Studying how the hippocampal-prefrontal-hypothalamic circuit encodes social dominance

项目摘要 社会缺陷在精神疾病中很常见，可用的治疗方法有限。我们缺乏基本的 关于大脑如何控制社会行为的知识使得开发社会行为的治疗方法具有挑战性。 赤字对于许多动物物种来说，社会等级决定了行为的许多方面，例如获得 资源和抗压能力。社会地位较高的人通常在社交活动中获胜的次数更多。 冲突（例如食物竞争），并表现出更多的竞争行为;集体性被称为优势 行为。跨物种的证据表明，内侧前额叶皮层（mPFC）在 社会支配地位然而，mPFC如何编码社会等级以及mPFC的输入和输出 对支配行为的贡献是未知的。多项研究表明，腹侧海马（vHPC）是 最近的一项研究表明，这种作用涉及mPFC的vHPC输入。 此外，初步数据表明，从mPFC到外侧下丘脑（LH）的投射， 调节社会支配行为。这些发现与文献相结合，提出了一个模型， mPFC从vHPC接收社会记忆信息，并通过调节LH来指导社会行为 GABA能和谷氨酸能亚群。在揭示社会行为的神经相关性方面的进展， 由于现有的社会测定缺乏试验，因此受到用于表征小鼠社会行为的工具的限制， 统计功效和社会行为的共同测量所需的结构过于简单（例如嗅探）。 克服这一挑战需要开发一种基于试验的社会竞争试验， 与笼中动物对抗，以获得一种音调作为信号的奖励。由于其试验结构，该测定有利于 社会行为的量化以及随后的社会支配的神经相关性的识别。 在这个试验中，占优势的小鼠赢得了试验中的大部分奖励，占据奖励端口并取代小鼠 从奖励端口发送的信息比从下属发送的要多。机器学习方法将用于分析 在竞争试验期间，在社会等级上观察到的行为差异。利用这个与人类行为学相关的 社会竞争测定、电路操作、体内神经记录方法和机器学习允许 测试三方vHPC-mPFC-LH回路编码社会优势的假设。总之，这 这项研究将为研究社会支配地位提供一种新的方法，并将进一步加深我们对社会支配地位是如何产生的理解。 mPFC的分布电路调节社会行为。此外，精确定位潜在的神经回路 社会行为将有助于识别潜在的治疗精神疾病的社会缺陷。 最后，完成这项研究将提供培训机会，在统计方法的行为 分析和新的电路解剖工具，这是必不可少的候选人成为专家，在社会 神经科学，并开始一个成功的独立研究计划。

Project Summary Social deficits are common in psychiatric disorders and available treatments are limited. Our lack of basic knowledge on how the brain controls social behaviors makes it challenging to develop therapeutics for social deficits. For numerous animal species, social rank dictates many aspects of behavior, such as access to resources and resilience to stress. Individuals with higher social rank typically win more often during social conflicts (e.g. food competition) and show more agonistic behaviors; collectivity referred to as dominance behaviors. Cross-species evidence suggests that the medial prefrontal cortex (mPFC) plays an important role in social dominance. However, exactly how the mPFC encodes social rank and which mPFC inputs and outputs contribute to dominance behaviors is unknown. Multiple studies show that the ventral hippocampus (vHPC) is necessary for social memory, and more recently, a study showed that this role involves vHPC input to the mPFC. Furthermore, preliminary data suggest that the projection from the mPFC to the lateral hypothalamus (LH) modulates social dominance behavior. These findings in combination with the literature suggest a model in which the mPFC receives social memory information from the vHPC and guides social behaviors via modulation of LH GABAergic and glutamatergic subpopulations. Progress in uncovering neural correlates of social behavior has been limited by the tools used to characterize murine social behavior, since existing social assays lack trial- structure needed for statistical power and common measurements of social behavior are simplistic (e.g. sniffing). Overcoming this challenge required developing a trial-based social competition assay in which mice compete against cagemates for a reward signaled by a tone. Due to its trial structure, this assay facilitates the quantification of social behaviors and subsequently the identification of neural correlates for social dominance. In this assay, dominant mice win most of the rewards across trials, occupy the reward port and displace mice from the reward port more often than subordinates. Machine learning approaches will be used to profile the behavioral differences seen across social rank during the competition assay. Utilizing this ethologically relevant social competition assay, circuit manipulations, in vivo neural recording methods and machine learning allows testing the hypothesis that the tripartite vHPC-mPFC-LH circuit encodes social dominance. Altogether, this research will provide a new approach to study social dominance and will further our understanding of how the distributed circuits of the mPFC modulate social behavior. Furthermore, pinpointing the neural circuits underlying social behaviors will facilitate identification of potential therapeutics for social deficits in psychiatric disorders. Finally, completion of this research will provide training opportunities in statistical approaches for behavioral analysis and new circuit dissection tools, which are essential for the candidate to become an expert in social neuroscience and to start a successful independent research program.