BACKGROUND The prefrontal cortex (PFC) has been implicated in the pathophysiology of social dysfunction, but the specific circuit partners mediating PFC function in health and disease are unclear. METHODS The excitatory designer receptor exclusively activated by designer drugs (DREADD) hM3Dq was used to induce PFC activation during social behavior measured in the three-chamber sociability assay (rats/mice). Functional magnetic resonance imaging was combined with hM3Dq-mediated PFC activation to identify novel nodes in the "social brain" in a hypothesis-free manner. In multiplexed DREADD experiments, hM3Dq and the inhibitory KORDi were used to bidirectionally modulate PFC activity and measure social behavior and global functional magnetic resonance imaging signature. To characterize the functional role of specific nodes identified in this functional magnetic resonance imaging screen, we used anterograde and retrograde tracers, optogenetic and DREADD-assisted circuit mapping, and circuit behavioral experiments. RESULTS PFC activation suppressed social behavior and modulated activity in a number of regions involved in emotional behavior. Bidirectional modulation of PFC activity further refined this subset of brain regions and identified the habenula as a node robustly correlated with PFC activity. Furthermore, we showed that the lateral habenula (LHb) receives direct synaptic input from the PFC and that activation of LHb neurons or the PFC inputs to the LHb suppresses social preference. Finally, we demonstrated that LHb inhibition can prevent the social deficits induced by PFC activation. CONCLUSIONS The LHb is thought to provide reward-related contextual information to the mesolimbic reward system known to be involved in social behavior. Thus, PFC projections to the LHb may represent an important part of descending PFC pathways that control social behavior.

中文翻译：

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识别调节社会导向行为的皮质 - 缰绳回路

背景前额叶皮层 (PFC) 与社会功能障碍的病理生理学有关，但在健康和疾病中介导 PFC 功能的特定回路伙伴尚不清楚。方法 在三室社交性试验（大鼠/小鼠）中测量的社交行为过程中，专门由设计药物激活的兴奋性设计受体 (DREADD) hM3Dq 用于诱导 PFC 激活。功能磁共振成像与 hM3Dq 介导的 PFC 激活相结合，以无假设的方式识别“社交大脑”中的新节点。在多路 DREADD 实验中，hM3Dq 和抑制性 KORDi 用于双向调节 PFC 活动并测量社会行为和全球功能磁共振成像特征。为了表征在此功能磁共振成像屏幕中确定的特定节点的功能作用，我们使用了顺行和逆行示踪剂、光遗传学和 DREADD 辅助电路映射以及电路行为实验。结果 PFC 激活抑制了社会行为并调节了许多涉及情绪行为的区域的活动。PFC 活动的双向调制进一步细化了这一大脑区域子集，并将缰核识别为与 PFC 活动密切相关的节点。此外，我们表明外侧缰核 (LHb) 接收来自 PFC 的直接突触输入，并且 LHb 神经元的激活或 PFC 输入到 LHb 会抑制社会偏好。最后，我们证明了 LHb 抑制可以防止 PFC 激活引起的社会缺陷。结论 LHb 被认为为已知参与社会行为的中脑边缘奖励系统提供与奖励相关的上下文信息。因此，PFC 对 LHb 的预测可能代表控制社会行为的下行 PFC 通路的重要组成部分。