Modulation of sex steroid-induced female social behaviors in an animal model

摘要 我们的长期目标是通过研究边缘-下丘脑来了解类固醇对社会互动的调节。 控制女性性欲和前凸的神经回路。我们在这条赛道内展示了， 雌二醇膜启动的信号通路激活弓状核(ARH)至视前内侧核 (MPN)投射负责完全性行为所需的瞬时μ阿片受体(MORS)激活 可接受性。这些MOR神经元又投射到下丘脑腹内侧核(VMH)。 调节前凸行为。目前的建议是基于这些结果和雄性小鼠的结果。 这表明杏仁背内侧核(MeApd)调节社会行为。因为在雌性中， MeApd预测影响社会行为，前凸，没有很好的定义，我们试图描述 调节雌性激素激活的ARH-MPN-VMH回路的特异性MeApd投射 性接受能力。我们将检验一般的假设，即MeApd可以获得雌激素启动的阿片类药物 对调节性接受能力的抑制。提出了三个具体的目标来从功能上剖析这一点 电路：1)选择性激活固有的ARH NPY神经元，抑制投射MPN的POMC终末 前凸。本实验正式测试了NPY和POMC神经元的顺序激活抑制 前凸。NPY-CRE和POMC-CRE神经元将感染依赖Cre的刺激性神经元 通道视紫红质(ChR2)腺相关病毒(AAV)和在行为雌性小鼠中的光刺激。2) MeApd通过谷氨酸能投射到MPN来不同地调节性感受性，并且 GABAeric到VMH。我们将使用AAV指导的ChR2的表达，以刺激或卤视紫质，以 抑制、谷氨酸和GABA能MeApd的输出。我们的预期是谷氨酸能输入到 MPN增强MOR介导的抑制前凸(无社会行为)，而GABA能传入 VMH促进感受性(社会行为)，通过对刺激男性的前凸反应来衡量。3) 性感受性涉及MeApd中从谷氨酸能到GABA能神经元的转换。 这些实验将确定女性是否像男性一样，通过MeApd控制社会行为 从谷氨酸(非社会性)输出转向GABA能(社会性)输出。首先，我们将确定 雌二醇和雌二醇对MeApd谷氨酸和GABA能神经元的激活作用 黄体酮与非接受性/非社会性行为向接受性/社会性行为的转变有关。 最后，我们将顺序抑制谷氨酸能和GABA能MeApd神经元在性腺完整、循环 VGLUT-Cre和vGAT-Cre小鼠使用依赖Cre的卤视紫质-AAV。总而言之，这些实验 将对边缘-下丘脑回路中的类固醇信号如何导致 典型的社交互动，前凸行为。

ABSTRACT Our long-term goal is to understand steroid regulation of social interaction by studying limbic-hypothalamic neural circuits that control female sexually receptivity, lordosis. We demonstrated that within this circuit, estradiol membrane-initiated signaling activates an arcuate nucleus (ARH) to medial preoptic nucleus (MPN) projection responsible for transient μ-opioid receptor (MORs) activation needed for full sexual receptivity. These MOR neurons in turn project to the ventromedial nucleus of the hypothalamus (VMH) modulating lordosis behavior. The present proposal is based on these results and on results in male mice that show that the posterodorsal medial amygdala (MeApd) modulates social behavior. Because in females, MeApd projections affecting the social behavior, lordosis, are not well defined, we seek to characterize specific MeApd projections that modulate the ARH-MPN-VMH circuit underlying steroid activation of female sexual receptivity. We will test the general hypothesis that the MeApd gates estradiol-initiated opioid inhibition to modulate sexual receptivity. Three Specific Aims are proposed to functionally dissect this circuit: 1) Selective activation of intrinsic ARH NPY neurons, and MPN-projecting POMC terminals inhibit lordosis. This experiment formally tests that the sequential activation of NPY and POMC neurons inhibits lordosis. NPY-Cre and POMC-Cre neurons will be infected with a stimulatory Cre-dependent channelrhodopsin (ChR2) adeno-associated virus (AAV) and photostimulated in behaving female mice. 2) The MeApd differentially modulates sexual receptivity through glutamatergic projections to the MPN, and GABAergic to the VMH. We will use AAV-directed expression of ChR2, to stimulate, or halorhodopsin, to inhibit, glutamatergic and GABAergic MeApd outputs. Our expectation is that glutamatergic inputs to the MPN enhance the MOR-mediated inhibition of lordosis (asocial behavior), while GABAergic inputs to the VMH promote receptivity (social behavior), as measured by the lordosis response to stimulus males. 3) Sexual receptivity involves a switch from glutamatergic to GABAergic neuron activation in the MeApd. These experiments will determine if in females, as in males, the MeApd controls social behavior through shift from glutamatergic (asocial) to GABAergic (social) outputs. First, we will determine the pattern of glutamatergic and GABAergic neuron activation in the MeApd induced by estradiol, and estradiol + progesterone is associated with the change from nonreceptive/asocial behavior to receptive/social behavior. Finally, we will sequentially inhibit glutamatergic and GABAergic MeApd neurons in gonadally intact, cycling vGLUT-Cre and vGAT-Cre mice using a Cre-dependent halorhodopsin-AAV. Together, these experiments will provide a functional circuit analysis of how steroid signaling in the limbic-hypothalamic circuit leads a prototypic social interaction, lordosis behavior.