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从小鼠内侧杏仁核（MeA）发出的神经通路的功能和解剖。这个核心调节许多行为，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。我们以前的工作（由先前的资助期）和其他人已经确定了一个小集合的芳香化酶表达神经元位于后背成分的MeA。芳香化酶和MeA都是交配和攻击性表现所必需的。有趣的是，我们的工作表明，与女性相比，男性的MeA中有更多的芳香化酶+神经元。因此，我们假设芳香化酶+ MeA神经元影响交配和侵略的二态显示。在目标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先前生成的芳香酶报告小鼠中进行，以允许c-Fos和芳香酶的敏感共标记。在目标2中，我们将追踪芳香化酶+ MeA神经元的连接。我们将使用Cre依赖性伪狂犬病病毒进行跨突触逆行标记，以及我们开发的用于标记芳香化酶+神经元的投射的新型Cre依赖性神经示踪剂编码病毒。这些研究将使用我们设计的新型芳香化酶-Cre小鼠品系进行。我们还将联合收割机c-Fos标记与霍乱毒素B（一种逆行示踪剂）结合，以确定由不同刺激激活的芳香化酶+神经元是否投射到不同的靶点。在目标3中，我们将使用强大的光遗传效应子刺激（通道视紫红质2）和抑制（盐视紫红质3）芳香化酶+ MeA神经元，以确定这些细胞与交配和攻击的二态显示的功能相关性。因此，我们的研究将提供深入了解芳香化酶+ MeA神经元的神经通路及其在体内的功能相关性。健康相关性：神经精神疾病通常反映神经回路在宏观或微观水平上的功能障碍，这些仍然知之甚少，治疗上难以解决。人类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导致创伤后应激障碍和自闭症谱系障碍的原因。我们提出的工作将阐明杏仁核神经元子集的连接和功能，从而推动对该区域及其在健康中发挥作用的神经回路的基本科学认识，并最终有助于指导未来治疗或诊断杏仁核疾病的应用。

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.