Hippocampus最新文献

Our understanding of how the medial temporal lobe (MTL) contributes to human cognition has advanced enormously over the past half a century. My work in the 1990s characterizing the role of recollection and familiarity processes in episodic memory led me to study the MTL's role in these two memory processes. In the current paper, I provide a personal commentary in which I describe the motivating ideas, as well as the invaluable impact of mentors, colleagues, and students that led to a series of studies showing that conscious recollection is critically dependent on the hippocampus, whereas familiarity-based judgments are dependent on regions such as the perirhinal cortex.

Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration, somatodendritic backpropagation, and plateau potential generation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.

Memories formed in adulthood can last a lifetime, whereas those formed early in life are rapidly forgotten through a process known as infantile amnesia. In recent years, tremendous progress has been made in understanding the memory engram—the physical trace of a memory in the brain—and how it transforms as memories evolve from recent to remote. This review focuses on engram cells and examines their roles in memory encoding, consolidation, retrieval, and forgetting from development to adulthood. We concentrate on four key brain regions: the hippocampus, the retrosplenial cortex, the medial prefrontal cortex, and the anterior thalamic nuclei. We first focus on the adult brain, highlighting recent studies that reveal the distinct contributions of engram cells in each brain region, with particular emphasis on synaptic plasticity and memory consolidation. We then explore how coordinated activity across these regions supports long-term memory. In the second section, we review emerging knowledge of engram cells in the developing brain, examining how developmental differences in their functions contribute to infant memory generalization and infantile amnesia. Compared to adults, much less is known about how, or to what extent, early-life memories undergo consolidation. In the final section, we synthesize current knowledge of memory consolidation and retrieval in the adult brain with what is known about the development of the four brain regions we discuss. We then propose key directions for future research. In sum, this review brings together recent findings that deepen our understanding of the dynamic changes in memory engrams that underlie consolidation and long-term storage and explores how developmental differences may shape the maturation of memory processes.

The dorsal and ventral hippocampus have distinct processing properties, but it remains unclear if interneuron subtypes differ in connectivity along the dorsoventral axis. Oriens lacunosum-moleculare (OLM) interneurons, identified by the Chrna2 gene, are known to regulate memory processes differently along this axis. OLMɑ2 cells bidirectionally modulate risk-taking behavior, while ventral hippocampal medial prefrontal cortex (mPFC)-projecting neurons regulate approach and avoidance behaviors. Using rabies virus-mediated monosynaptic retrograde tracing, we show that OLMɑ2 cells receive differential innervation across the dorsal, intermediate, and ventral hippocampus. We find that CA1 and CA3 inputs differ between hippocampal poles, suggesting that OLMɑ2 cells may have distinct feedback and feed-forward inhibitory roles in the hippocampal microcircuit. Intermediate OLMɑ2 cells uniquely receive substantial input from the subiculum and dorsal/medial raphe nuclei, as well as widespread CA2 inputs potentially linked to social memory. The medial septum and diagonal band of Broca provide cholinergic, GABAergic, and glutamatergic inputs across the axis, likely influencing disinhibition and oscillatory activity during various behavioral states. Excitatory input to intermediate-ventral OLMɑ2 cells partly arises from CA1 projection neurons targeting the mPFC. This suggests a gate-switching function that favors CA3 input to projection neurons by two different mechanisms related to feedback and feed-forward inhibition. In conclusion, OLMɑ2 cells exhibit distinct presynaptic input profiles along the dorsoventral axis, with major differences in the proportions of intrahippocampal inputs, highlighting their diverse roles in hippocampal microcircuits.

Early-life stress and depression among youths are linked to hippocampal gray- and white-matter alterations. Less is known about hippocampal alterations in adolescent anxiety disorders (Anx) or the role that stress or comorbid depressive disorders (Anx + Dep) might play. Here, structural- and diffusion-MRI along with early-life stress-exposure reports were acquired from 197 adolescents (13.58–17.00 years) with Anx, Anx + Dep, and those without (Controls). A normative model externally validated on a large, healthy sample revealed that Anx were more likely than Controls and Anx + Dep to exhibit undersized hippocampal gray-matter volumes for their ages. Volume reductions among Anx were further localized to subfield CA1. No significant gray-matter differences were observed between Anx + Dep and Controls. Standardized probabilistic tractography in hippocampal white-matter pathways demonstrated that, relative to Controls, Anx and Anx + Dep exhibited lower fractional anisotropy specifically in the cingulum-temporal branch. All effects were specific to hippocampal structures. Group differences were not accounted for by early-life stress exposures, despite Anx and Anx + Dep reporting more than Controls. Findings indicated that gray-matter expansion, principally within CA1, may be disrupted among adolescents with anxiety disorders, but not those with comorbid depression. The progressive strengthening of hippocampal-cortical circuits occurring during adolescence may also be disrupted in adolescents with anxiety disorders, regardless of depression.

In the hippocampus, there is a region- and synapse-specific N-methyl-D-aspartate receptor (NMDAR) co-agonist preference for induction of long-term potentiation (LTP). Schaffer collateral (SC)-CA1 synapses, enriched in GluN2A-containing NMDARs, favor D-serine, while medial perforant path (MPP) to dentate gyrus (DG) synapses that are rich in GluN2B-containing NMDARs prefer glycine for LTP induction. This study investigated the role of astrocytes in providing these co-agonists. We confirmed in rat hippocampal slices that exogenous D-serine (10 μM) is sufficient to restore LTP at SC-CA1 synapses blocked under astrocyte calcium (Ca²⁺) -clamp conditions, consistent with previous findings. However, exogenous glycine (10 μM) also rescued the LTP. In contrast, at MPP-DG synapses, 100 μM exogenous glycine, but not 10 μM nor 100 μM D-serine, restored the LTP blocked by astrocyte Ca²⁺-clamping. Our findings support the view that, as for serine in CA1, astrocytes are the cellular source of the glycine required for LTP induction at MPP-DG synapses.