Activity-Dependent Plasticity in an Associative Hippocampal Circuit: Mechanisms, Synaptic Learning Rules and Involvement in Disease

关联海马回路中的活动依赖性可塑性：机制、突触学习规则和疾病参与

• 批准号: 10647661
• 负责人: PABLO E CASTILLO
• 金额: $ 53.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647661
• 关键词: Adenosine; Adult; Animals; Anxiety; Area; Axon; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Cells; Contralateral; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dendrites; Disease; Dorsal; Electrophysiology (science); Emotional; Endocannabinoids; Epilepsy; Epileptogenesis; Equilibrium; Exhibits; Genes; Genetic; Glutamates; Heterogeneity; Hilar; Hippocampus; In Vitro; Interneurons; Knowledge; Learning; Life; Long-Term Potentiation; Mediating; Memory; Mental Depression; Modification; Molecular; N-Methyl-D-Aspartate Receptors; Neurons; Output; Parahippocampal Gyrus; Pattern; Perforant Pathway; Play; Positioning Attribute; Process; Property; Recurrence; Reporting; Research Proposals; Rodent; Role; Schizophrenia; Sentinel; Signal Transduction; Slice; Source; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Translating; Work; adult neurogenesis; awake; behavioral study; cell type; dentate gyrus; detector; endogenous cannabinoid system; entorhinal cortex; environmental change; environmental enrichment for laboratory animals; experience; granule cell; hippocampal pyramidal neuron; imaging study; improved; in vivo; information processing; memory encoding; mossy fiber; neural circuit; neuronal cell body; neuropsychiatry; novel; optogenetics; place fields; postsynaptic; presynaptic; spatial memory; synaptic function; transmission process; two-photon

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation by transforming patterns of cortical inputs into new patterns of output to the CA3 area. Although the cellular and synaptic basis of this important transformation remain poorly understood, two excitatory cell types in the DG, granule cells (GC) and hilar mossy cells (MC), play a major role. MCs mediate an intrinsic, hetero-associative (GC-MC-GC) excitatory loop, receiving powerful input from a relatively small number of GCs, and providing highly distributed excitatory output to a large number of GCs. MCs project their associational and commissural axons to the ipsi- and contralateral inner molecular layer of the DG, where they synapse onto proximal dendrites of GCs. Moreover, MCs also project their axons along the septotemporal axis of the hippocampus, thereby connecting functionally diverse areas of this structure. By projecting to most areas of the DG along the septotemporal axis, MCs could provide important contextual content to the information arising from the cortex. In order to understand how information is processed in the DG and how dysregulation of this circuit may contribute to disease, a better knowledge of the hetero-associative GC-MC-GC circuit and its dynamic properties is required. We have recently reported that MC-GC synapses undergo a novel presynaptic, NMDA-receptor independent form of long-term potentiation (LTP) that requires postsynaptic brain-derived neurotrophic factor (BDNF)/TrkB and presynaptic cyclic AMP(cAMP)/PKA signaling. We hypothesize that this novel form of plasticity enhances GC output at the associative MC-GC recurrent circuit, and may contribute to DG-dependent forms of learning and brain disease, such as epilepsy. A large number of questions regarding this circuit remain unanswered. Preliminary data indicates that MC-GC LTP is induced in vivo by experience and epileptic activity, is critically regulated by endogenous systems (e.g. endocannabinoid and adenosine signaling), and it can be accompanied by LTP of inhibitory transmission. Here, using a combination of experimental approaches both in vitro and in vivo, we aim to (1) characterize the synaptic learning rules of MC plasticity, (2) identify the molecular mechanism underlying MC-GC LTP, (3) determine the properties and mechanism underlying inhibitory LTP, and (4) determine the functional relevance of MC plasticity in vivo. By identifying the main properties and mechanisms of activity-dependent plasticity in a crucial recurrent circuit in the DG, our proposed studies may not only improve our understanding of the precise role of this circuit in DG information processing and memory encoding, but also assess how dysregulation of this circuit may contribute to brain disease, including epilepsy, anxiety, schizophrenia and depression.

海马体的齿状回（DG）通过改变记忆模式在记忆形成中起着关键作用