A proportion of hippocampal CA1 neurons function as place cells from the onset of navigation, which are referred to as early place cells. It is not clear whether this subset of neurons is predisposed to become place cells during early stages, or if all neurons have this potential. Here, we longitudinally imaged the activity of CA1 neurons in developing male rats during navigation with both one-photon and two-photon microscopy. Our results suggested that a largely consistent population of cells functioned as early place cells, demonstrating higher spatial coding abilities across environments and a tendency to form more synchronous cell assemblies. Early place cells were present in both deep and superficial layers of CA1. Cells in the deep layer exhibited greater synchrony than those in the superficial layer during early ages. These results support the theory that an initial cognitive map is primarily shaped by a predetermined set of hippocampal cells.

It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27 June 2023 for studies on hippocampal neurogenesis in adult primates, excluding review papers. Screening, quality assessment and data extraction was done by independent co-raters. We synthesised evidence from 112 relevant papers. We found robust evidence, primarily supported by immunohistochemical examination of tissue samples and neuroimaging, for newly generated neurons, first detected in the subgranular zone of the dentate gyrus, that mature over time and migrate to the granule cell layer, where they become functionally integrated with surrounding neuronal networks. AHN has been repeatedly observed in both humans and other primates and gradually diminishes with age. Transient increases in AHN are observed following acute insults such as stroke and epileptic seizures, and following electroconvulsive therapy, and AHN is diminished in neurodegenerative conditions. Markers of AHN correlate positively with measures of learning and short-term memory, but associations with antidepressant use and mood states are weaker. Heterogeneous outcome measures limited quantitative syntheses. Further research should better characterise the neuropsychological function of neurogenesis in healthy subjects.

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CBR, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Engineered biological neural networks are indispensable models for investigation of neural function and dysfunction from the subcellular to the network level. Notably, advanced neuroengineering approaches are of significant interest for their potential to replicate the topological and functional organization of brain networks. In this study, we reverse engineered feedforward neural networks of primary cortical and hippocampal neurons, using a custom-designed multinodal microfluidic device with Tesla valve inspired microtunnels. By interfacing this device with nanoporous microelectrodes, we show that the reverse engineered multinodal neural networks exhibit capacity for both segregated and integrated functional activity, mimicking brain network dynamics. To advocate the broader applicability of our model system, we induced localized perturbations with amyloid beta to study the impact of pathology on network functionality. Additionally, we demonstrate long-term culturing of subregion- and layer specific neurons extracted from the entorhinal cortex and hippocampus of adult Alzheimer's-model mice and rats. Our results thus highlight the potential of our approach for reverse engineering of anatomically relevant multinodal neural networks to study dynamic structure-function relationships in both healthy and pathological conditions.

The hippocampus is a brain region that is essential for the initial encoding of episodic memories. However, the consolidation of these memories is thought to occur in the neocortex, under guidance of the hippocampus, over the course of days and weeks. Communication between the hippocampus and the neocortex during hippocampal sharp wave-ripple oscillations is believed to be critical for this memory consolidation process. Yet, the synaptic and circuit basis of this communication between brain areas is largely unclear. To address this problem, we perform in vivo whole-cell patch-clamp recordings in the frontal neocortex and local field potential recordings in CA1 of head-fixed mice exposed to a virtual-reality environment. In mice trained in a goal-directed spatial task, we observe a depolarization in frontal principal neurons during hippocampal ripple oscillations. Both this ripple-associated depolarization and goal-directed task performance can be disrupted by chemogenetic inactivation of somatostatin-positive (SOM) interneurons. In untrained mice, a ripple-associated depolarization is not observed, but it emerges when frontal parvalbumin-positive (PV) interneurons are inactivated. These results support a model where SOM interneurons inhibit PV interneurons during hippocampal activity, thereby acting as a disinhibitory gate for hippocampal inputs to neocortical principal neurons during learning.

The hypothalamic supramammillary nucleus (SuM) projects heavily to the hippocampus to regulate hippocampal activity and plasticity. Although the projections from the SuM to the dentate gyrus (DG) and CA2 have been extensively studied, whether the SuM projects to CA1, the main hippocampal output region, is unclear. Here, we report a glutamatergic pathway from the SuM that selectively excites CA1 interneurons in the border between the stratum radiatum (SR) and the stratum lacunosum-moleculare (SLM). We find that the SuM projects selectively to a narrow band in the CA1 SR/SLM and monosynaptically excites SR/SLM interneurons, including vasoactive intestinal peptide-expressing (VIP) and neuron-derived neurotrophic factor-expressing (NDNF) cells, but completely avoids making monosynaptic contacts with CA1 pyramidal neurons (PNs) or parvalbumin-expressing (PV) or somatostatin-expressing (SOM) cells. Moreover, SuM activation drives spikes in most SR/SLM interneurons to suppress CA1 PN excitability. Taken together, our findings reveal that the SuM can directly regulate hippocampal output region CA1, bypassing CA2, CA3, and the DG.

Contextual memories are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the underlying circuit mechanisms remain largely enigmatic. Here, we demonstrate that extinction of contextual fear conditioning recruits somatostatin interneurons (SST-INs) in the ventral hippocampus. Correspondingly, real-time activity of SST-INs correlates with transitions between immobility and movement, signaling exit from defensive freezing bouts. Optogenetic manipulation of SST-INs but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in freezing that are specific to the context in which extinction was acquired. Finally, similar effects were obtained following extinction of sucrose-based appetitive conditioning, in which SST-IN inhibition triggers relapse to reward seeking. These data suggest that ventral hippocampal SST-INs play a fundamental role in extinction that is independent of affective valence and may be related to their disruption of spontaneous emotional responses.