Elucidating the mechanisms by which estradiol regulates female striatal neuron excitability

阐明雌二醇调节女性纹状体神经元兴奋性的机制

• 批准号: 9075099
• 负责人: John Meitzen
• 金额: $ 35.79万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-19 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9075099
• 关键词: Action Potentials; Address; Adult; Attention deficit hyperactivity disorder; Behavior; Biological Models; Cognitive; Corpus striatum structure; Data; Development; Disease; Dopamine; Drug Addiction; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrous Cycle; Female; Foundations; Future; Genetic; Gilles de la Tourette syndrome; Glutamates; Goals; Gonadal Steroid Hormones; Health; Hormones; Huntington Disease; Incidence; Individual; Knowledge; Lead; Link; Mediating; Membrane; Mission; Neurons; Neurotransmitters; Outcomes Research; Output; Parkinson Disease; Pathology; Process; Property; Puberty; Public Health; Rattus; Regulation; Research; Role; Schizophrenia; Severities; Sex Bias; Sex Characteristics; Sodium Channel; Synapses; System; Tardive Dyskinesia; Testing; Work; base; behavior influence; electrical property; improved; male; neurotransmission; postnatal; prepuberty; programs; public health relevance; receptor; relating to nervous system; response; sex; voltage

 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.

 描述（由申请人提供）：纹状体介导的认知和感觉运动行为的性别差异已被证明了几十年。女性的这些行为和纹状体本身的功能对类固醇性激素17β-雌激素（雌二醇）的作用敏感，但男性则不然。同样，许多与纹状体相关的疾病对雌二醇的作用敏感，并且/或者在发病率和/或严重程度上表现出性别偏见。值得注意的是，雌二醇组织和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的变化还没有得到很好的理解，提供了这个建议的理由。本提案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学如何通过类固醇性激素和遗传性别进行调节，以产生功能和病理的性别差异。为了做到这一点，我们将重点放在纹状体的主导和输出神经元：中型棘神经元（MSN），并使用大鼠作为模型系统。MSN动作电位构成纹状体处理的输出。因此，所有纹状体的性别差异最终都必须影响MSN的电特性，从而影响行为。一个关键的电特性是内在膜兴奋性，其支配神经元响应于电和突触输入而产生动作电位的能力。我们最近发现，MSN兴奋性增加，青春期前的女性相比，男性，和兴奋性迅速调节雌二醇。增加的女性MSN兴奋性不被阻断的谷氨酸能和GABA能受体拮抗剂，这意味着增加的兴奋性在女性MSN是不介导的经典的快速神经传递。同样，在兴奋性突触输入中没有检测到性别差异。由于MSN兴奋性的性别差异发生在青春期前，这提出了令人兴奋的可能性，即这是在成年前组织的，在青春期重新编程，并通过成人雌二醇作用进行急性调节。这个项目的中心假设，这是基于这些初步的发现，是这样的：雌二醇组织，然后通过性别特异性机制急性调节MSN兴奋性。我们将在以下三个具体目标上检验这一假设：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。这些研究将有一个重要的积极影响，因为他们将解决神经电生理机制的雌二醇行动在纹状体功能。这将是基础知识的重要进步，可能有助于理解纹状体病理学性别差异的机制，并产生性别特异性治疗的新靶点。更广泛地说，这项研究将有助于更好地了解 雌二醇、遗传性别和神经元电生理特性之间的关系。