GENETIC AND NEUROENDOCRINE CONTROL OF BEHAVIORAL SYSTEMS

描述(摘自申请者的摘要)：这一新研究项目的目标是确定经典雌激素受体(ERpha，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”荷尔蒙，但它对男性的生理和行为有很多影响。关于男性性行为控制的一个非常有影响力的假说，即所谓的芳香化理论，认为在发育过程中和成年后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，这决定了成年后行为的表达。许多激素和药物研究表明，女婴接触雌激素会增加她们成年后表现出男性行为的可能性。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行为互动。此外，最近的研究将芳香酶系统与儿茶酚胺联系在一起，特别是多巴胺，众所周知，多巴胺在男性的性动机中发挥着作用。在这项提议中，将使用基因工程基因敲除小鼠。使用这一模型产生的成年动物在发育和成年期完全被剥夺了雌激素的作用，只通过其基因组中的一个雌激素受体。最近发现雌激素具有多种受体亚型，这使得这只缺乏功能的小鼠在脑中具有新的特征的ERb(ERb)，对于区分雌激素对其受体亚型的作用具有重要价值。目前还没有区分不同ER的药理学工具。考虑到上面回顾的数据，有人预测，ERA的中断将导致男性性动机不足。然而，该实验室和其他实验室收集的数据表明，带有时代中断的雄性小鼠的性动机和行为(称为ERaKO)可以通过经验和/或类固醇激素水平来改变。将进行实验，对ERaKO小鼠的性动机和表现进行批判性评估和量化。特别是，剥夺Era会改变神经元对雄激素的敏感性，以及睾酮(T)水平的升高可以弥补Era的缺乏，这一假设将得到检验。如果T能够产生正常的男性行为，要么ERb对于雌激素对正常男性发育的作用是必不可少的，要么成人可以克服发育过程中缺乏ERE的问题。或者，如果T替换不能恢复ERAKO的正常行为，这证明该基因的缺失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是必不可少的这一假设，新生儿将接受芳香酶抑制剂的治疗，该抑制剂可以阻止T向雌二醇的转化。这将消除ERaKO和WT小鼠在关键期内ERb的任何潜在作用。为了评估这一假说，即在发育过程中丢失ERA会导致作为雄性交配行为基础的基本神经回路发生不可逆转的变化，将使用FOS免疫细胞化学来检测野生型和ERaKO雄性对特定特征的神经反应。多巴胺在发育过程中对雌激素的影响高度敏感，可能调节芳香酶。此外，这种单胺在雄性大鼠性动机和交配中起着明显的作用。因此，为了验证这一假说，即时代颠覆通过其对多巴胺的作用而影响男性行为，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时代对动机行为的作用。此外，这些研究还研究了代偿机制在神经元发育的关键时期过去很长一段时间后仍能对成人神经系统起作用的可能性。

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.