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

动物模型中性类固醇诱导的女性社会行为的调节

• 批准号: 10582700
• 负责人: PAUL E MICEVYCH
• 金额: $ 42.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582700
• 关键词: Acute; Affect; Amygdaloid structure; Animal Model; Behavior; Cell Nucleus; Dependovirus; Dorsal; Estradiol; FOS gene; Female; Glutamates; Goals; Gonadal Steroid Hormones; Halorhodopsins; Hormonal; Hypothalamic structure; Lasers; Light; Lordosis; Measures; Medial; Mediating; Membrane; Methods; Morphology; Mus; Neurons; Opioid; Opioid Receptor; Output; Pattern; Progesterone; Regulation; Reproductive Behavior; Rodent; Role; Sensory; Signal Transduction; Site; Social Behavior; Social Controls; Social Interaction; Steroids; Stimulus; Structure of nucleus infundibularis hypothalami; Testing; Work; behavior test; beta-Endorphin; expectation; experimental study; immunoreactivity; male; medial preoptic nucleus; motivated behavior; mu opioid receptors; neural circuit; neuroregulation; optogenetics; preoptic nucleus; prototype; response; social

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.

摘要 我们的长期目标是通过研究边缘-下丘脑， 控制女性性感受性和脊柱前凸的神经回路我们证明了在这个电路中， 雌二醇膜启动信号激活弓状核（ARH）至内侧视前核 (MPN)负责完全性行为所需的短暂μ-阿片受体（MORs）激活的投射 接受性这些莫尔神经元依次投射到下丘脑腹内侧核（VMH） 调节脊柱前凸行为。目前的建议是基于这些结果和在雄性小鼠中的结果 这表明背后内侧杏仁核（MeApd）调节社会行为。因为在女性中， 影响社会行为、脊柱前凸的MeApd预测尚未明确，我们试图描述 调节ARH-MPN-VMH回路的特异性MeApd投射，其是雌性类固醇激活的基础 性接受能力我们将检验MeApd门控雌二醇启动的阿片类药物的一般假设 抑制调节性感受性。提出了三个具体目标，以功能性地剖析这一点 回路：1）选择性激活内源性ARH NPY神经元，和MPN投射的POMC终末抑制 脊柱前凸本实验正式测试了NPY和POMC神经元的顺序激活抑制了 脊柱前凸NPY-Cre和POMC-Cre神经元将被刺激性Cre依赖性 通道视紫红质（ChR 2）腺相关病毒（AAV）和光刺激的行为雌性小鼠。（二） MeApd通过向MPN的突触能投射来不同地调节性感受性， GABA能对VMH的影响我们将使用AAV定向表达ChR 2，以刺激或盐视紫红质， 抑制、谷氨酸能和GABA能MeApd输出。我们的期望是， MPN增强了MOR介导的前凸抑制（反社会行为），而GABA能输入到 VMH促进接受性（社会行为），如通过对刺激男性的脊柱前凸反应所测量的。第三章 性感受性涉及MeApd中从谷氨酸能神经元激活到GABA能神经元激活的转换。 这些实验将确定在女性中，MeApd是否像在男性中一样，通过以下方式控制社会行为： 从谷氨酸能（反社会）输出转向GABA能（社会）输出。首先，我们将确定 雌二醇和雌二醇+ β-D-半乳糖诱导的MeApd中谷氨酸能和GABA能神经元激活 孕酮与从非接受性/反社会行为到接受性/社会行为的变化有关。 最后，我们将依次抑制性腺完整、周期性的多巴胺能和GABA能MeApd神经元。 vGLUT-Cre和vGAT-Cre小鼠使用Cre依赖性盐视紫红质-AAV。总之，这些实验 将提供一个功能电路分析如何类固醇信号在边缘下丘脑电路导致 典型的社会互动，脊柱前凸行为