Hippocampus最新文献

Memory is a cornerstone of human behavior, and addiction offers a compelling model of its persistence and plasticity. The scope of engram research has rapidly expanded to include addiction-related phenomena. Addiction-related memories, like strong aversive memories, are often highly resistant to extinction and can continue to drive relapse long after drug use has ceased. These enduring behavioral effects suggest that drug engrams, sparsely distributed neural ensembles encoding drug-associated experiences, are stabilized by powerful synaptic and molecular plasticity. At the same time, their very malleability may hold the key to developing new treatments. This minireview synthesizes emerging findings on drug engrams, highlighting the specialized circuits, molecular mechanisms, and behavioral consequences tied to addiction-related memory traces. We focus on how engram tagging and reactivation techniques have revealed addiction-specific ensembles across several brain regions and important pathways that promote or attenuate drug-seeking behavior. We also discuss how direct manipulation of drug engrams may hold promise for weakening the influence of drug-associated cues and other relapse triggers, while enhancing protective circuits to reduce relapse risk. Still, fundamental questions remain such as how do drug engrams evolve during the transition from recreational use to addiction? Addressing these questions will be critical for developing circuit-informed, lasting interventions that target the memory systems sustaining addiction.

Neural activity and bodily functions are inherently rhythmic and related to each other. The occurrence of hippocampal sharp-wave ripples (SPW-Rs) and dentate spikes (DSs) supporting memory consolidation is regulated by the overall state of the brain, and they also seem to aggregate to a certain phase of the breathing cycle in naturally sleeping mice. Further, SPW-Rs and DSs synchronize to a variable degree between hemispheres, but how this is affected by the neural and bodily state is unclear. Here, we recorded dorsal hippocampal local-field potentials, electrocardiogram, and respiration for several hours under urethane anesthesia in adult male Sprague–Dawley rats. For a subset of rats, we injected atropine (50 mg/kg, i.p.) halfway into the recording to decrease cholinergic and parasympathetic tone. We found variable relation of hippocampal oscillations to breathing phase and none to the cardiac cycle phase. A decrease in breathing rate implying increased parasympathetic tone preceded the start of SPW-R bouts. Roughly 90% of DSs and half of SPW-Rs were unilateral. In most rats, SPW-Rs were more often bilateral during slow breathing compared to faster breathing. Atropine reduced the proportion of bilateral SPW-Rs. Both nonrapid eye movement sleep-like state and atropine increased the proportion of bilateral DSs under urethane anesthesia. Finally, in naturally sleeping rats, both DSs and SPW-Rs were bilateral ~60% of the time. In sum, urethane seems to desynchronize DSs but not SPW-Rs, and a low cholinergic and/or parasympathetic tone seems to dissociate SPW-Rs and to synchronize DSs in the two hippocampi. Whether these findings have relevance in terms of memory consolidation and behavior should be investigated in the future.

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.