GENETIC AND NEUROENDOCRINE CONTROL OF BEHAVIORAL SYSTEMS

描述（改编自申请人摘要）：这个新研究项目的目标是确定经典雌激素受体（erα，或ERa）如何控制动机行为的表达。虽然雌激素通常被认为是一种“女性”激素，但它对男性的生理和行为有许多影响。一个非常有影响力的关于男性性行为控制的假说，即所谓的芳构化理论，认为在发育和成年期间都需要雌激素来组织和激活男性的性行为。早期雌激素的作用被认为会导致永久性的神经元变化，这决定了成年期的行为表达。许多激素和药物研究表明，女性新生儿接触雌激素会增加她们成年后表现出男性化行为的潜力。相比之下，缺乏雌激素的男性更不倾向于选择女性伴侣并进行性互动。此外，最近的研究将芳香化酶系统与儿茶酚胺，特别是多巴胺联系起来，众所周知，多巴胺在男性性动机中起着重要作用。为了这个提议，基因工程敲除小鼠将被利用。使用这个模型产生了一个在发育和成年期间完全被剥夺了雌激素作用的成年人，通过它的一个基因组雌激素受体。最近发现雌激素具有多种受体亚型，这使得这种缺乏功能性ERa但在大脑中具有新特征的erβ (ERb)的小鼠，对于区分雌激素对其受体亚型的作用具有宝贵的价值。目前还没有药物工具来区分不同的急诊室。根据上述数据，可以预测，ERa的破坏将导致男性性动机的缺失。然而，本实验室和其他实验室收集的数据表明，具有ERa破坏（称为ERaKOs）的雄性小鼠的性动机和行为可以通过经验和/或类固醇激素水平来改变。实验将对ERaKO小鼠的性动机和性表现进行批判性评估和量化。特别是，关于缺乏ERa会改变神经元对雄激素的敏感性，以及睾酮(T)水平升高可以补偿ERa缺乏的假设，将会得到检验。如果T能产生正常的男性行为，要么ERb是雌激素在正常男性发育中所必需的，要么在成人发育过程中ERa的缺乏是可以克服的。或者，如果T替代不能恢复ERaKOs的正常行为，这证明缺乏这种基因永久性地改变了调节这些动机行为的神经回路。为了验证ERb在发育过程中对男性性行为的表达至关重要的假设，新生儿将接受芳香酶抑制剂治疗，该抑制剂可以阻止T向雌二醇的转化。这将消除ERb在ERaKO和WT小鼠的关键时期的任何潜在作用。为了评估这一假设，即在发育过程中ERa的缺失会导致雄性交配行为基础神经回路的不可逆改变，fos免疫细胞化学将用于检测野生型和ERaKO雄性对特异性的神经反应。多巴胺在发育过程中对雌激素的影响高度敏感，并可能调节芳香化酶。此外，这种单胺在雄性大鼠的性动机和交配中起着显著的作用。因此，为了验证ERa破坏通过其对多巴胺的作用影响男性行为的假设，将采用神经解剖学和行为学研究。这些研究批判性地评估了ERa在动机行为中的作用。此外，这些研究还考察了代偿机制在成熟的神经发育关键期过去后仍能长期作用于成人神经系统的可能性。

DESCRIPTION (Adapted From The Applicant's Abstract): The goal of this new research program is to determine how the classic estrogen receptor (ERalpha, or ERa) controls expression of motivated behaviors. Although often considered a "female" hormone, estrogen has numerous effects on male physiology and behavior. One highly influential hypothesis on the control of male sexual behavior, the so-called aromatization theory, states that estrogen is required both during development and in adulthood to organize and activate male sexual behaviors. The actions of early estrogens are thought to cause permanent neuronal changes, which dictate expression of behavior in adulthood. Many hormone and drug studies have shown that exposure to estrogen in female neonates increases their potential to display masculine behavior in adulthood. In contrast, males deprived of estrogen are less apt to select female partners and engage in sexual interactions. In addition, recent studies have linked the aromatase system to catecholamines, particularly dopamine, which is well known to play a role in male sexual motivation. For this proposal, genetically engineered knockout mice will be utilized. Use of this model yields an adult that has been completely deprived, during development and adulthood, of estrogens' actions via just one of its genomic estrogen receptors. The recent discovery that estrogen has multiple receptor subtypes makes this mouse, which lacks functional ERa, yet has the newly characterized ERbeta (ERb) in brain, invaluable for distinguishing the actions of estrogen on its receptor subtypes. There are no pharmacological tools that distinguish between the various ERs. Given the data reviewed above, it was predicted that the disruption of ERa would cause a deficit in male sexual motivation. However, data collected by this lab and others suggest that sexual motivation and behavior in male mice with the ERa disruption (referred to as ERaKOs) can be modified by experience and/or steroid hormone level. Experiments will be conducted to critically evaluate and quantify the sexual motivation and performance of the ERaKO mice. In particular, the hypotheses that deprivation of ERa alters neuronal sensitivity to androgens, and that elevated levels of testosterone (T) can compensate for the lack of ERa, will be tested. If T can produce normal masculine behavior, either the ERb is essential for estrogen's actions on normal masculine development, or the lack of ERa during development can be overcome in the adult. Alternatively, if T replacement does not reinstate normal behavior in ERaKOs, this proves that lack of this gene permanently alters the neurocircuitry which regulates these motivated behaviors. To test the hypothesis that the ERb is essential during development for expression of male sexual behaviors, neonates will be treated with an aromatase inhibitor, which blocks the conversion of T to estradiol. This will eliminate any potential actions of the ERb during the critical period in both ERaKO and WT mice. To assess the hypothesis that loss of ERa during development causes irreversible alterations in the basic neural circuitry that underlies male copulatory behaviors, fos immuno- cytochemistry will be used to detect neural responses to specifics in wildtype and ERaKO males. Dopamine is highly sensitive to the effects of estrogen during development and may regulate aromatase enzyme. Moreover, this monoamine plays a pronounced role in male rat sexual motivation and copulation. Thus, to test the hypothesis that ERa disruption affects masculine behavior by its actions on dopamine, both neuroanatomical and behavioral studies will be employed. These studies critically evaluate the role of the ERa on motivated behaviors. Moreover, the studies examine the possibility that compensatory mechanisms can act on the adult nervous system long after well established critical periods of neuronal development have passed.