats and constructed four-dimensional (4D) tuning curves across 2D position and 2D velocity. In order to combat the sparse sampling of such a large behavioral space, we applied Gaussian Process (GP) methods to estimate firing rates at un-sampled points. Comparing GP model-derived tuning curves to those predicted by a fully separable model revealed that some cells exhibited significant non-separability of position and velocity tuning, and suggested a data coverage threshold necessary to observe this non-separability. In summary, our use of GPs allowed us to distinguish interactions in position-velocity tuning across a 4D behavioral space that have not been apparent in 2D analyses.

By keeping its activity low even when strongly stimulated, the dentate gyrus (DG) serves as the main entry point to the hippocampal circuit and helps separate different patterns of incoming information. However, the mechanisms supporting this low-level activity remain unclear. Here, we used in vitro patch-clamp recordings, two-photon calcium imaging, and optogenetics in hippocampal slices from adult mice to understand how local GABAergic interneurons control lateral entorhinal cortex (LEC) input-mediated drive in the DG. Under control conditions, LEC inputs rarely elicited granule cell (GC) firing because GABAA receptor-mediated inhibition strongly restrained GC excitability. Whole-cell patch clamp recordings of DG interneurons revealed that LEC activation prevalently recruited fast-spiking parvalbumin-expressing and molecular layer interneurons, while most dendrite-targeting interneuron types responded only weakly to LEC input and fired action potentials only after feedback excitation from GCs was enhanced by pharmacological block of GABAA-receptors. Optogenetic inhibition of defined interneuron populations showed that silencing dendrite-targeting interneurons caused a larger increase in GC population spiking than silencing perisomatic-targeting interneurons, suggesting that both molecular layer and feedback-recruited interneurons have a prevalent role in controlling DG recruitment after an increase in LEC drive. In summary, our data indicate that GABAergic inhibition engages distinct DG interneuron types in feedforward and feedback circuits to tightly gate entorhinal inputs. By maintaining sparse GC firing, this dynamic inhibitory gating supports the role of the dentate gyrus in the hippocampal pattern-separation process.