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: 10254625
• 负责人: PABLO E CASTILLO
• 金额: $ 8万
• 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/10254625
• 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; Glutamates; Heterogeneity; Hilar; Hippocampus (Brain); 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; Structure of molecular layer of cerebellar cortex; 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; 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; Glutamates; Heterogeneity; Hilar; Hippocampus (Brain); 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; Structure of molecular layer of cerebellar cortex; 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.

海马的齿状回（DG）通过转化的模式在记忆形成中起关键作用 皮质输入成CA3区域的新输出模式。虽然该细胞和突触基础 重要的转化仍然很了解，DG中的两种兴奋性细胞类型（GC）和 Hilar Mossy细胞（MC）起着主要作用。 MCS介导了固有的，杂种（GC-MC-GC）兴奋性 循环，从相对较少的GC中获得强大的输入，并提供高度分布的兴奋性 输出大量GC。 MCS将其关联和合并轴突投射到Ipsi-和 DG的对侧内分子层，在那里它们突触到GC的近端树突上。而且， MC还沿着海马的隔离轴伸出轴突，从而在功能上连接 该结构的各个领域。通过沿隔膜轴投影到DG的大多数区域，MC可以 为皮质产生的信息提供重要的上下文内容。为了了解如何 信息是在DG中处理的，以及该电路的失调可能导致疾病，更好 需要了解杂项缔合性GC-MC-GC电路及其动态特性。我们有 最近报道，MC-GC突触经历了一种新型的突触前NMDA受体独立形式 长期增强（LTP）需要突触后脑衍生的神经营养因子（BDNF）/TRKB和 突触前环状AMP（CAMP）/PKA信号传导。我们假设这种新颖的可塑性增强了GC 在关联MC-GC复发电路处的输出，可能有助于DG依赖的学习形式和 脑疾病，例如癫痫。有关该电路的许多问题仍未得到解决。 初步数据表明MC-GC LTP是通过经验和癫痫活性在体内诱导的，至关重要 由内源系统（例如内源性大麻素和腺苷信号传导）调节，可以是 伴随着抑制性传播的LTP。在这里，使用一系列实验方法的组合 体外和体内，我们的目标是（1）表征MC可塑性的突触学习规则，（2）确定 MC-GC LTP的分子机制，（3）确定属性和机制 抑制性LTP，（4）确定MC可塑性在体内的功能相关性。通过识别主要 在DG中关键的复发电路中活性依赖性可塑性的特性和机制，我们提出 研究不仅可以提高我们对该电路在DG信息处理中的确切作用的理解 和记忆编码，但还评估该电路失调可能导致脑部疾病， 包括癫痫，焦虑，精神分裂症和抑郁症。