Neurobiology of stress in the cerebellar circuitry

小脑回路应激的神经生物学

基本信息

批准号：
10419685
负责人：
Yi-Mei (Amy) Yang
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-09 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10419685
关键词：
Action Potentials Address Adverse event Affect Animals Anxiety Anxiety Disorders Area Axon Back Behavioral Brain Brain region Cell membrane Cerebellar Cortex Cerebellar Diseases Cerebellar Nuclei Cerebellum Childhood Corticosterone Cre lox recombination system Data Dependovirus Disease Electrophysiology (science)Epigenetic Process Feedback Fluorescence-Activated Cell Sorting Frequencies Gene Expression Gene Expression Profile Gene Transfer Genes Genomics Glucocorticoid Receptor Histone Acetylation Hormones Impaired cognition Impairment Ion Channel Knock-out Knowledge Life Mediating Mediator of activation protein Membrane Memory Loss Mental Depression Mental Health Mental disorders Messenger RNA Methods Molecular Morphology Motor Mus Neocortex Neonatal Neurobiology Neurons Output Pathway interactions Positioning Attribute Potassium Channel Predisposition Process Psychological Stress Psychopathology Purkinje Cells Reporting Rodent Role Slice Social Change Social isolation Specific qualifier value Stimulus Stress Structure Synapses System Techniques Testing Thalamic structure Therapeutic Transcriptional Regulation Up-Regulation Ventral Lateral Thalamic Nucleus Ventral Tegmental Area Vestibular nucleus structure Viral Genes Work adeno-associated viral vector base behavioral phenotyping biological adaptation to stress cell type chromatin immunoprecipitation cohort designer receptors exclusively activated by designer drugs early life stress gene network genome-wide improved insight interdisciplinary approach knock-down maladaptive behavior neural circuit neuronal circuitry neuropsychiatric disorder new therapeutic target novel novel therapeutic intervention overexpression patch clamp patch sequencing promoter prospective psychiatric symptom psychological stressor response single-cell RNA sequencing social spatiotemporal stressor transcriptome transcriptome sequencing

项目摘要

ABSTRACT Social isolation (SI) during childhood increases the susceptibility to neuropsychiatric disorders, including anxiety disorders, depression, and cognitive impairments. Limited treatment for these disorders highlights the importance of identifying new therapeutic targets. Recent evidence has underscored the role of the cerebellum in early-life stress. For example, the neonatal cerebellum contains the highest level of glucocorticoid receptor (GR) in the entire brain, indicating that the cerebellum is enriched in the molecular machinery for processing the stress response. The cerebellum is extensively connected to brain networks that are sensitive to psychological stress. However, whether and how SI stress regulates gene expression in the cerebellum to result in cerebellar dysfunction and maladaptive behaviors remain elusive. To address the knowledge gap, we isolated experimental mice in singly housed cages. They displayed behavioral changes reminiscent of high anxiety, depression, and social memory loss. Moreover, we found that SI impaired intrinsic excitability of Purkinje cells (PCs), the sole output neurons in the cerebellar cortex. And cerebellar gene expression was highly responsive to stress stimuli such as an elevation of corticosterone, a stress hormone, in rodents. These findings fuel our central hypothesis that SI impairs the cerebellar output activity by specifically affecting the intrinsic excitability of PCs; and restoring PC excitability rectifies SI-caused behavioral deficits via the cerebello-cortical networks. To test the hypothesis, we propose a multidisciplinary approach with three specific aims: (1) Determine the molecular basis of reduced PC intrinsic excitability by SI. We will employ two genome-wide RNA sequencing techniques to obtain an unbiased view of transcriptional signatures and epigenetic modifications of SI as well as to identify SI-responsive ion channels in PCs, e.g., Kv1.5. PC-specific knockout of GR will uncover the GR-dependent genomic reprogramming by SI. (2) Define the significance of PC activity in systemic response to SI. Using viral gene transfer, we will gain precise spatiotemporal control of PC excitability to test the necessity and sufficiency of cerebellar activity in mediating the system-wide response to SI. (3) Specify the cerebellum-cortex gateways underlying maladaptive behaviors of SI. Our efforts will be focused on dissecting the neural circuits that connect the cerebellum to the downstream sub/cortical areas and their contributions to the behavioral phenotypes of SI. Completion of this work will advance our understanding of the molecular, cellular and circuitry mechanisms underpinning the non-conventional role of the cerebellum in the stress response, and the results will ultimately help develop novel therapeutic strategies to improve mental health.

抽象的童年时期的社会隔离（SI）会增加对神经精神疾病（包括焦虑）的易感性疾病、抑郁和认知障碍。对这些疾病的有限治疗凸显了确定新的治疗靶点的重要性。最近的证据强调了小脑的作用在早期生活的压力下。例如，新生儿小脑含有最高水平的糖皮质激素受体（GR）在整个大脑中，表明小脑富含处理应激反应。小脑与对心理敏感的大脑网络有着广泛的联系。压力。然而，SI应激是否以及如何调节小脑中的基因表达从而导致小脑功能障碍和适应不良行为仍然难以捉摸。为了解决知识差距，我们隔离了实验老鼠被关在单独的笼子里。他们表现出的行为变化让人想起高度焦虑、抑郁和社会记忆丧失。此外，我们发现 SI 损害了浦肯野细胞 (PC) 的内在兴奋性，而浦肯野细胞是唯一的细胞。小脑皮质的输出神经元。小脑基因表达对应激刺激高度敏感例如啮齿动物体内皮质酮（一种应激激素）的升高。这些发现推动了我们的中心假设 SI 通过专门影响 PC 的内在兴奋性来损害小脑输出活动；并恢复 PC 兴奋性通过小脑皮质网络纠正 SI 引起的行为缺陷。为了检验假设，我们提出了一种具有三个具体目标的多学科方法：（1）确定减少的分子基础 SI 引起的 PC 内在兴奋性。我们将采用两种全基因组 RNA 测序技术来获得公正地看待 SI 的转录特征和表观遗传修饰，并识别 SI 响应 PC 中的离子通道，例如 Kv1.5。 PC 特异性敲除 GR 将揭示 GR 依赖性基因组通过 SI 重新编程。 (2) 定义 PC 活性在 SI 系统反应中的重要性。利用病毒基因转移，我们将获得 PC 兴奋性的精确时空控制，以测试 PC 兴奋性的必要性和充分性小脑活动介导全系统对 SI 的反应。 (3) 指定小脑皮质网关 SI 潜在的适应不良行为。我们的努力将集中于剖析连接的神经回路小脑到下游亚/皮质区域及其对 SI 行为表型的贡献。完成这项工作将增进我们对分子、细胞和电路机制的理解支持小脑在应激反应中的非常规作用，结果最终将帮助制定新的治疗策略以改善心理健康。