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

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

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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.

项目摘要/摘要抑制性GABA能神经元仅占大脑中所有神经元的15％对于大脑功能和GABA神经元功能障碍至关重要神经系统疾病和精神疾病。特别是，抑制作用可能起独特的作用和海马区域CA3中的重要作用。在CA3区域，DG神经元突触到CA3 通过巨型兴奋性苔藓纤维末端和CA3神经元通过锥体神经元使许多经常连接。因此，在CA3中激发失控的潜力很高。进料认为从DG到CA3的抑制作用被认为是至关重要的，允许特定的兴奋性输入产生有意义的活动模式。尽管海马面积CA3可能有抑制作用，但很少有研究直接研究了GABA神经元活性如何控制CA3锥体神经元活动。我们确定了一组靶向树突的GABA神经元，这些神经元通常表达突触蛋白Kirrel3。 Kirrel3蛋白对于形成MF丝状突触是必要的将DG神经元与GABA神经元连接并介导的兴奋性突触类型向前抑制至CA3。因为Kirrel3必须在突触前和后的后表达神经元成为突触，强烈建议Kirrel3-Expressingn GABA神经元是直接的 MF丝状靶标和K3-GABA神经元的研究将揭示精确的功能 MF丝霉素介导的CA3抑制作用。我们将在跨越超微结构的三个目标中进行测试分析大规模功能细胞成像到行为。在整个过程中，我们将检查通过将其功能与soma- 靶向不表达kirrel3的神经元。无论结果如何促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通性基因的GABA神经元的新框架。