GENETIC AND NEUROENDOCRINE CONTROL OF BEHAVIORAL SYSTEMS

行为系统的遗传和神经内分泌控制

• 批准号: 2842348
• 负责人: Emilie F. Rissman
• 金额: $ 16.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2842348
• 关键词: androgen receptor; aromatase; behavioral /social science research tag; behavioral genetics; estrogen receptors; gene targeting; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; male; microinjections; motivation; neuroanatomy; neuroendocrine system; neuroregulation; newborn animals; odors; olfactory stimulus; oxidoreductase inhibitor; sex behavior; testosterone

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.

描述（改编自申请人的摘要）：这项新研究计划的目标是确定经典的雌激素受体（ER α，或ER α）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。一个关于男性性行为控制的非常有影响力的假说，即所谓的芳构化理论，认为在发育期间和成年期都需要雌激素来组织和激活男性性行为。早期雌激素的作用被认为会引起永久性的神经元变化，这决定了成年后的行为表现。许多激素和药物研究表明，雌性新生儿接触雌激素会增加其成年后表现出男性行为的潜力。相比之下，缺乏雌激素的男性则不太倾向于选择女性伴侣和进行性互动。此外，最近的研究已经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发挥作用。对于该提议，将使用基因工程敲除小鼠。使用该模型产生的成年人在发育和成年期间已经完全被剥夺了雌激素的作用，仅通过其基因组雌激素受体之一。最近发现雌激素具有多种受体亚型，使得这种缺乏功能性ER α的小鼠在脑中具有新特征的ER β（ERb），这对于区分雌激素对其受体亚型的作用是非常宝贵的。没有药理学工具可以区分各种ER。鉴于上述数据，预计ERa的破坏将导致男性性动机的不足。然而，该实验室和其他实验室收集的数据表明，ER α破坏（称为ERaKO）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。将进行实验以批判性地评估和量化ERaKO小鼠的性动机和表现。特别是，ER α的剥夺改变了神经元对雄激素的敏感性，以及睾酮（T）水平升高可以弥补ER α的缺乏，这一假设将得到检验。如果T可以产生正常的男性行为，那么ERb对于雌激素对正常男性发育的作用是必不可少的，或者发育期间缺乏ERa可以在成年时克服。或者，如果T替代不能恢复ERaKO的正常行为，这证明缺乏这种基因永久地改变了调节这些动机行为的神经回路。为了检验ERb在男性性行为的表达发育过程中是必不可少的这一假设，新生儿将用芳香酶抑制剂治疗，该抑制剂阻断T向雌二醇的转化。这将消除ERa KO和WT小鼠在关键期期间ERb的任何潜在作用。为了评估发育期间ER α的缺失导致雄性交配行为基础的基本神经回路的不可逆改变的假设，将使用fos免疫细胞化学来检测野生型和ERaKO雄性中对特异性的神经应答。多巴胺在发育过程中对雌激素的作用高度敏感，并可调节芳香化酶。此外，这种单胺在雄性大鼠的性动机和交配中起着明显的作用。因此，为了检验ER α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对动机行为的作用。此外，这些研究还探讨了在神经元发育的关键时期过去很久之后，补偿机制仍能作用于成年神经系统的可能性。