Increased flexibility of CA3 memory representations following environmental enrichment.

Environmental enrichment (EE) improves memory, particularly the ability to discriminate similar past experiences.1,2,3,4,5,6 The hippocampus supports this ability via pattern separation, the encoding of similar events using dissimilar memory representations.7 This is carried out in the dentate gyrus (DG) and CA3 subfields.8,9,10,11,12 Upregulation of adult neurogenesis in the DG improves memory through enhanced pattern separation.1,2,3,4,5,6,11,13,14,15,16 Adult-born granule cells (abGCs) in DG are suggested to contribute to pattern separation by driving inhibition in regions such as CA3,13,14,15,16,17,18 leading to sparser, nonoverlapping representations of similar events (although a role for abGCs in driving excitation in the hippocampus has also been reported16). Place cells in the hippocampus contribute to pattern separation by remapping to spatial and contextual alterations to the environment.19,20,21,22,23,24,25,26,27 How spatial responses in CA3 are affected by EE and input from increased numbers of abGCs in DG is, however, unknown. Here, we investigate the neural mechanisms facilitating improved memory following EE using associative recognition memory tasks that model the automatic and integrative nature of episodic memory. We find that EE-dependent improvements in difficult discriminations are related to increased neurogenesis and sparser memory representations across the hippocampus. Additionally, we report for the first time that EE changes how CA3 place cells discriminate similar contexts. CA3 place cells of enriched rats show greater spatial tuning, increased firing rates, and enhanced remapping to contextual changes. These findings point to more precise and flexible CA3 memory representations in enriched rats, which provides a putative mechanism for EE-dependent improvements in fine memory discrimination.

Intrinsic and Synaptic Contributions to Repetitive Spiking in Dentate Granule Cells.

Repetitive firing of granule cells (GCs) in the dentate gyrus (DG) facilitates synaptic transmission to the CA3 region. This facilitation can gate and amplify the flow of information through the hippocampus. High-frequency bursts in the DG are linked to behavior and plasticity, but GCs do not readily burst. Under normal conditions, a single shock to the perforant path in a hippocampal slice typically drives a GC to fire a single spike, and only occasionally more than one spike is seen. Repetitive spiking in GCs is not robust, and the mechanisms are poorly understood. Here, we used a hybrid genetically encoded voltage sensor to image voltage changes evoked by cortical inputs in many mature GCs simultaneously in hippocampal slices from male and female mice. This enabled us to study relatively infrequent double and triple spikes. We found GCs are relatively homogeneous and their double spiking behavior is cell autonomous. Blockade of GABA type A receptors increased multiple spikes and prolonged the interspike interval, indicating inhibitory interneurons limit repetitive spiking and set the time window for successive spikes. Inhibiting synaptic glutamate release showed that recurrent excitation mediated by hilar mossy cells contributes to, but is not necessary for, multiple spiking. Blockade of T-type Ca2+ channels did not reduce multiple spiking but prolonged interspike intervals. Imaging voltage changes in different GC compartments revealed that second spikes can be initiated in either dendrites or somata. Thus, pharmacological and biophysical experiments reveal roles for both synaptic circuitry and intrinsic excitability in GC repetitive spiking.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function.

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

Circuit-based intervention corrects excessive dentate gyrus output in the fragile X mouse model.

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell hypo-excitability is caused by increased Kv7 function in Fmr1 knockout (KO) mice. By reducing the excitatory drive onto local hilar interneurons, hypo-excitability of mossy cells results in increased excitation/inhibition ratio in granule cells and thus paradoxically leads to excessive dentate output. Circuit-wide inhibition of Kv7 channels in Fmr1 KO mice increases inhibitory drive onto granule cells and normalizes the dentate output in response to physiologically relevant theta-gamma coupling stimulation. Our study suggests that circuit-based interventions may provide a promising strategy in this disorder to bypass irreconcilable excitability defects in different cell types and restore their pathophysiological consequences at the circuit level.

Pre- versus Post-synaptic Forms of LTP in Two Branches of the Same Hippocampal Afferent.

There has been considerable controversy about pre- versus postsynaptic expression of memory-related long-term potentiation (LTP), with corresponding disputes about underlying mechanisms. We report here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type 1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within the hippocampus depending upon the pattern of activity arriving over the parent axon.

Engram reactivation mimics cellular signatures of fear.

Engrams, or the physical substrate of memory, recruit heterogeneous cell types. Targeted reactivation of neurons processing discrete memories drives the behavioral expression of memory, though the underlying landscape of recruited cells and their real-time responses remain elusive. To understand how artificial stimulation of fear affects intra-hippocampal neuron-astrocyte dynamics as well as their behavioral consequences, we express channelrhodopsin-2 in an activity-dependent manner within dentate gyrus neurons while recording both cell types with fiber photometry in hippocampal ventral CA1 across learning and memory. Both cell types exhibit shock responsiveness, with astrocytic calcium events uniquely modulated by fear conditioning. Optogenetic stimulation of a hippocampus-mediated engram recapitulates coordinated calcium signatures time locked to freezing, mirroring those observed during natural fear memory recall. Our findings reveal cell-type-specific dynamics in the hippocampus during freezing behavior, emphasizing neuronal-astrocytic coupling as a shared mechanism enabling both natural and artificially induced memory retrieval and the behavioral expression of fear.

Robust and consistent measures of pattern separation based on information theory and demonstrated in the dentate gyrus.

Pattern separation is a valuable computational function performed by neuronal circuits, such as the dentate gyrus, where dissimilarity between inputs is increased, reducing noise and increasing the storage capacity of downstream networks. Pattern separation is studied from both in vivo experimental and computational perspectives and, a number of different measures (such as orthogonalisation, decorrelation, or spike train distance) have been applied to quantify the process of pattern separation. However, these are known to give conclusions that can differ qualitatively depending on the choice of measure and the parameters used to calculate it. We here demonstrate that arbitrarily increasing sparsity, a noticeable feature of dentate granule cell firing and one that is believed to be key to pattern separation, typically leads to improved classical measures for pattern separation even, inappropriately, up to the point where almost all information about the inputs is lost. Standard measures therefore both cannot differentiate between pattern separation and pattern destruction, and give results that may depend on arbitrary parameter choices. We propose that techniques from information theory, in particular mutual information, transfer entropy, and redundancy, should be applied to penalise the potential for lost information (often due to increased sparsity) that is neglected by existing measures. We compare five commonly-used measures of pattern separation with three novel techniques based on information theory, showing that the latter can be applied in a principled way and provide a robust and reliable measure for comparing the pattern separation performance of different neurons and networks. We demonstrate our new measures on detailed compartmental models of individual dentate granule cells and a dentate microcircuit, and show how structural changes associated with epilepsy affect pattern separation performance. We also demonstrate how our measures of pattern separation can predict pattern completion accuracy. Overall, our measures solve a widely acknowledged problem in assessing the pattern separation of neural circuits such as the dentate gyrus, as well as the cerebellum and mushroom body. Finally we provide a publicly available toolbox allowing for easy analysis of pattern separation in spike train ensembles.

Genetic labeling of embryonically-born dentate granule neurons in young mice using the PenkCre mouse line.

The dentate gyrus (DG) of the hippocampus is a mosaic of dentate granule neurons (DGNs) accumulated throughout life. While many studies focused on the morpho-functional properties of adult-born DGNs, much less is known about DGNs generated during development, and in particular those born during embryogenesis. One of the main reasons for this gap is the lack of methods available to specifically label and manipulate embryonically-born DGNs. Here, we have assessed the relevance of the PenkCre mouse line as a genetic model to target this embryonically-born population. In young animals, PenkCre expression allows to tag neurons in the DG with positional, morphological and electrophysiological properties characteristic of DGNs born during the embryonic period. In addition, PenkCre+ cells in the DG are distributed in both blades along the entire septo-temporal axis. This model thus offers new possibilities to explore the functions of this underexplored population of embryonically-born DGNs.

Altered hippocampal neurogenesis in a mouse model of autism revealed by genetic polymorphisms and by atypical development of newborn neurons.

Individuals with autism spectrum disorder (ASD) often exhibit atypical hippocampal anatomy and connectivity throughout their lifespan, potentially linked to alterations in the neurogenic process within the hippocampus. In this study, we performed an in-silico analysis to identify single-nucleotide polymorphisms (SNPs) in genes relevant to adult neurogenesis in the C58/J model of idiopathic autism. We found coding non-synonymous (Cn) SNPs in 33 genes involved in the adult neurogenic process, as well as in 142 genes associated with the signature genetic profile of neural stem cells (NSC) and neural progenitors. Based on the potential alterations in adult neurogenesis predicted by the in-silico analysis, we evaluated the number and distribution of newborn neurons in the dentate gyrus (DG) of young adult C58/J mice. We found a reduced number of newborn cells in the whole DG, a higher proportion of early neuroblasts in the subgranular layer (SGZ), and a lower proportion of neuroblasts with morphological maturation signs in the granule cell layer (GCL) of the DG compared to C57BL/6J mice. The observed changes may be associated with a delay in the maturation trajectory of newborn neurons in the C58/J strain, linked to the Cn SNPs in genes involved in adult hippocampal neurogenesis.

Waveform-based classification of dentate spikes.

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer's Disease Neuropathology in a Mouse Model.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-ß (Aß) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aß in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aß accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aß levels and therefore has translational implications.

An enhancer-AAV approach selectively targeting dentate granule cells of the mouse hippocampus.

The mammalian brain contains a diverse array of cell types, including dozens of neuronal subtypes with distinct anatomical and functional characteristics. The brain leverages these neuron-type specializations to perform diverse circuit operations and thus execute different behaviors properly. Through the use of Cre lines, access to specific neuron types has improved over past decades. Despite their extraordinary utility, development and cross-breeding of Cre lines is time consuming and expensive, presenting a significant barrier to entry for investigators. Furthermore, cell-based therapeutics developed in Cre mice are not clinically translatable. Recently, several adeno-associated virus (AAV) vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer-AAVs) were developed that overcome these limitations. Using a publicly available RNA sequencing (RNA-seq) dataset, we evaluated the potential of several candidate enhancers for neuron-type-specific targeting in the hippocampus. Here, we demonstrate that a previously identified enhancer-AAV selectively targets dentate granule cells over other excitatory neuron types in the hippocampus of wild-type adult mice.

Granule cells perform frequency-dependent pattern separation in a computational model of the dentate gyrus.

Mnemonic discrimination (MD) may be dependent on oscillatory perforant path input frequencies to the hippocampus in a "U"-shaped fashion, where some studies show that slow and fast input frequencies support MD, while other studies show that intermediate frequencies disrupt MD. We hypothesize that pattern separation (PS) underlies frequency-dependent MD performance. We aim to study, in a computational model of the hippocampal dentate gyrus (DG), the network and cellular mechanisms governing this putative "U"-shaped PS relationship. We implemented a biophysical model of the DG that produces the hypothesized "U"-shaped input frequency-PS relationship, and its associated oscillatory electrophysiological signatures. We subsequently evaluated the network's PS ability using an adapted spatiotemporal task. We undertook systematic lesion studies to identify the network-level mechanisms driving the "U"-shaped input frequency-PS relationship. A minimal circuit of a single granule cell (GC) stimulated with oscillatory inputs was also used to study potential cellular-level mechanisms. Lesioning synapses onto GCs did not impact the "U"-shaped input frequency-PS relationship. Furthermore, GC inhibition limits PS performance for fast frequency inputs, while enhancing PS for slow frequency inputs. GC interspike interval was found to be input frequency dependent in a "U"-shaped fashion, paralleling frequency-dependent PS observed at the network level. Additionally, GCs showed an attenuated firing response for fast frequency inputs. We conclude that independent of network-level inhibition, GCs may intrinsically be capable of producing a "U"-shaped input frequency-PS relationship. GCs may preferentially decorrelate slow and fast inputs via spike timing reorganization and high frequency filtering.

Variations of the grid and place cells in the entorhinal cortex and dentate gyrus of 6 individuals aged 56 to 87 years.

INTRODUCTION: The relationship between the entorhinal cortex (EC) and the hippocampus has been studied by different authors, who have highlighted the importance of grid cells, place cells, and the trisynaptic circuit in the processes that they regulate: the persistence of spatial, explicit, and recent memory and their possible impairment with ageing. OBJECTIVE: We aimed to determine whether older age causes changes in the size and number of grid cells contained in layer III of the EC and in the granular layer of the dentate gyrus (DG) of the hippocampus. METHODS: We conducted post-mortem studies of the brains of 6 individuals aged 56-87 years. The brain sections containing the DG and the adjacent EC were stained according to the Klüver-Barrera method, then the ImageJ software was used to measure the individual neuronal area, the total neuronal area, and the number of neurons contained in rectangular areas in layer III of the EC and layer II of the DG. Statistical analysis was subsequently performed. RESULTS: We observed an age-related reduction in the cell population of the external pyramidal layer of the EC, and in the number of neurons in the granular layer of the DG. CONCLUSION: Our results indicate that ageing causes a decrease in the size and density of grid cells of the EC and place cells of the DG.

Event Integration and Temporal Differentiation: How Hierarchical Knowledge Emerges in Hippocampal Subfields through Learning.

Everyday life is composed of events organized by changes in contexts, with each event containing an unfolding sequence of occurrences. A major challenge facing our memory systems is how to integrate sequential occurrences within events while also maintaining their details and avoiding over-integration across different contexts. We asked if and how distinct hippocampal subfields come to hierarchically and, in parallel, represent both event context and subevent occurrences with learning. Female and male human participants viewed sequential events defined as sequences of objects superimposed on shared color frames while undergoing high-resolution fMRI. Importantly, these events were repeated to induce learning. Event segmentation, as indexed by increased reaction times at event boundaries, was observed in all repetitions. Temporal memory decisions were quicker for items from the same event compared to across different events, indicating that events shaped memory. With learning, hippocampal CA3 multivoxel activation patterns clustered to reflect the event context, with more clustering correlated with behavioral facilitation during event transitions. In contrast, in the dentate gyrus (DG), temporally proximal items that belonged to the same event became associated with more differentiated neural patterns. A computational model explained these results by dynamic inhibition in the DG. Additional similarity measures support the notion that CA3 clustered representations reflect shared voxel populations, while DG's distinct item representations reflect different voxel populations. These findings suggest an interplay between temporal differentiation in the DG and attractor dynamics in CA3. They advance our understanding of how knowledge is structured through integration and separation across time and context.

Protein 4.1N Plays a Cell Type-Specific Role in Hippocampal Glutamatergic Synapse Regulation.

Many glutamatergic synapse proteins contain a 4.1N protein binding domain. However, a role for 4.1N in the regulation of glutamatergic neurotransmission has been controversial. Here, we observe significantly higher expression of protein 4.1N in granule neurons of the dentate gyrus (DG granule neurons) compared with other hippocampal regions. We discover that reducing 4.1N expression in rat DG granule neurons of either sex results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses. By contrast, we find reduction of 4.1N expression in hippocampal CA1 pyramidal neurons has no impact on basal glutamatergic neurotransmission. We also find 4.1N's C-terminal domain (CTD) to be nonessential to its role in the regulation of glutamatergic synapses of DG granule neurons. Instead, we show that 4.1N's four-point-one, ezrin, radixin, and moesin (FERM) domain is essential for supporting synaptic AMPA receptor (AMPAR) function in these neurons. Altogether, this work demonstrates a novel, cell type-specific role for protein 4.1N in governing glutamatergic synapse function.SIGNIFICANCE STATEMENT Glutamatergic synapses exhibit immense molecular diversity. In comparison to heavily studied Schaffer collateral, CA1 glutamatergic synapses, significantly less is known about perforant path-dentate gyrus (DG) synapses. Our data demonstrate that compromising 4.1N function in CA1 pyramidal neurons produces no alteration in basal glutamatergic synaptic transmission. However, in DG granule neurons, compromising 4.1N function leads to a significant decrease in the strength of glutamatergic neurotransmission at perforant pathway synapses. Together, our data identifies 4.1N as a cell type-specific regulator of synaptic transmission within the hippocampus and reveals a unique molecular program that governs perforant pathway synapse function.

Regional and interhemispheric differences of neuronal representations in dentate gyrus and CA3 inferred from expression of zif268.

The hippocampal formation is one of the best studied brain regions for spatial and mnemonic representations. These representations have been reported to differ in their properties for individual hippocampal subregions. One approach that allows the detection of neuronal representations is immediate early gene imaging, which relies on the visualization of genomic responses of activated neuronal populations, so called engrams. This method permits the within-animal comparison of neuronal representations across different subregions. In this work, we have used compartmental analysis of temporal activity by fluorescence in-situ hybridisation (catFISH) of the immediate early gene zif268/erg1 to compare neuronal representations between subdivisions of the dentate gyrus and CA3 upon exploration of different contexts. Our findings give an account of subregion-specific ensemble sizes. We confirm previous results regarding disambiguation abilities in dentate gyrus and CA3 but in addition report novel findings: Although ensemble sizes in the lower blade of the dentate gyrus are significantly smaller than in the upper blade both blades are responsive to environmental change. Beyond this, we show significant differences in the representation of familiar and novel environments along the longitudinal axis of dorsal CA3 and most interestingly between CA3 regions of both hemispheres.

Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.

Neuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices, coupled with fast metabolite preservation and followed by mass spectrometry (MS) imaging, to generate spatially resolved metabolomics and isotope-tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs. Increased glucose metabolism in response to stimulation is accompanied by mobilization of endogenous inosine into pentose phosphates via the action of purine nucleotide phosphorylase (PNP). The PNP reaction is an integral part of the neuronal response to stimulation, because inhibition of PNP leaves DGCs energetically impaired during recovery from strong activation. Performing MS imaging on brain slices bridges the gap between live-cell physiology and the deep chemical analysis enabled by MS.

Sharpening the blades of the dentate gyrus: how adult-born neurons differentially modulate diverse aspects of hippocampal learning and memory.

For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above-mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into "supra-pyramidal" and "infra-pyramidal". Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.

Phase information is conserved in sparse, synchronous population-rate-codes via phase-to-rate recoding.

Neural computation is often traced in terms of either rate- or phase-codes. However, most circuit operations will simultaneously affect information across both coding schemes. It remains unclear how phase and rate coded information is transmitted, in the face of continuous modification at consecutive processing stages. Here, we study this question in the entorhinal cortex (EC)- dentate gyrus (DG)- CA3 system using three distinct computational models. We demonstrate that DG feedback inhibition leverages EC phase information to improve rate-coding, a computation we term phase-to-rate recoding. Our results suggest that it i) supports the conservation of phase information within sparse rate-codes and ii) enhances the efficiency of plasticity in downstream CA3 via increased synchrony. Given the ubiquity of both phase-coding and feedback circuits, our results raise the question whether phase-to-rate recoding is a recurring computational motif, which supports the generation of sparse, synchronous population-rate-codes in areas beyond the DG.