Genetic and Neuroendocrine Control of Behavioral Systems

描述(申请人提供)：这些研究的长期目标是了解基因、激素和环境如何相互作用并最终控制复杂的社会行为。人类和小鼠的基因组已经被测序。人类内分泌突变在临床上很常见，转基因和自发性小鼠突变以及激素受体可用于许多调节激素合成的酶。因此，主要荷尔蒙及其受体的遗传基础是众所周知的。但行为如何影响基因功能的反向关系相对来说还没有被研究过。这里提出的研究将剖析基因、激素和行为的相互作用，并阐明类固醇激素受体和雌激素受体α影响构成男性性行为的进化必需和保守的行为集的机制。我们将使用中枢注射多巴胺来激活缺乏功能性雌激素受体α基因的雄性小鼠的性行为，我们将探索性体验是否可以补偿外源性多巴胺。在体内，将进行微透析以确定雌激素和/或气体神经递质一氧化氮是否可以刺激视前内侧区域的多巴胺释放。此外，我们将询问雌激素受体阿尔法是否是女性在大脑中诱导多巴胺释放所必需的，以及这是否被性行为经验所改变。为了确定哪种多巴胺受体对这种行为是必不可少的，我们将使用多巴胺受体激动剂和拮抗剂、适当的多巴胺受体基因敲除小鼠和孕激素受体基因敲除小鼠来询问多巴胺是否通过未被占据的孕激素受体来启动幼稚男性的性行为。该计划的创新方面包括使用药理学、基因敲除小鼠和生活经历作为影响基因作用的因素。包括早泄和勃起障碍在内的性功能障碍在男性中很常见。我们对这些疾病的神经生物学了解有限，性经验因素和治疗之间的相互作用也是未知的。男性勃起障碍的几种临床治疗方法包括我们将在工作中使用的药物：一氧化氮供体和多巴胺激动剂。我们将产生的信息可能有助于解释为什么接受类似药物或激素治疗的患者在治疗结果上往往表现出很大的个体差异。

DESCRIPTION (provided by applicant): The long term objective of these studies is to understand how genes, hormones, and environment interact and ultimately control complex social behaviors. The human and mouse genomes have been sequenced. Human endocrine mutations are common in the clinic, and engineered and sponateous mouse mutants along with hormone receptors are available for many of the enzymes that regulate hormone sythesis. Thus, the genetic bases of major hormones and their receptors are well known. But the inverse relationship, how behavior affects gene function, is relatively unexplored. The studies proposed here will dissect gene, hormone, and behavior interactions and elucidate the mechanisms by which the steroid hormone receptor, estrogen receptor alpha affects the evolutionarily essential and conserved set of behaviors that consititute male sexual behavior. We will use central administration of dopamine to activate sexual behavior in male mice lacking a functional estrogen receptor alpha gene, and we will ask if sexual experience can compensate for exogenous dopamine. In vivo microdialysis will be conducted to determine if estrogen and/or the gaseous neurotransmitter, nitric oxide, can stimulate dopamine release in the medial preoptic area. In addition, we will ask if the estrogen receptor alpha is required for female-induced dopamine release in the brain and if this is modified by sex experience. To pinpoint which dopamine receptor is essential for this behavior we will use dopamine receptor agonists and antagonists, appropriate doamine receptor knockout mice, and the progestin receptor knockout mouse to ask if dopamine acts via the unoccupied progestin receptor to initiate sexual behavior in naive males. The innovative aspects of this program include the use of pharmacology, knockout mice, and life experiences as factors that affect gene actions. Sexual dysfunctions including premature ejaculation and erectile disorders are common in men. Our understanding of the neurobiology of these disorders is limited, and the interactions between sexual experiential factors and treatment are unknown. Several clinical treatments for erectile disorder in men incorporate the use of drugs we will use for our work; nitric oxide donors and dopamine agonists. The information we will generate may help explain why patients undergoing similar drug or hormone therapies often display wide individual variations in treatment outcomes.