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Circuit-based study of sex differences in stress-induced dopamine down regulation

基于回路的压力诱导多巴胺下调性别差异研究

基本信息

批准号：
9257545
负责人：
Millie Rincon Cortes
金额：
$ 5.43万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257545
关键词：
Acute Affect Amygdaloid structure Anhedonia Animal Model Anxiety Disorders Behavior Behavioral Behavioral Assay Chronic Chronic stress Clinical Corticosterone Data Development Diagnosis Disease Dopamine Down-Regulation Drug Addiction Electrophysiology (science)Etiology Exhibits Exposure to Female Financial compensation Functional disorder Globus Pallidus Gonadal Hormones Hippocampus (Brain)Intervention Lateral Lead Learned Helplessness Light Link Measures Medial Mediating Mental Depression Mental disorders Mood Disorders Motivation Nature Neurobiology Neurons Nucleus Accumbens Paper Pathway interactions Pattern Population Predisposition Prefrontal Cortex Prevalence Rattus Regulation Rewards Risk Factors Schizophrenia Sex Characteristics Stimulus Stress Sucrose Sum Swimming System Testing Therapeutic Ventral Tegmental Area Woman Women&apos s Role acute stress attenuation base behavior test depressive symptoms designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron experience extracellular functional disability improved in vivo indexing insight interest male men mesolimbic system neurobehavioral novel pleasure preclinical study preference relating to nervous system response sex sexual dimorphism social stress disorder stressor symptomatology treatment strategy

项目摘要

PROJECT SUMMARY Women are twice more likely than men to be diagnosed with depression, and depression is more severe and associated with greater functional impairment in women. However, the neurobiological underpinnings of this increased female susceptibility to depression are unknown. The dopamine (DA) system has traditionally been associated with anhedonia, the inability to derive pleasure from normally rewarding stimuli, and has been recently implicated in the pathophysiology in depression. Importantly, anhedonia is a core symptom of depression and other psychiatric diseases involving DA system dysregulation and characterized by substantial sex differences in their prevalence and nature, such as schizophrenia and drug addiction. Indeed, recent evidence has demonstrated a causal link between a hypofunctioning DA system (i.e. decreased DA neuron activity) and depression-related behaviors (i.e. anhedonia, despair). Surprisingly, little is known about DA system function in females. Thus, characterizing baseline DA system function, as well as stress-induced alterations within this system, is an essential step in understanding sexual dimorphism in the etiology of depression and other psychiatric disorders. Moreover, given the strong link between the DA system and depression, there is a significant potential benefit from novel interventions targeting DA system dysfunction in depression. In sum, the purpose of this proposal is threefold: 1) to define baseline behavioral and DA system function in male and female rats 2) to compare stress-induced behavioral and VTA DA neuron adaptations in male and female rats and 3) to identify potential pathways mediating susceptibility to stressors (i.e. acute, chronic) that differentially impact females. Our overarching hypothesis is that females are more susceptible to the deleterious effects of stress on behavior and VTA activity, and that these effects are mediated by decreased compensation (i.e. activity) in the vSub-NAc pathway. To test this, we will use an integrated systems-oriented approach focused on behavioral assays in vivo electrophysiology, chemogenetics. In this way, we hope to provide a unique perspective on the regulation of the DA system in males and females, the role of the DA system in stress-induced depressive-like symptomatology (i.e. anhedonia, despair), and the mechanisms underlying modulation of the DA system in both sexes under baseline conditions, following acute stress (i.e. post-FST) and after UCMS. Ultimately, these findings could shed light on the increased female vulnerability to depression and lead to the development of novel treatment strategies for depression and other psychiatric disorders implicating aberrant DA system function and anhedonia.

项目总结