A Ram Model of Neuroendocrine Function

神经内分泌功能的 Ram 模型

• 批准号: 8013487
• 负责人: CHARLES E. ROSELLI
• 金额: $ 3.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013487
• 关键词: Ablation; Address; Adult; Affect; Androgen Receptor; Androgens; Animal Model; Animals; Apoptosis; Apoptotic; Architecture; Aromatase Inhibitors; Basic Science; Behavior; Biological; Birth; Brain; Cell Nucleus; Clinical Trials; Complex; Congenital adrenal hyperplasia; Counseling; Cues; Development; Discrimination; Dissection; Estrogens; Etiology; Event; Exhibits; Experimental Models; Exposure to; Female; Fetal Development; Fetus; Genetic; Goals; Gonadal Steroid Hormones; Gonadotropins; Grant; Hormonal; Human; In Situ Nick-End Labeling; Incidence; Individual; Irrigation; Link; Mediating; Medical; Methods; Modeling; National Institute of Child Health and Human Development; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Nervous system structure; Neurons; Neurosecretory Systems; Nose; Olfactory Epithelium; Partner in relationship; Pathway interactions; Population; Pregnancy; Procaine; Proteins; Psychosexual Development; Research; Rodent; Sex Behavior; Sex Orientation; Sexual Partners; Sexuality; Sheep; Social Behavior; Steroids; Study models; Syndrome; Testing; Testosterone; Time; Translating; Variant; Work; Zinc Sulfate; brain behavior; caspase-3; fetal; grasp; immunocytochemistry; insight; interest; male; neuromechanism; neuron apoptosis; olfactory bulb; preference; prenatal; pro-apoptotic protein; programs; reproductive success; sex; systems research

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the biological mechanisms that regulate male-typical sexual partner preference, and, thereby, to develop a better understanding of mammalian sexual differentiation and psychosexual development. The successful counseling of individuals who have issues and concerns related to their sexuality requires a comprehensive grasp of the biological underpinnings of human psychosexual development. However, clinical investigations of the contribution of fetal sex hormone exposure to sexual differentiation are limited to the study of extremely rare medical syndromes that are often difficult to interpret. Our studies address the critical need for a relevant animal model to further understanding of the etiology of neural mechanisms controlling mammalian sexual attraction. Thus, we will test the hypothesis that individual variations in adult mate recognition and neuroendocrine function of males depends on developmental events influencing the timing or extent of brain exposure to androgens. The ram is an exceptional model because variations in male-typical sexual partner preference occur spontaneously with as many as 8 percent of the population exhibiting a preference for same-sex mating partners (male-oriented rams). Sheep have a long period of gestation that closely approximates human fetal development making them an excellent experimental model for the study of possible links between fetal neuroendocrine programming and adult sexual behavior. We now know that the ovine sexually dimorphic nucleus (oSDN) is larger in rams that are attracted to females (female-oriented) than in male-oriented rams, and that it develops prior to birth. These results support the view that sexual preferences are hard-wired in the brain. However, the cellular and genetic mechanisms underlying these profound differences in oSDN architecture are unknown. Thus, our next critical step will be to establish the causal relationships between oSDN differentiation, adult function, and mate preferences. In our current working model, we hypothesize that testosterone acts directly through the androgen receptor pathway to protect developing oSDN neurons from undergoing programmed cell death. This, in turn, leads to the development of male-typical olfactory discrimination and sexual partner preference. Thus, we propose to: 1) test the hypothesis that oSDN volume and sexual partner preference are organized through an androgen receptor-mediated mechanism; 2) test the hypothesis that neuronal apoptosis contributes to the sexual differentiation of the oSDN; 3) test the hypothesis that chemosensory cues detected by the main olfactory bulb are necessary for the expression of sexual partner preferences in rams. Advancing the sheep model will provide a valuable animal system for research that bridges the central research interests of NICHD (mechanisms of steroid action in development of brain and behavior; NIMH (etiology of neural mechanisms that control a complex social behavior that is crucial to reproductive success); and NINDS (basic research to gain understanding the structure of the nervous system). Project Narrative The successful counseling of individuals who have issues and concerns related to their sexuality would benefit from a comprehensive grasp of the biological underpinnings of human psychosexual development. However, clinical investigations of the contribution of fetal sex hormone exposure to sexual differentiation are limited to the study of extremely rare medical syndromes that are often difficult to interpret. Our studies address the critical need for a relevant animal model to further understanding of the etiology of neural mechanisms controlling mammalian sexual attraction. Thus, we will test the hypothesis that individual variations in adult mate recognition and neuroendocrine function of males depend on developmental events influencing the timing or extent of brain exposure to androgens.

描述（由申请人提供）：该提案的目的是确定调节男性性伴侣偏好的生物学机制，从而更好地了解对哺乳动物性别分化和心理性发展的更好理解。与性行为有关的个人的成功咨询需要对人类心理发展的生物学基础进行全面掌握。但是，对暴露于性别分化的胎儿性激素的贡献的临床研究仅限于对通常难以解释的极罕见的医学综合症的研究。 我们的研究涉及相关动物模型的关键需求，以进一步理解控制哺乳动物性吸引力的神经机制的病因。因此，我们将检验以下假设：男性成人伴侣识别和神经内分泌功能的个体变化取决于影响大脑暴露于雄激素的时间或程度的发育事件。 RAM是一个非凡的模型，因为男性性伴侣偏好的变化自发发生，多达8％的人口表现出对同性交配伴侣（以男性为导向的公羊）的偏好。绵羊的妊娠期很长，可以紧密近似人类的胎儿发育，这是研究胎儿神经内分泌程序和成人性行为之间可能联系的出色实验模型。我们现在知道，在被雌性吸引（以女性为导向的女性）的公羊中，卵形性二态核（OSDN）大于以男性为导向的公羊，并且它在出生前就会发展。这些结果支持这样一种观点，即性偏爱在大脑中是用力连接的。但是，OSDN结构上这些深刻差异的基础的细胞和遗传机制尚不清楚。因此，我们的下一个关键步骤将是建立OSDN分化，成人功能和伴侣偏好之间的因果关系。在当前的工作模型中，我们假设睾丸激素直接通过雄激素受体途径起作用，以保护发育中的OSDN神经元免受程序性细胞死亡的影响。反过来，这导致了男性典型的嗅觉歧视和性伴侣偏爱的发展。因此，我们建议：1）检验以下假设：OSDN体积和性伴侣的偏好是通过雄激素受体介导的机制组织的； 2）检验神经元凋亡有助于OSDN的性分化的假设； 3）检验以下假设：主要嗅球检测到的化学感应提示对于在RAM中表达性伴侣偏好是必要的。推进绵羊模型将为研究提供有价值的动物系统，该系统桥接了NICHD的中心研究兴趣（类固醇作用在大脑和行为开发中的机制； NIMH（神经机制的病因，这些神经机制控制着复杂的社会行为，这对于生殖成功至关重要）；和NIND）和NIND（基础研究以了解神经系统的结构）。 项目叙述 与性行为有关的个人的成功咨询将受益于对人类心理性发展的生物学基础的全面掌握。但是，对暴露于性别分化的胎儿性激素的贡献的临床研究仅限于对通常难以解释的极罕见的医学综合症的研究。我们的研究涉及相关动物模型的关键需求，以进一步理解控制哺乳动物性吸引力的神经机制的病因。因此，我们将检验以下假设：男性成年伴侣识别和神经内分泌功能的个体变化取决于影响大脑暴露于雄激素的时间或程度的发育事件。