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: 10197242
• 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/10197242
• 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

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）通过改变记忆的模式在记忆形成中发挥着关键作用。 皮质输入转化为 CA3 区域的新输出模式。尽管这种现象的细胞和突触基础 重要的转化仍然知之甚少，DG 中的两种兴奋性细胞类型，颗粒细胞 (GC) 和 肺门苔藓细胞（MC）发挥主要作用。 MC 介导内在的异质关联 (GC-MC-GC) 兴奋性 循环，从相对较少数量的 GC 接收强大的输入，并提供高度分布的兴奋性 输出到大量GC。 MC 将其关联轴突和连合轴突投射到 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 还沿着海马的中隔颞轴投射轴突，从而实现功能性连接 该结构的不同领域。通过沿间隔颞轴投影到 DG 的大部分区域，MC 可以 为皮层产生的信息提供重要的上下文内容。为了了解如何 信息在 DG 中处理，以及该回路的失调如何导致疾病，更好的方法 需要了解异相联 GC-MC-GC 电路及其动态特性。我们有 最近报道，MC-GC 突触经历了一种新颖的突触前、NMDA 受体独立形式 长时程增强 (LTP) 需要突触后脑源性神经营养因子 (BDNF)/TrkB 和 突触前循环 AMP(cAMP)/PKA 信号传导。我们假设这种新型的可塑性可以增强 GC 关联 MC-GC 循环电路的输出，可能有助于 DG 依赖形式的学习和 脑部疾病，例如癫痫。有关该电路的大量问题仍未得到解答。 初步数据表明，MC-GC LTP 是由经验和癫痫活动在体内诱导的，对于 受内源性系统（例如内源性大麻素和腺苷信号传导）调节，并且它可以 伴有抑制性传播的LTP。在这里，结合使用实验方法 在体外和体内，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)确定其性质和机制 抑制性 LTP，(4) 确定体内 MC 可塑性的功能相关性。通过识别主要 DG 中关键循环回路中活动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 信息处理中的精确作用的理解 和记忆编码，还评估该回路的失调如何导致脑部疾病， 包括癫痫、焦虑症、精神分裂症和抑郁症。