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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交互动的调节 控制女性性接受、脊柱前凸的神经回路。我们证明了在这个电路中, 雌二醇膜启动的信号传导激活弓状核(ARH)至内侧视前核 (MPN) 投射负责完全性行为所需的瞬时 μ-阿片受体 (MOR) 激活 接受能力。这些 MOR 神经元依次投射到下丘脑的腹内侧核 (VMH) 调节脊柱前凸行为。目前的提议是基于这些结果和雄性小鼠的结果 这表明后背内侧杏仁核(MeApd)调节社会行为。因为对于女性来说, MeApd 预测影响社会行为、脊柱前凸,尚未明确定义,我们试图描述 调节女性类固醇激活的 ARH-MPN-VMH 回路的特定 MeApd 预测 性接受能力。我们将检验 MeApd 控制雌二醇引发的阿片类药物的一般假设 抑制调节性接受。提出了三个具体目标来从功能上剖析这一点 电路:1) 选择性激活内在 ARH NPY 神经元,并且 MPN 投射 POMC 终端抑制 脊柱前凸。该实验正式测试了 NPY 和 POMC 神经元的顺序激活抑制 脊柱前凸。 NPY-Cre 和 POMC-Cre 神经元将被刺激性 Cre 依赖性病毒感染 视紫红质通道蛋白 (ChR2) 腺相关病毒 (AAV) 和行为雌性小鼠的光刺激。 2) MeApd 通过向 MPN 的谷氨酸能投射来差异调节性接受能力,并且 VMH 的 GABA 能。我们将使用 AAV 定向的 ChR2 表达来刺激,或使用盐视紫红质来刺激 抑制、谷氨酸能和 GABA 能 MeApd 输出。我们的期望是谷氨酸能输入 MPN 增强 MOR 介导的脊柱前凸抑制(反社会行为),而 GABA 能输入 VMH 促进接受性(社会行为),通过对刺激男性的脊柱前凸反应来测量。 3) 性接受涉及 MeApd 中从谷氨酸能神经元激活到 GABA 能神经元激活的转变。 这些实验将确定女性和男性中的 MeApd 是否通过以下方式控制社会行为: 从谷氨酸能(非社会性)输出转向 GABA 能(社会性)输出。首先,我们要确定模式 雌二醇诱导的 MeApd 中谷氨酸能和 GABA 能神经元的激活,以及雌二醇 黄体酮与从不接受/反社会行为到接受/社会行为的转变有关。 最后,我们将依次抑制性腺完整、循环中的谷氨酸能和 GABA 能 MeApd 神经元 使用 Cre 依赖性盐视紫红质 AAV 的 vGLUT-Cre 和 vGAT-Cre 小鼠。这些实验一起 将提供边缘-下丘脑回路中类固醇信号如何导致的功能回路分析 原型社会互动,脊柱前凸行为。
英文摘要
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.
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Modulation of sex steroid-induced female social behaviors in an animal model
Modulation of sex steroid-induced female social behaviors in an animal model
CORE--NEUROCYTOLOGY/CELLULAR IMAGING
CORE--NEUROCYTOLOGY /CELLULAR IMAGING
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