Development and function of a neural circuit underlying sex-specificity of social behaviors

项目摘要/摘要 为什么男性和女性对相同的感官提示会有不同的反应？行为性行为- 特异性在男性和女性对相同的反应的社会行为中表现得最为明显 社交暗示。根据大脑性别分化的经典模型，分子和结构差异 大脑回路负责调节行为中的性别差异。或者，男性和女性 大脑可能共享一个调制方式不同的中央回路。出现了对第二种模式的强烈支持 从Trpc2基因敲除小鼠的研究和最近的观察来看，在这些小鼠中，犁鼻感觉受到了损害 在包括人类在内的各种动物物种中。反过来，这些数据提出了一个问题--大脑是如何 产生性行为特异性？此外，人们对循环中的荷尔蒙和 青春期的神经活动激活了性特定行为的休眠神经回路--这一过程很可能是 与突触强度和基因表达的协调变化有关。我正在开发一种强大的 研究基因定义的神经回路中原位基因表达动力学的新工具。我要用这个 探讨和检验青春期基因表达程序作用于男性类似回路的假设 而女性决定了社会行为的性别专一性。在初步实验中，我从基因上 确定了小鼠下丘脑中控制行为性别特异性的神经元的一个子集。在研究中 在这里，我将研究与行为相关的神经回路的发展和功能 通过实现以下目标来实现性别特异性：在目标1中，我将确定遗传识别神经元的作用 在下丘脑中使用cre依赖的病毒工具进行细胞消融的行为性别特异性。接下来，我 将使用一种新的细胞类型特异性基因表达分析工具来检查这些细胞中的分子变化 神经元过了青春期。在目标2中，我将使用依赖cre的病毒工具来追踪单突触输入和 这些神经元的输出。最后，在目标3中，我将使用全细胞膜片钳电生理学结合 光遗传学和基因表达分析以检查这些区域的输入特定突触和分子变化 伴随着青春期过渡的神经元。 该奖项的培训阶段在Catherine Dulac博士和Venkatesh博士的实验室进行 哈佛大学的Murthy概述了一项全面的计划，以获得技术和专业 使我能够过渡到独立研究岗位的技能。成功地完成这项工作 项目将为未来旨在了解开发和体系结构的实验提供平台 作为社交行为基础的神经回路。

PROJECT SUMMARY/ABSTRACT Why do males and females behave differently in response to the same sensory cues? Behavioral sex- specificity is most evident in the displays of social behaviors by males and females in response to identical social cues. According to classical models of brain sex differentiation, molecular and architectural differences in brain circuitry are responsible for mediating sex differences in behavior. Alternatively, male and female brains may share a central circuit that is modulated differently. Strong support for this second model emerged from studies of Trpc2 knockout mice in which vomeronasal sensing is impaired, and from recent observations in various animal species including humans. In turn, these data raise the question - how does the brain generate behavior sex specificity? Moreover, little is known about how changes in circulating hormones and neural activity during puberty activate dormant neural circuits for sex specific behaviors – a process likely to be associated with coordinated changes in synaptic strength and gene expression. I am developing a powerful new tool for studying in situ gene expression dynamics in genetically defined neural circuits. I will use this approach and test the hypothesis that gene expression programs during puberty act on similar circuits in males and females to determine the sex specificity of social behaviors. In preliminary experiments, I have genetically identified a subset of neurons in the mouse hypothalamus that gate behavioral sex-specificity. In the research proposed here, I will investigate the development and function of this neural circuit associated with behavioral sex-specificity by fulfilling the following aims: In Aim 1, I will establish the role of genetically identified neurons in the hypothalamus in gating behavioral sex-specificity using cre-dependent viral tools for cell ablation. Next, I will use a novel tool for cell type specific gene expression analysis to examine the molecular changes in these neurons over puberty. In Aim 2, I will use cre-dependent viral tools to trace the monosynaptic inputs and outputs of these neurons. Finally, in Aim 3, I will use whole cell patch clamp electrophysiology combined with optogenetics and gene expression analysis to examine input specific synaptic and molecular changes in these neurons that accompany the transition through puberty. The training phase of the award, conducted in the laboratories of Dr. Catherine Dulac and Dr. Venkatesh Murthy at Harvard University, outlines a comprehensive plan for the acquisition of technical and professional skills that will enable my transition to an independent research position. The successful completion of this project will provide a platform for future experiments aimed at understanding the development and architecture of neural circuits underlying social behaviors.