Characterization of Sexual Dimorphism in the Brain

描述(由申请人提供)：我们资助申请的目标是对小鼠杏仁内侧核(Mea)发出的神经通路进行功能和解剖解剖。这个核团调节许多行为，包括社会记忆、对捕食者和其他应激源的反应，以及交配和攻击。MEA是异质性的，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(由前一次拨款资助)和其他人的工作已经确定了位于MeA后气味部分的少量芳香酶表达神经元的集合。芳香酶和MeA对于交配和攻击性的展示都是必不可少的。有趣的是，我们的研究表明，与女性相比，男性大脑中脑区有更多的芳香酶+神经元。因此，我们假设芳香酶+MeA神经元影响交配和攻击的二态表现。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之前培育的芳香酶报告鼠中进行，以允许对c-Fos和芳香酶进行敏感的联合标记。在目标2中，我们将追踪芳香酶+MeA神经元的联系。我们将使用依赖于Cre的伪狂犬病病毒进行跨突触逆行标记，以及我们开发的一种新的依赖Cre的神经示踪剂编码病毒来标记芳香酶+神经元的投射。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。我们还将结合c-Fos标记和霍乱毒素B(一种逆行示踪剂)来确定不同刺激激活的芳香酶+神经元是否会投射到不同的靶点。在目标3中，我们将使用强大的光遗传效应器来刺激(通道视紫红质2)和抑制(卤代紫质3)芳香酶+mea神经元，以确定这些细胞与交配和攻击的二相性显示的功能相关性。因此，我们的研究将为深入了解芳香酶+MeA神经元的神经通路及其在体内的功能相关性提供依据。与健康相关：神经精神疾病通常在大体或微观水平上反映神经回路的功能障碍，这些问题仍然知之甚少，在治疗上难以解决。人类杏仁核对识别社交和情感线索至关重要，杏仁核功能障碍被认为是创伤后应激障碍和自闭症谱系障碍的原因之一。我们拟议的工作将阐明杏仁核神经元子集的连接和功能，从而促进对该区域及其在其中发挥健康功能的神经回路的基本科学了解，并最终可能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.