CNS Estrogen Receptors and Social Behavior

描述（由申请人提供）：雌激素受体a（ER a）使男性行为男性化，这通常与低水平的亲社会（积极）行为有关，例如形成长期的配对关系和父母照顾。在此基础上，我完成了一系列的实验，以测试的假设，在特定区域的高度社会化的男性的中枢神经系统中观察到的低水平的ER α是必要的/允许高水平的积极的社会（亲社会）行为的表达。使用含有ER a cDNA的腺相关病毒载体（AAV）来增加社会性单配型雄性草原田鼠（Microtus ochrogaster）的内侧杏仁核（MeA）中ER a的表达（由R21-MH 068278支持）。MeA是“社会神经回路”的一部分，也影响着“奖励系统”。“因此，MeA的变化可能对社会行为的表达产生重大影响。研究结果支持了这一假设，因为ER α的增加降低了自发的同种异体父母照顾，并破坏了异性伴侣偏好的形成。虽然这些结果表明，低水平的雌激素受体α是必要的男性表达高水平的亲社会行为的下一个关键部分是证明，减少雌激素受体α在男性，通常不显示高水平的亲社会行为将增加亲社会行为的表达。本研究的第一个目的是使用含有ER α RNAi（其抑制ER α的表达）的AAV来减少/抑制雄性草甸田鼠（Microtus pennaculicus）MeA中ER α的表达。在ERa减少后，将测试雄性动物的亲社会行为、同种异体和异性恋社会偏好以及雄性/雄性攻击性的表达，预测ERa减雄性动物将表现出增加的社会行为和减少的攻击性。本研究的第二个目的是确定ER α的减少是否增加精氨酸加压素（AVP）刺激男性亲社会行为表达的能力。ER α的变化可能直接调节雄性亲社会行为的表达，但也可能通过调节对AVP的反应而影响社会行为的表达。AVP已被证明调节许多男性社会行为，并且AVP的许多作用是类固醇依赖性的。因此，减少雌激素受体α可能会增加男性亲社会行为的“允许”AVP的社会影响。这些研究的结果将为男性社会行为的调节提供重要的见解。这些信息是至关重要的，因为许多社会病理和心理健康状况与缺乏社会或非典型社会行为有关，了解调节社会行为的机制将有助于开发潜在的治疗方法。公共卫生相关性：雌激素受体α（ER α）参与男性行为的男性化。本研究的目的是检验这一假设，即在调节社会行为表达的大脑区域中减少ER α对于男性表达高水平的积极/亲和行为（如配对关系形成和父母照顾）是必要的。这将通过抑制通常不显示高水平社会行为的雄性啮齿动物（草地田鼠）中ER a的表达来实现。了解社会行为的调节是重要的，因为许多心理健康疾病与社会行为的缺陷或不适当的表达有关。

DESCRIPTION (provided by applicant): Estrogen receptor a (ERa) masculinizes male behavior, which is typically associated with low levels of prosocial (positive) behavior, such as formation of long-term pair bonds and parental care. Based upon this I completed a series of experiments to test the hypothesis that the low level of ERa observed in specific regions of the CNS of highly social males is necessary for/permits the expression of high levels of positive social (prosocial) behavior. An adeno-associated viral vector (AAV) containing ERa cDNA was used to increase the expression of ERa in the medial amygdala (MeA) of the socially monogamous male prairie vole (Microtus ochrogaster) (supported by R21-MH068278). The MeA is part of the "social neural circuit" and also influences the "reward system." Therefore, a change in the MeA could have a major impact on the expression of social behavior. The results supported the hypothesis, as increasing ERa decreased spontaneous alloparental care and disrupted the formation of a heterosexual partner preference. While these results indicate that low levels of ERa are necessary for males to express high levels of prosocial behavior the next critical piece is to demonstrate that decreasing ERa in a male that typically does not display high levels of prosocial behavior will increase the expression of prosocial behavior. The first goal of this study is to use AAV containing ERa RNAi (which inhibits the expression of ERa) to reduce/inhibit the expression of ERa in the MeA of male meadow voles (Microtus pennsylvanicus). Following the reduction of ERa, males will be tested for the expression of prosocial behavior, alloparental and heterosexual social preference, and male/male aggression with the prediction being that ERa minus males will display increased social behavior and decreased aggression. The second goal of this study is to determine if a reduction in ERa increases the ability of arginine vasopressin (AVP) to stimulate the expression of male prosocial behavior. Changes in ERa may directly regulate the expression of male prosocial behavior, but it may also influence the expression of social behavior by regulating the response to AVP. AVP has been shown to regulate a number of male social behaviors and many of the effects of AVP are steroid dependent. Therefore, a reduction in ERa may increase male prosocial behavior by "permitting" the social effects of AVP. The results from these studies will provide significant insight into the regulation of male social behavior. This information is vital as many social pathologies and mental health conditions are associated with either a lack of social or atypical social behavior, and understanding the mechanisms regulating social behavior will aid in developing potential treatments. PUBLIC HEALTH RELEVANCE: Estrogen receptor alpha (ERa) is involved in the masculinization of male behavior. The goal of this study is to test the hypothesis that a reduction of ERa in areas of the brain that regulate the expression of social behavior is necessary for males to express high levels of positive/affliative behavior, such as pair bond formation and parental care. This will be accomplished by inhibiting the expression of ERa in male rodents (meadow voles) that do not typically display high levels of social behavior. Understanding the regulation of social behavior is important as many mental health pathologies are associated with deficits or inappropriate expression of social behavior.