Neural Circuit Mechanisms of Stress-Impaired Social Reward

摘要： 人类的创伤社交经历会损害大脑的奖励功能，导致严重的社交回避。 啮齿动物的应激模式，如慢性社会失败应激(CSDS)，也会导致严重的社交回避 这部分是通过改变奖赏回路功能来实现的。由此引发的突出问题之一是 啮齿类动物的研究是指这种社交回避行为是否由于失去社会奖励或偏好而发生。 使用标准的CSDS模型，我们测量了与威胁(攻击性CD-1小鼠)和 非威胁性(同性别3周龄幼龄C57BL6/J小鼠)社会靶标小鼠。我们发现CSDS导致了 雄性和雌性小鼠对威胁和非威胁社会目标的社交回避 被称为易感的。对照小鼠和弹性小鼠对这两种目标小鼠都不表现出社交回避。至 测量社会奖励，我们利用了社会条件性位置偏好(CPP)分析，其中实验小鼠 用同性别的3周龄幼虫C57BL6/J进行条件化处理。 易感但不具弹性的雄性和雌性小鼠的社会CPP。接下来，我们使用全脑iDisco清除和 CSDS暴露小鼠青少年社会互动后的c-Fos图谱发现几个脑区 C-Fos在易感小鼠中的表达增加。外侧隔(LS)--应激反应脑 区域-在易感小鼠中高度激活，但在有弹性或对照组的小鼠中不被激活。我们在现场进行了 用杂交方法鉴定LS中的特定细胞类型并发现神经降压素(LSNT)阳性的GABA能 仅在易感小鼠的青少年社交中激活的种群。接下来我们利用体内纤维 光度法和GCAMP6介导的钙离子成像以及化学发生学证实LSNT神经元 在青少年社交过程中被实时激活，并调节社交回避和社交CPP。 为了确定下行LSNT连接，我们使用来自IDisco c-Fos的预测相关矩阵 表达图谱来识别功能相连的区域，然后确认这些与病毒的联系 追踪工具和光遗传学。我们发现LSNT神经元和细胞核之间存在功能联系 伏隔核是调节社会互动的斜带的壳/核。我们的研究提供了一个电路- 理解社会行为缺陷的层次框架，这些缺陷在许多与压力有关的人中很常见 疾病，如抑郁症。

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.