Characterization of Sexual Dimorphism in the Brain

描述（由申请人提供）：我们的资助申请的目标是对小鼠内侧杏仁核（MeA）发出的神经通路进行功能和解剖解剖。这个核调节着许多行为，包括社会记忆，对捕食者和其他压力源的反应，以及交配和攻击。MeA是异质的，包含许多具有不同身份的神经元池。解释MeA功能多样性的一个假设是，不同的MeA神经元池具有不同的功能。我们之前的工作（由先前的资助期资助）和其他人的工作已经确定了位于MeA后嗅部分的一小部分表达芳香酶的神经元。芳香化酶和MeA都是显示交配和攻击行为所必需的。有趣的是，我们的研究表明，与雌性相比，雄性的MeA中有更多的芳香化酶+神经元。因此，我们假设芳香化酶+ MeA神经元影响交配和攻击的二态表现。在Aim 1中，我们将使用c-Fos表达来识别激活这些神经元的行为和化学感觉刺激；我们的研究将在我们之前生成的芳香酶报告小鼠中进行，以便对c-Fos和芳香酶进行敏感的共标记。在Aim 2中，我们将追踪芳香化酶+ MeA神经元的连接。我们将使用cre依赖的伪狂犬病毒进行跨突触逆行标记，以及我们开发的一种新的cre依赖的神经示踪编码病毒，用于标记芳香化酶+神经元的投影。这些研究将使用我们设计的一种新型芳香酶- cre小鼠品系进行。我们还将c-Fos标记与霍乱毒素B（一种逆行示踪剂）相结合，以确定不同刺激激活的芳香化酶+神经元是否会投射到不同的目标。在Aim 3中，我们将使用强大的光遗传效应物来刺激（通道视紫红素2）和抑制（盐视紫红素3）芳香化酶+ MeA神经元，以确定这些细胞与交配和攻击二态表现的功能相关性。因此，我们的研究将深入了解芳香化酶+ MeA神经元发出的神经通路及其在体内的功能相关性。健康相关性：神经精神疾病通常在肉眼或显微镜水平上反映神经回路功能障碍，这些疾病仍然知之甚少，治疗上难以解决。人类的杏仁核对于识别社会和情感线索至关重要，杏仁核功能障碍被认为是造成创伤后应激障碍和自闭症谱系障碍的原因之一。我们提出的工作将阐明杏仁核神经元子集的连通性和功能，从而导致对该区域及其在健康中起作用的神经回路的基础科学理解的进步，并最终有助于指导未来杏仁核疾病的治疗或诊断应用。

DESCRIPTION (provided by applicant): The goal of our grant application is a functional and anatomic dissection of the neural pathways emanating from the mouse medial amygdala (MeA). This nucleus regulates many behaviors, including social memory, the response to predators and other stressors, and mating and aggression. The MeA is heterogeneous and contains many neuronal pools with distinct identities. One hypothesis to account for the functional diversity of the MeA is that different MeA neuronal pools serve distinct functions. Our previous work (funded by the prior grant period) and that of others has identified a small collection of aromatase-expressing neurons located in the posterodorsal component of the MeA. Both aromatase and the MeA are essential for the display of mating and aggression. Intriguingly, our work shows that there are more aromatase+ neurons in the MeA in males compared to females. We therefore hypothesize that aromatase+ MeA neurons influence the dimorphic displays of mating and aggression. In Aim 1, we will use c-Fos expression to identify the behavioral and chemosensory stimuli that activate these neurons; our studies will be performed in an aromatase reporter mouse we have previously generated to allow sensitive co-labeling for c-Fos and aromatase. In Aim 2, we will trace the connections of aromatase+ MeA neurons. We will use a Cre-dependent pseudorabies virus for trans-synaptic retrograde labeling, and a novel Cre-dependent neural tracer encoding virus we have developed for labeling the projections of aromatase+ neurons. These studies will be performed using a novel aromatase-Cre mouse strain we have engineered. We will also combine c-Fos labeling with cholera toxin B, a retrograde tracer, to determine if aromatase+ neurons activated by different stimuli project to distinct targets. In Aim 3, we will use powerful optogenetic effectors to stimulate (channelrhodopsin2) and inhibit (halorhodopsin3) aromatase+ MeA neurons to determine the functional relevance of these cells to dimorphic displays of mating and aggression. Thus, our studies will provide insight into the neural pathways emanating from aromatase+ MeA neurons and their functional relevance in vivo. Health Relatedness: Neuro-psychiatric conditions often reflect dysfunction of neural circuitry at a gross or microscopic level, and these remain poorly understood and therapeutically intractable. The human amygdala is critical for recognition of social and emotional cues, and amygdalar dysfunction is thought to contribute to post-traumatic stress disorder and autism spectrum disorders. Our proposed work will shed light on the connectivity and functions of a subset of amygdalar neurons, thereby leading to an advance in basic scientific understanding of this region and the neural circuits within which it functions in health, and it may ultimately help guide future therapeutic or diagnostic applications for disorders of the amygdala. PUBLIC HEALTH RELEVANCE: Dysfunction of neuronal circuits is thought to underlie many devastating neuro-psychiatric conditions. Our basic research is focused on elucidating the connections and functions of the amygdala, a brain region that has been implicated in post-traumatic stress disorder and autism spectrum disorders. Our work will shed light on how the amygdala functions in health, and ultimately may help guide future therapeutic and diagnostic applications for amygdalar dysfunction.