Genetic and Neuroendocrine Control of Behavioral Systems

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测序。人类内分泌突变在临床上是常见的，并且工程化的和自发的小鼠突变体沿着激素受体可用于调节激素合成的许多酶。因此，主要激素及其受体的遗传基础是众所周知的。但是相反的关系，行为如何影响基因功能，是相对未探索的。本文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、雌激素受体α影响进化上必要的和保守的行为的机制，这些行为构成了男性性行为。我们将使用多巴胺的中央给药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，并且我们将询问性经历是否可以补偿外源多巴胺。将进行体内微透析以确定雌激素和/或气态神经递质一氧化氮是否可以刺激内侧视前区的多巴胺释放。此外，我们还将询问雌激素受体α是否是女性诱导的多巴胺在大脑中释放所必需的，以及这是否会被性经验所改变。为了确定哪种多巴胺受体对这种行为至关重要，我们将使用多巴胺受体激动剂和拮抗剂，适当的多胺受体敲除小鼠，以及多巴胺受体敲除小鼠，以询问多巴胺是否通过未占据的多巴胺受体来启动幼稚雄性的性行为。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验作为影响基因作用的因素。性功能障碍包括早泄和勃起障碍在男性中很常见。我们对这些疾病的神经生物学的理解是有限的，性经验因素和治疗之间的相互作用是未知的。一些男性勃起障碍的临床治疗包括使用我们将用于我们工作的药物;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广泛的个体差异。

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.