Neural Circuit Mechanisms of Stress-Impaired Social Reward

摘要： 人类的创伤性社会经历会损害大脑的奖励功能，导致严重的社交回避。 啮齿类动物的压力模型，如慢性社交失败压力（CSDS），也会导致严重的社交回避 部分是通过改变奖赏回路功能来调节的。由此产生的一个突出问题是， 啮齿类动物的研究是这样的社会回避行为是否由于社会奖励或偏好的丧失而发生。 使用标准的CSDS模型，我们测量了威胁性（攻击性CD-1小鼠）和攻击性CD-1小鼠的社会互动。 非威胁性（相同性别的3周龄幼年C57 BL 6/J小鼠）社会目标小鼠。我们发现CSDS导致 雄性和雌性小鼠对威胁性和非威胁性社交目标的社交回避 称为敏感。对照和弹性小鼠不表现出对任一目标小鼠的社交回避。到 为了测量社会奖励，我们利用了社会条件性位置偏好（CPP）测定，其中实验小鼠 我们发现CSDS损害了C57 BL 6/J的形成， 易感但无弹性的雄性和雌性小鼠的社会CPP。我们接下来使用全脑iDisco清除， CSDS暴露小鼠在青少年社会互动后的c-Fos图谱，发现几个脑区具有 在易感小鼠中特异性增加c-Fos表达。侧隔（LS）-压力反应大脑 区域-在易感小鼠中高度激活，但在恢复性小鼠或对照小鼠中没有。我们在现场表演 杂交以鉴定LS中的特定细胞类型，并发现神经降压素（LSNT）阳性GABA能 群体在青少年社会互动期间仅在易感小鼠中激活。我们接下来利用体内纤维 光度法和GCAMP 6介导的Ca 2+成像沿着和化学遗传学，以证实LSNT神经元 在青少年社会交往中被实时激活，并调节社会回避和社会CPP。 为了确定下游LSNT连接，我们使用来自iDisco c-Fos的预测相关矩阵 表达图谱，以确定功能连接的区域，然后证实这些连接与病毒 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 调节社会互动的斜角带的壳/核。我们的研究提供了一个电路- 水平的框架来理解社会行为中的缺陷，这在许多与压力有关的 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.