Neural Circuit Mechanisms of Stress-Impaired Social Reward

摘要： 人类的创伤性社交经历会损害大脑奖励功能，导致严重的社交回避。 啮齿动物应激模型，例如慢性社交失败应激（CSDS），也会导致严重的社交回避 部分是通过改变奖励回路功能来调节的。由此产生的突出问题之一 啮齿动物研究的重点是这种社交回避行为是否由于社会奖励或偏好的丧失而发生。 使用标准 CSDS 模型，我们测量了与威胁性（攻击性 CD-1 小鼠）和 非威胁性（同性 3 周龄幼年 C57BL6/J 小鼠）社交目标小鼠。我们发现 CSDS 导致 雄性和雌性小鼠对威胁性和非威胁性社会目标的社交回避 称为易感者。对照小鼠和复原小鼠均不会对任一目标小鼠表现出社交回避。至 为了衡量社会奖励，我们使用了社会条件位置偏好（CPP）测定，其中实验小鼠 用同性别的 3 周龄幼鱼 C57BL6/J 进行条件反射。我们发现 CSDS 会损害 易感但不具有弹性的雄性和雌性小鼠中的社会 CPP。接下来我们使用全脑 iDisco 清理和 对暴露于 CSDS 的小鼠进行青少年社交互动后的 c-Fos 绘图，发现几个大脑区域 尤其是在易感小鼠中，c-Fos 表达增加。侧隔膜（LS）——压力反应大脑 该区域在易感小鼠中高度激活，但在弹性小鼠或对照小鼠中则没有。我们现场表演 杂交鉴定 LS 中的特定细胞类型，并发现神经降压素 (LSNT) 阳性 GABA 能 仅在易感小鼠中，群体在青少年社会互动过程中被激活。接下来我们利用体内纤维 光度测定和 GCAMP6 介导的 Ca2 成像以及化学遗传学证实 LSNT 神经元 在青少年社交互动过程中实时激活，它们调节社交回避和社交 CPP。 为了确定下游 LSNT 连接，我们使用 iDisco c-Fos 的预测相关矩阵 表达图谱来识别功能连接区域，然后用病毒证实这些连接 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 调节社会互动的对角带的伏核壳/核。我们的研究提供了一个电路- 水平框架来理解社会行为缺陷，这在许多与压力相关的人中很常见 疾病，例如抑郁症。

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.