The Molecular Mechanisms Underlying Basolateral Amygdala Neuron Development

基底外侧杏仁核神经元发育的分子机制

• 批准号: 10513479
• 负责人: Rothem Kovner
• 金额: $ 0.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513479
• 关键词: Adult; Amygdaloid structure; Behavior; Biological Assay; Brain region; Cell Nucleus; Cells; ChIP-seq; Complex; Cues; Data; Data Set; Development; EMSA; Electrophoretic Mobility Shift Assay; Emotional; Emotions; Etiology; Event; Functional disorder; Gene Expression Profile; Genetic; Genetic Models; Genomics; Genotype; Glutamates; Human; In Situ Hybridization; Interneurons; Knockout Mice; Laboratories; Lateral; Learning; Light; Luciferases; Memory; Molecular; Motivation; Mus; Negative Valence; Neurodevelopmental Disorder; Neurons; Nuclear RNA; Output; Participant; Play; Population; Positive Valence; Prefrontal Cortex; Process; Rewards; Role; Small Nuclear RNA; Social Behavior; Source; Stimulus; Stream; Structure; Techniques; Testing; Time; Validation; Work; cell type; chromatin immunoprecipitation; conditional knockout; excitatory neuron; experimental study; gene regulatory network; member; migration; mouse genetics; neuron development; neuropsychiatric disorder; prenatal; programs; response; transcription factor; transcription regulatory network; transcriptome sequencing; transcriptomics

ABSTRACT The amygdala is a formation of interconnected nuclei essential for encoding the emotional and motivational components of behavior, learning, and memory. Perturbations of amygdala development are thought to contribute to many neuropsychiatric disorders, but neither the timing of nor the precise cellular substrates subject to these perturbations are well understood. Consequently, assessing the molecular identities and developmental programs governing the amygdala is essential for understanding the etiology of neuropsychiatric disease. Here, I propose to decipher the gene regulatory networks necessary for the development of the basolateral amygdala complex (BLA), a group of nuclei comprised largely of glutamatergic cells that serve as the primary functional input to the amygdala. Studies from our laboratory have identified transcription factors that play critical roles in the development of glutamatergic neurons, similar to those that populate the amygdala. In this proposal I will focus on one transcription factor, characterizing its role in the migration and survival of different types of BLA glutamatergic neurons and identify its downstream effectors. To do so, I will use a conditional knockout mouse and conduct single nuclear RNA sequencing (snRNA-Seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and validation experiments of candidate downstream effectors. Cellular, molecular, and genomic techniques are well established in the Sestan laboratory, and this expertise will allow me to both elucidate the molecular processes governing BLA glutamatergic projection neuron specification and identity and aid in deciphering the relevant developmental context underlying numerous neuropsychiatric disorders.

摘要 杏仁核是由相互连接的核组成的，对编码情绪和动机是必不可少的。 行为、学习和记忆的组成部分。杏仁核发育的干扰被认为是 导致许多神经精神障碍，但既不是时间的选择也不是确切的细胞底物 对于这些扰动是很好理解的。因此，评估分子同一性和发育 控制杏仁核的程序对于了解神经精神疾病的病因学是必不可少的。这里, 我建议破译杏仁基底外侧核发育所必需的基因调控网络。 复合体(BLA)，一组核，主要由谷氨酸能细胞组成，充当主要功能 杏仁核的输入。我们实验室的研究已经确定了转录因子在 谷氨酸能神经元的发育，类似于杏仁核中的神经元。在这项提议中，我将 聚焦于一种转录因子，描述其在不同类型白血球的迁移和存活中的作用 谷氨酸能神经元并确定其下游效应器。为此，我将使用有条件的敲除鼠标 并进行单核RNA测序(SnRNA-Seq)、染色质免疫沉淀 候选下游效应器的测序(CHIP-SEQ)和验证实验。细胞、分子和 基因组技术在Sestan实验室已经建立得很好了，这种专业知识将使我能够既 阐明控制BLA谷氨酸能投射神经元特性和特性的分子过程 帮助破译许多神经精神障碍背后的相关发育背景。