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Projection-specific gene expression in resilience to chronic stress

慢性应激恢复能力中的投射特异性基因表达

基本信息

批准号：
10444242
负责人：
Michelle Suzanne Mazei-Robison
金额：
$ 60万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2016-09-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444242
关键词：
Address Affect Affinity Chromatography Amygdaloid structure Androgen Receptor Anhedonia Anxiety Automobile Driving Behavior Behavior assessment Behavioral Behavioral Assay Binding Biological Brain Cell physiology Chronic stress Cytosol DNA Data Female Fright Functional disorder Funding Gene Expression Gene Targeting Glutamates Hippocampus (Brain)Individual Knock-out Major Depressive Disorder Mental Health Mental disorders Molecular Mood Disorders Mus National Institute of Mental Health Neurobiology Neurons Nuclear Nucleus Accumbens Patients Pharmacology Process Receptor Signaling Research Ribosomes Role Sex Differences Signal Transduction Stress System Techniques Testosterone Therapeutic Intervention Transgenic Mice Translating Viral Viral Vector Woman Work antagonist base brain circuitry chromatin immunoprecipitation designer receptors exclusively activated by designer drugs emotion regulation experience health disparity hedonic innovation interest male men novel novel therapeutic intervention patient subsets public health relevance receptor function resilience response sex sexual disparity stress resilience therapeutic target tool treatment strategy

项目摘要

SUMMARY Stressful and traumatic experiences can contribute to mood disorders in some individuals while others are resilient to this process, and pharmacological tools for treating major depression (MDD) are effective on only a subset of patients. Moreover, MDD affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Over the past five years of the current funded project, we demonstrated that lower excitability of ventral hippocampal glutamatergic projections to nucleus accumbens (vHPC-NAc) drives increased resilience to stress-induced anhedonia in male mice compared to females, and that this effect is caused directly by testosterone in males. However, the mechanisms by which testosterone regulates excitability of the vHPC-NAc remain unknown. Testosterone produces many of its effects through activation of the androgen receptor (AR) which can alter cell function through signaling cascades in the cytosol or through directly binding to DNA and altering gene expression. We have shown that vHPC-NAc neurons produce AR and respond to AR antagonists, and our preliminary data show that eliminating AR in vHPC-NAc neurons increases excitability. This leads to our overarching hypothesis for years 6-10: that testosterone activation of ARs in vHPC-NAc decreases excitability through changes in gene expression to drive behavioral resilience to stress. This is significant, as identification of AR targets/mechanisms driving resilience may generate novel therapeutic strategies that would be particularly beneficial in females, an unmet need due to the sexual disparity in mood disorders. We will address this using three specific aims: 1) Uncover the mechanisms of testosterone-driven reduction in vHPC-NAc excitability using novel transgenic mice and classical pharmacology; 2) Uncover the mechanisms of testosterone-driven resilience to stress using novel mouse lines and a circuit- specific intersection dual viral vector approach; and 3) Determine circuit-specific gene expression driven by sex, testosterone, and the androgen receptor using translating ribosome affinity purification. Given the established role of vHPC circuitry in emotional regulation, the gene expression studies proposed here will meaningfully impact basic psychiatric research and may elucidate novel treatment strategies for psychiatric disorders that could be particularly beneficial to female patients. Moreover, our understanding of basal sex differences in brain circuitry is lacking, so this work will inform not only stress studies, but will increase understanding of sex as a biological variable in all behaviors that engage vHPC circuitry.

总结