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Neural Circuit Mechanisms of Stress-Impaired Social Reward

压力受损社会奖赏的神经回路机制

基本信息

批准号：
10314885
负责人：
SCOTT JAMES RUSSO
金额：
$ 59.1万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10314885
关键词：
Adolescent Adult Anhedonia Behavior Behavioral Biological Biological Assay Brain Brain region Chronic Complex Cues Data Development Diagonal Band Nucleus Dissection FOS gene Feeling Female Fiber Fright Histologic Human Image Impairment In Situ Hybridization Lateral Lead Link Maps Measures Mediating Mental Depression Modeling Molecular Motivation Mus Neurons Neurotensin Nucleus Accumbens Pattern Photometry Physiological Population Predisposition Property Reaction Research Rewards Risk Rodent Rodent Model Role Same-sex Signal Transduction Slice Social Behavior Social Conditions Social Interaction Social isolation Stimulus Stress Syndrome Testing Time Viral Work avoidance behavior brain circuitry bullying cell type conditioned place preference experience gamma-Aminobutyric Acid in vivo interest male mouse model neural circuit neuropsychiatry novel optogenetics pleasure preference prevent relating to nervous system response reward circuitry social social defeat social stress tool

项目摘要

Abstract: Traumatic social experience in humans can impair brain reward function leading to severe social avoidance. Rodent stress models such as chronic social defeat stress (CSDS), can also cause severe social-avoidance mediated, in part, through altered reward circuit function. One of the prominent questions arising from such rodent studies is whether such social avoidance behaviors occurs due to a loss of social reward or preference. Using a standard CSDS model, we measured social interaction with threatening (aggressive CD-1 mice) and non-threatening (same sex 3-week old juvenile C57BL6/J mice) social target mice. We find that CSDS leads to social avoidance to both threatening and non-threatening social targets in a subset of male and female mice termed susceptible. Control and resilient mice do not exhibit social avoidance to either target mouse. To measure social reward, we utilized a social conditioned place preference (CPP) assay, where experimental mice were conditioned with a same sex 3-week old juvenile C57BL6/J. We find that that CSDS impairs formation of social CPP in susceptible, but not resilient, male and female mice. We next used whole brain iDisco clearing and c-Fos mapping following juvenile social interaction in CSDS-exposed mice and found several brain regions with increased c-Fos expression specifically in susceptible mice. The lateral septum (LS)—a stress responsive brain region—was highly activated in susceptible mice, but not resilient or control mice. We performed in situ hybridization to identify specific cell types in the LS and found a neurotensin (LSNT) positive GABAergic population activated during juvenile social interaction only in susceptible mice. We next utilized in vivo fiber photometry and GCAMP6-mediated Ca2+ imaging along with and chemogenetics to confirm that LSNT neurons are activated in real-time during juvenile social interaction and they regulate social avoidance and social CPP. To determine downstream LSNT connections, we used predicted correlation matrices from iDisco c-Fos expression maps to identify functionally connected regions and then confirmed these connections with viral tracing tools and optogenetics. We found a functional connection between LSNT neurons and the nucleus accumbens shell/nucleus of the diagonal band that regulates social interaction. Our research provides a circuit- level framework to understanding deficits in social behavior, that are common among many stress-related illnesses, such as depression.

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