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Cell-type and whole-brain dynamics underlying operant social stress resiliency

操作性社会压力弹性背后的细胞类型和全脑动力学

基本信息

批准号：
10676636
负责人：
Jovana Navarrete
金额：
$ 4.77万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676636
关键词：
Acute Affective Anatomy Automobile Driving Awareness Behavior Behavioral Biological Brain Brain region Calcium Chronic Classification Clinical Complex Consult Coping Skills Data Decision Making Depressed mood Development Diagnosis Dopamine Receptor Emotions Exhibits Experimental Designs Exposure to Female Fiber Future Goals Health Care Costs Health Professional Image Immunohistochemistry Individual Individual Differences Injections Institution Investigation Light Literature Major Depressive Disorder Maps Microscopy Modeling Modernization Mood Disorders Motivation Mus Neurons Neurosciences Nucleus Accumbens Phenotype Photometry Population Population Heterogeneity Predisposition Procedures Recombinant adeno-associated virus (rAAV)Reproducibility Research Rewards Rhodopsin Role Running Sensory Social Behavior Societies Stains Stress Techniques Time Tracer Training Transgenic Mice Viral Woman Work awake cell type comorbidity computational neuroscience computer framework coping coping mechanism effective therapy genetic approach insight interest machine learning pipeline machine learning prediction male men neural neural network neuromechanism neuropsychiatry novel optogenetics pre-clinical resilience resilient behavior response reward circuitry sex social social contact social defeat social deficits social metrics social stress stress resilience temporal measurement wireless

项目摘要

Project Summary Prolonged elevated levels of stress are comorbid with many neuropsychiatric illnesses such as major depressive disorder (MDD), and can have devastating effects on individuals, their caretakers, and healthcare professionals. MDD is typically demarcated as exhibiting emotions of sadness, significant loss of motivation, and can be defined by social deficits. A growing literature indicates that major depressive disorder is influenced by dysregulation in limbic brain regions including stress and reward circuitry. Despite a significant clinical awareness, direct preclinical characterization of affective disorder circuitry and associated neuronal mechanisms inclusive of sex as a biological variable are currently absent, and notably do not include social decision making and motivation as behavioral metrics. Therefore, the aim of my proposal is to obtain the necessary computational, behavioral and anatomical training to identify, interrogate, and manipulate neural populations that modulate these complex social behaviors. This project will focus on identifying nucleus accumbens (NAc) circuit and cell type specific mechanisms that regulate resiliency to operant social stress (OSS), and then further interrogate the afferent projections driving these populations. OSS incorporates social decision making and social reward as metrics for social stress resiliency. The choice of this brain region is based on converging preliminary data, implicating that the NAc dopamine receptor (Drd) 1 and Drd2 medium spiny neurons (MSNs) confer opposing roles in regulating resiliency to social stress. NAc circuit and cell-type specific activation will be identified using a combination of whole brain clearing, Fos (a marker of neuronal activity) immunohistochemistry, and retrograde viral tracing. Because of the limited temporal resolution of Fos during these behaviors, awake-behaving fiber photometry recordings will be used to observe how NAc MSNs encode varying levels of susceptibility and resiliency to OSS in real-time. Next, the causal significance of the NAc and its afferent projections will be examined using region, circuit, and cell type specific optogenetic manipulations. Understanding the neural mechanisms driving operant social stress in a sex-dependent manner will allow for the development of more specific and effective treatments for affective mood disorders such as major depressive disorder (MDD).

项目总结