Elucidating the mechanisms by which estradiol regulates female striatal neuron excitability

 描述(由申请者提供)：纹状体介导的认知和感觉运动行为的性别差异已经被证明几十年了。这些行为和纹状体本身的功能对类固醇性激素17β-雌二醇(雌二醇)的作用在女性身上很敏感，但在男性身上不敏感。同样，许多与纹状体有关的疾病对雌二醇的作用很敏感，和/或在发病率和/或严重程度上表现出性别偏见。值得注意的是，雌二醇组织并随后调节纹状体神经元电生理特性的机制和程度最终使这些功能和行为发生变化的机制和程度尚不清楚，这为这一提议提供了理论基础。这项建议的总体目标是填补这一关键的知识空白，努力实现我们的长期目标，即了解纹状体内在和突触电生理如何受到类固醇性激素和遗传性性别的调节，从而产生功能和病理上的性别差异。为此，我们将重点研究纹状体的主要神经元和输出神经元：中棘神经元(MSN)，并以大鼠为模型系统。MSN动作电位构成纹状体处理的输出。因此，所有纹状体性别差异最终必然会影响MSN的电特性，从而影响行为。一个关键的电特性是固有的膜兴奋性，它控制着神经元对电和突触输入产生动作电位的能力。我们最近发现，与男性相比，青春期前女性的MSN兴奋性增加，而且兴奋性迅速受到雌二醇的调节。女性MSN兴奋性的增加不能被谷氨酸和GABA能受体拮抗剂阻断，这意味着女性MSN的兴奋性增加不是由经典的快速神经传递介导的。同样，在兴奋性突触输入方面没有发现性别差异。由于MSN兴奋性的性别差异在青春期前就出现了，这增加了一种令人兴奋的可能性，即这种差异在成年期之前就已经组织起来，在青春期期间重新编程，并受到成年雌激素作用的剧烈调节。基于这些初步发现，该项目的中心假设是：雌二醇通过性别特异性机制组织并敏锐地调节MSN的兴奋性。我们将通过以下三个具体目标来检验这一假说：1)阐明雌二醇对MSN兴奋性的组织作用机制；2)描述雌二醇对MSN兴奋性快速作用的机制；3)确定雌二醇作用对特定MSN亚型兴奋性的功能影响。这些研究将产生重要的积极影响，因为它们将解决雌二醇在纹状体功能中潜在的神经电生理机制。这将是基础知识的一项重要进步，可能有助于理解纹状体病理中性别差异的潜在机制，并为性别特异性治疗产生新的靶点。更广泛地说，这项研究将有助于更好地理解 雌二醇、遗传性别和神经元电生理特性之间的关系。

 DESCRIPTION (provided by applicant): Sex differences in striatal-mediated cognitive and sensorimotor behaviors have been demonstrated for decades. These behaviors and the function of the striatum itself are sensitive to the action of the steroid sex hormone 17β-estradil (estradiol) in females but not males. Likewise, many disorders linked to the striatum are sensitive to estradiol action and/or show a sex bias in incidence and/or severity. Remarkably, the mechanisms and extent to which estradiol organizes and then modulates the striatal neuron electrophysiological properties that ultimately enable these changes in function and behavior are not well understood, providing the rationale for this proposal. The overall goal of this proposal is to fill this critical knowledge gap, working towards our long-term goal of understanding how striatal intrinsic and synaptic electrophysiology can be modulated by steroid sex hormones and genetic sex to generate sex differences in function and pathologies. To do this we will focus on the predominant and output neurons of the striatum: the medium spiny neurons (MSNs), and use rats as a model system. MSN action potentials constitute the output of striatal processing. Thus all striatal sex differences must ultimately influence MSN electrical properties to influence behavior. One key electrical property is intrinsic membrane excitability, which governs the ability of a neuron to produce action potentials in response to electrical and synaptic input. We recently discovered that MSN excitability is increased in prepubertal females compared to males, and that excitability is rapidly modulated by estradiol. Increased female MSN excitability was not blocked by glutamatergic and GABAergic receptor antagonists, meaning that increased excitability in female MSNs is not mediated by classical fast neurotransmission. Likewise, no sex differences were detected in excitatory synaptic input. Since sex differences in MSN excitability occur pre-puberty, this raises the exciting possibility that this is organized before adulthood, is re-programmed during puberty, and acutely modulated by adult estradiol action. The central hypothesis of this project, which is based upon these initial findings, is this: estradiol organizes and then acutely regulates MSN excitability vi sex specific mechanisms. We will test this hypothesis over the following three specific aims: 1) Elucidate the mechanism underlying organizational actions of estradiol on MSN excitability; 2) Delineate the mechanism underlying rapid actions of estradiol on MSN excitability; and 3) Determine the functional impact of estradiol actions on the excitability of specific MSN subtypes. These studies will have an important positive impact because they will address the neural electrophysiological mechanisms underlying estradiol action in striatal function. This will be an important advancement in fundamental knowledge that is potentially useful for understanding the mechanisms underlying sex differences in striatal pathologies and generating new targets for sex-specific therapies. More broadly, this research will help lead to a better understanding of the relationship between estradiol, genetic sex, and neuron electrophysiological properties.