Neural Circuit Mechanisms of Stress-Impaired Social Reward

压力受损社会奖赏的神经回路机制

• 批准号: 10579476
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 5.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10579476
• 关键词: Adolescent; Anhedonia; Biological; Biological Assay; Brain; Brain region; Chronic; Diagonal Band Nucleus; FOS gene; Female; Fiber; Human; Image; Impairment; In Situ Hybridization; Lateral; Lead; Maps; Measures; Mediating; Mental Depression; Modeling; Mus; Neurons; Neurotensin; Nucleus Accumbens; Photometry; Population; Research; Rewards; Risk; Rodent; Same-sex; Social Behavior; Social Conditions; Social Interaction; Stimulus; Stress; Time; Viral; avoidance behavior; brain dysfunction; cell type; conditioned place preference; experience; in vivo; interest; male; mouse model; neural circuit; optogenetics; pleasure; preference; social; social defeat; social stress; tool

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.

抽象的： 人类的创伤社会经历会损害大脑奖励功能，从而导致严重的社会回避。 啮齿动物压力模型，例如慢性社会失败压力（CSD），也可能导致严重的社会避免 部分通过改变奖励电路功能进行介导。此类引起的突出问题之一 啮齿动物的研究是，这种社会回避行为是否是由于失去社会奖励或偏好而发生的。 使用标准CSD模型，我们测量了威胁性的社会互动（积极的CD-1小鼠），然后 非威胁性（3周老年少年C57BL6/J小鼠）社交目标小鼠。我们发现CSD导致 在男性和女性小鼠的一部分中，社会避免威胁和无威胁的社会目标 被称为易感。控制和弹性小鼠不存在任何一种靶向鼠标的社会回避。到 衡量社会奖励，我们利用了一个社会条件的地方偏好（CPP）测定 用同种性爱的3周少少年C57BL6/J进行调节。我们发现CSD会损害 易感性但不具有弹性的男性和雌性小鼠的社交CPP。接下来，我们使用了整个脑idisco清理和 C-FOS映射是在暴露于CSD的小鼠中的少年社交互动后的 在易感小鼠中特别增加了C-FOS表达。侧隔（LS） - 应力反应性大脑 区域 - 在易感小鼠中高度激活，但没有弹性或对照小鼠。我们原地表演 杂交以鉴定LS中的特定细胞类型并发现神经素（LSNT）阳性GABA能 在少年社交互动期间，人口仅在易感小鼠中被激活。接下来，我们在体内纤维中使用 光度法和GCAMP6介导的Ca2+成像以及化学遗传学，以确认LSNT神经元 在青少年社交互动期间实时激活，并调节社会回避和社会CPP。 为了确定下游LSNT连接，我们使用了Idisco C-Fos的预测相关物质 表达图以识别功能连接的区域，然后用病毒确认这些连接 追踪工具和光遗传学。我们发现LSNT神经元与细胞核之间的功能连接 调节社会相互作用的对角线带的伏伏壳/核。我们的研究提供了电路 - 在社会行为中理解定义的水平框架，这些框架在许多与压力有关的框架中很常见 疾病，例如抑郁症。