Inhibitory regulation of hippocampal CA3 neuron activity, learning, and memory

海马 CA3 神经元活动、学习和记忆的抑制性调节

基本信息

批准号：
10753861
负责人：
JAMES Gerard HEYS
金额：
$ 58.56万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753861
关键词：
Adhesions Affect Area Axon Behavior Brain Brain Diseases Brain region Defect Dendrites Discrimination Distal Electron Microscopy Elements Environment Equilibrium Excitatory Synapse Face Filopodia Fright Genes Genetic Glutamates Head Hippocampus Image Individual Intellectual functioning disability Knowledge Learning Mediating Memory Mental disorders Mus Neuronal Dysfunction Neurons Outcome Parvalbumins Pattern Physiological Play Presynaptic Terminals Proteins Pyramidal Cells Recurrence Regulation Risk Factors Role Runaway Site Specificity Structure Synapses Testing Work autism spectrum disorder cellular imaging conditioned fear dentate gyrus designer receptors exclusively activated by designer drugs experimental study fear memory gamma-Aminobutyric Acid hippocampal pyramidal neuron inhibitory neuron memory encoding memory retrieval mossy fiber nervous system disorder neuronal cell body postsynaptic neurons predictive modeling presynaptic presynaptic neurons public health relevance selective expression virtual reality

项目摘要

PROJECT SUMMARY/ABSTRACT Inhibitory GABAergic neurons comprise only about 15% of all neurons in the brain yet their activity is critical for all aspects of brain function and GABA neuron dysfunction is implicated in many neurological disorders and mental illnesses. In particular, inhibition likely plays a unique and important role in hippocampal area CA3. In the CA3 region, DG neurons synapse onto CA3 pyramidal neurons via giant excitatory mossy fiber terminals and CA3 neurons make many recurrent connections. Thus, the potential for runaway excitation in CA3 is high. Feed-forward inhibition from DG to CA3 is thought to be critical allow specific excitatory inputs to generate meaningful activity patterns. Despite the likely importance of inhibition in hippocampal area CA3, few studies have directly examined how GABA neuron activity controls CA3 pyramidal neuron activity. We identified a group of dendrite-targeting GABA neurons that commonly express the synaptogenic protein Kirrel3. Kirrel3 protein is necessary to form MF filopodia synapses, a special type of excitatory synapse that connects DG neurons to GABA neurons and mediates feed- forward inhibition to CA3. Because Kirrel3 must be expressed in both the pre- and post-synaptic neuron to make a synapse, it strongly suggests Kirrel3-expressingn GABA neurons are direct targets of MF filopodia and the study of K3-GABA neurons will shed light on the precise function of MF filopodia-mediated inhibition in CA3. We will test this in three aims spanning ultrastructural analysis to large-scale functional cell imaging to behavior. Throughout, we will examine the selectivity of this group of dendrite-targeting GABA neurons by comparing their function to soma- targeting neurons that do not express Kirrel3. Regardless of outcome, our results are expected advance our understanding of GABA neuron activity in learning and memory and could provide a new framework for studying GABA neurons that share synaptic connectivity genes.

项目概要/摘要抑制性 GABA 能神经元仅占大脑所有神经元的 15%，但它们的活动对大脑功能的各个方面都至关重要，GABA 神经元功能障碍与许多疾病有关神经系统疾病和精神疾病。特别是，抑制可能发挥着独特的作用海马CA3区有重要作用。在 CA3 区域，DG 神经元突触到 CA3 锥体神经元通过巨大的兴奋性苔藓纤维末端和 CA3 神经元使许多重复连接。因此，CA3 失控激发的可能性很高。前馈从 DG 到 CA3 的抑制被认为是至关重要的，允许产生特定的兴奋性输入有意义的活动模式。尽管抑制海马区 CA3 可能很重要，很少有研究直接研究 GABA 神经元活性如何控制 CA3 锥体神经元活动。我们鉴定了一组针对树突的 GABA 神经元，它们通常表达突触蛋白 Kirrel3。 Kirrel3 蛋白是形成 MF 丝状伪足突触所必需的，这是一种特殊的连接 DG 神经元和 GABA 神经元并介导进食的兴奋性突触类型对 CA3 的正向抑制。因为Kirrel3必须在突触前和突触后均表达神经元形成突触，这强烈表明表达 Kirrel3 的 GABA 神经元是直接的 MF丝状伪足的靶点和K3-GABA神经元的研究将揭示其精确功能 MF 丝状伪足介导的 CA3 抑制作用。我们将在超微结构的三个目标中对此进行测试对大规模功能细胞成像和行为进行分析。在整个过程中，我们将检查通过比较这组树突靶向 GABA 神经元的功能与体细胞的选择性靶向不表达 Kirrel3 的神经元。无论结果如何，我们的结果都是预期的增进我们对学习和记忆中 GABA 神经元活动的理解，并可以提供研究共享突触连接基因的 GABA 神经元的新框架。