Perpetual step-like restructuring of hippocampal circuit dynamics.

Representation of the environment by hippocampal populations is known to drift even within a familiar environment, which could reflect gradual changes in single cell activity or result from averaging across discrete switches of single neurons. Disambiguating these possibilities is crucial, as they each imply distinct mechanisms. Leveraging change point detection and model comparison, we found that CA1 population vectors decorrelated gradually within a session. In contrast, individual neurons exhibited predominantly step-like emergence and disappearance of place fields or sustained change in within-field firing. The changes were not restricted to particular parts of the maze or trials and did not require apparent behavioral changes. The same place fields emerged, disappeared, and reappeared across days, suggesting that the hippocampus reuses pre-existing assemblies, rather than forming new fields de novo. Our results suggest an internally-driven perpetual step-like reorganization of the neuronal assemblies.

Selection of experience for memory by hippocampal sharp wave ripples.

Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered. When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials, and their specific spike content decoded the trial blocks that surrounded them. During postexperience sleep, SPW-Rs continued to replay those trial blocks that were reactivated most frequently during waking SPW-Rs. Replay content of awake SPW-Rs may thus provide a neurophysiological tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

Subfield-specific interneuron circuits govern the hippocampal response to novelty in male mice.

The hippocampus is the brain's center for episodic memories. Its subregions, the dentate gyrus and CA1-3, are differentially involved in memory encoding and recall. Hippocampal principal cells represent episodic features like movement, space, and context, but less is known about GABAergic interneurons. Here, we performed two-photon calcium imaging of parvalbumin- and somatostatin-expressing interneurons in the dentate gyrus and CA1-3 of male mice exploring virtual environments. Parvalbumin-interneurons increased activity with running-speed and reduced it in novel environments. Somatostatin-interneurons in CA1-3 behaved similar to parvalbumin-expressing cells, but their dentate gyrus counterparts increased activity during rest and in novel environments. Congruently, chemogenetic silencing of dentate parvalbumin-interneurons had prominent effects in familiar contexts, while silencing somatostatin-expressing cells increased similarity of granule cell representations between novel and familiar environments. Our data indicate unique roles for parvalbumin- and somatostatin-positive interneurons in the dentate gyrus that are distinct from those in CA1-3 and may support routing of novel information.

Case report: Anti N-methyl-D-aspartate autoimmune encephalitis following a mildly symptomatic COVID-19 infection in an adolescent male.

Background: Antibodies against N-methyl-D-aspartate receptors are the most commonly identified cause of autoimmune encephalitis. While predominantly associated with malignancies, cases of anti-N-methyl-D-aspartate receptor autoimmune encephalitis have been reported after infections with the herpes-simplex virus or, more recently, in patients with severe COVID-19 disease. Case presentation: A previously healthy 17-year-old male adolescent acutely developed psychosis with auditory and visual hallucinations, fluctuating mental status, and an isolated seizure 5 weeks after a mildly symptomatic COVID-19 infection. The symptoms continued to worsen, accompanied by catatonia, and additional neurological symptoms developed during the initial antipsychotic treatment. A diagnostic workup revealed antibodies against N-methyl-D-aspartate receptors in the cerebrospinal fluid without other major abnormalities. After establishing the diagnosis, initiation of immunomodulatory therapy stopped the symptom progression and led to full recovery within 2 months. Conclusion: The case is remarkable in that anti-N-methyl-D-aspartate receptor autoimmune encephalitis developed shortly after a COVID-19 infection in an adolescent, despite the individual experiencing only mild COVID symptoms. The diagnosis should be considered in cases of acute-onset psychotic symptoms during or after COVID-19 infection, particularly in individuals without a prior psychiatric history, who present with atypical psychiatric or neurological features.

Selection of experience for memory by hippocampal sharp wave ripples.

A general wisdom is that experiences need to be tagged during learning for further consolidation. However, brain mechanisms that select experiences for lasting memory are not known. Combining large-scale neural recordings with a novel application of dimensionality reduction techniques, we observed that successive traversals in the maze were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered (trial number). When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials and their unique spike content most often decoded the trial in which they occurred. In turn, during post-experience sleep, SPW-Rs continued to replay those trials that were reactivated most frequently during awake SPW-Rs. These findings suggest that replay content of awake SPW-Rs provides a tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

The hippocampus converts dynamic entorhinal inputs into stable spatial maps.

The medial entorhinal cortex (MEC)-hippocampal network plays a key role in the processing, storage, and recall of spatial information. However, how the spatial code provided by MEC inputs relates to spatial representations generated by principal cell assemblies within hippocampal subfields remains enigmatic. To investigate this coding relationship, we employed two-photon calcium imaging in mice navigating through dissimilar virtual environments. Imaging large MEC bouton populations revealed spatially tuned activity patterns. MEC inputs drastically changed their preferred spatial field locations between environments, whereas hippocampal cells showed lower levels of place field reconfiguration. Decoding analysis indicated that higher place field reliability and larger context-dependent activity-rate differences allow low numbers of principal cells, particularly in the DG and CA1, to provide information about location and context more accurately and rapidly than MEC inputs. Thus, conversion of dynamic MEC inputs into stable spatial hippocampal maps may enable fast encoding and efficient recall of spatio-contextual information.

Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories.

The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions, indicating that the rest of the hippocampus (CA1-CA3) can operate autonomously under certain conditions. An extensive body of theoretical work has proposed how the architectural elements and various cell types of the DG may underlie its function in cognition. Recent studies recorded and manipulated the activity of different neuron types in the DG during memory tasks and have provided exciting new insights into the mechanisms of DG computational processes, particularly for the encoding, retrieval and discrimination of similar memories. Here, we review these DG-dependent mnemonic functions in light of the new findings and explore mechanistic links between the cellular and network properties of, and the computations performed by, the DG.

Parallel emergence of stable and dynamic memory engrams in the hippocampus.

During our daily life, we depend on memories of past experiences to plan future behaviour. These memories are represented by the activity of specific neuronal groups or 'engrams'1,2. Neuronal engrams are assembled during learning by synaptic modification, and engram reactivation represents the memorized experience 1 . Engrams of conscious memories are initially stored in the hippocampus for several days and then transferred to cortical areas 2 . In the dentate gyrus of the hippocampus, granule cells transform rich inputs from the entorhinal cortex into a sparse output, which is forwarded to the highly interconnected pyramidal cell network in hippocampal area CA3 3 . This process is thought to support pattern separation 4 (but see refs. 5,6). CA3 pyramidal neurons project to CA1, the hippocampal output region. Consistent with the idea of transient memory storage in the hippocampus, engrams in CA1 and CA2 do not stabilize over time7-10. Nevertheless, reactivation of engrams in the dentate gyrus can induce recall of artificial memories even after weeks 2 . Reconciliation of this apparent paradox will require recordings from dentate gyrus granule cells throughout learning, which has so far not been performed for more than a single day6,11,12. Here, we use chronic two-photon calcium imaging in head-fixed mice performing a multiple-day spatial memory task in a virtual environment to record neuronal activity in all major hippocampal subfields. Whereas pyramidal neurons in CA1-CA3 show precise and highly context-specific, but continuously changing, representations of the learned spatial sceneries in our behavioural paradigm, granule cells in the dentate gyrus have a spatial code that is stable over many days, with low place- or context-specificity. Our results suggest that synaptic weights along the hippocampal trisynaptic loop are constantly reassigned to support the formation of dynamic representations in downstream hippocampal areas based on a stable code provided by the dentate gyrus.

Joint CP-AMPA and group I mGlu receptor activation is required for synaptic plasticity in dentate gyrus fast-spiking interneurons.

Hippocampal principal cell (PC) assemblies provide the brain with a mnemonic representation of space. It is assumed that the formation of cell assemblies is supported by long-lasting modification of glutamatergic synapses onto perisomatic inhibitory interneurons (PIIs), which provide powerful feedback inhibition to neuronal networks. Repetitive activation of dentate gyrus PIIs by excitatory mossy fiber (MF) inputs induces Hebbian long-term potentiation (LTP). In contrast, long-term depression (LTD) emerges in the absence of PII activity. However, little is known about the molecular mechanisms underlying synaptic plasticity in PIIs. Here, we examined the role of group I metabotropic glutamate receptors 1 and 5 (mGluRs1/5) in inducing plastic changes at MF-PII synapses. We found that mGluRs1/5 are located perisynaptically and that pharmacological block of mGluR1 or mGluR5 abolished MF-LTP. In contrast, their exogenous activation was insufficient to induce MF-LTP but cleared MF-LTD. No LTP could be elicited in PIIs loaded with blockers of G protein signaling and Ca(2+)-dependent PKC. Two-photon imaging revealed that the intracellular Ca(2+) rise necessary for MF-LTP was largely mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs), but less by NMDA receptors or mGluRs1/5. Thus, our data indicate that fast Ca(2+) signaling via CP-AMPARs and slow G protein-mediated signaling via mGluRs1/5 converge to a PKC-dependent molecular pathway to induce Hebbian MF-LTP. We further propose that Hebbian activation of mGluRs1/5 gates PIIs into a "readiness mode" to promote MF-LTP, which, in turn, will support timed PII recruitment, thereby assisting in PC assembly formation.