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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.

摘要