Seasonal Plasticity in Steroid-Sensitive Neural Circuits

描述（由申请人提供）：理解大脑的可塑性是神经科学面临的主要挑战。对这些研究有用的一类动物模型涉及大脑的变化，这些变化是对调节生殖生理季节变化的显著环境刺激的自然反应。鸣禽大脑的季节性变化是这种自然神经可塑性最引人注目的例子之一。本研究分析了类固醇激素对歌唱行为和歌唱控制核形态可塑性影响的解剖回路和细胞事件，并探讨了歌唱对大脑可塑性的可能影响。目的1将确定类固醇是否直接作用于唱歌时活跃的神经元（实验1）。Aim II通过分析酪氨酸羟化酶免疫反应输入与鸣叫控制核、即时早期基因表达（IEG）和类固醇受体之间的关系，关注儿茶酚胺在鸣叫产生中的作用（见图2-4）。目的III和IV将研究类固醇控制的细胞信号，这些信号与新神经元的募集和存活有关，这些神经元有助于大脑的季节性变化。Aim III将分析类固醇是否直接作用于产生脑源性神经营养因子（BDNF）的细胞，并将研究唱歌对歌核中BDNF表达的影响（实验5-6）。实验7将用反义技术测试歌唱诱导的IEG表达是否需要刺激BDNF的产生。Reelin是一种糖蛋白，在个体发育过程中对神经元定位起关键作用，最近被证明在成年鸟类鸣叫核HVc中存在并受睾酮(T)调节。目的IV将通过确定新生HVc神经元中是否存在reelin受体（预期8），表征T对reelin表达的影响（预期9-12），以及评估reelin表达操纵对神经元整合的影响（预期13），探索reelin在新神经元向HVc募集中的作用。Aim V （expt 14）将研究T对鸣叫的影响和对鸣叫控制核生长的影响之间的季节性分离是否可以通过在项目初始阶段研究的一些细胞反应对T的反应的解耦来解释。这些研究将为介导歌曲表达和相关的季节性神经可塑性的细胞机制提供一个综合的观点，并将有助于理解大脑的变化是否可以通过行为表达的变化来介导。

DESCRIPTION (provided by applicant): Understanding brain plasticity is a major challenge facing the neurosciences. One class of animal models useful for these studies involves brain changes that occur naturally in response to salient environmental stimuli that regulate seasonal variation in reproductive physiology. Seasonal changes in the brain of songbirds are one of the most dramatic examples of this natural neuroplasticity. This proposal analyzes the anatomical circuits and cellular events that mediate the effects of steroid hormones on singing behavior and on the morphological plasticity of song control nuclei and investigates the possible effects of singing on brain plasticity. Aim I will determine whether steroids act directly on neurons that are active during singing (Expt 1). Aim II concerns the role of catecholamines in song production by analyzing the relationships among tyrosine hydroxylase-immunoreactive inputs to song control nuclei, immediate early gene expression (IEG) and steroid receptors (Expts 2-4). Aims III and IV will investigate steroid controls of cellular signals that are implicated in the recruitment and survival of new neurons that contribute to seasonal changes in the brain. Aim III will analyze whether steroids act directly on cells that produce Brain Derived Neurotrophic Factor (BDNF) and will investigate the effects of singing on BDNF expression in song nuclei (Expts 5-6). Exp 7 will test with antisense techniques whether singing-induced IEG expression is required for the stimulaton of BDNF production. Reelin, a glycoprotein that plays a key role in neuronal positioning during ontogeny, was recently shown to be present and regulated by testosterone (T) in song nucleus HVc in adult birds. Aim IV will explore the role of reelin in the recruitment of new neurons into HVc by determining whether reelin receptors are present in newborn HVc neurons (Expt 8), characterizing the effects of T on reelin expression (Expts 9-12) and assessing the effects on neuronal incorporation of manipulations of reelin expression (Expt 13). Aim V (expt 14) will investigate whether the seasonal dissociations between the effects of T on song and on the growth of song control nuclei can be explained by the uncoupling of the response to T of some of the cellular responses investigated in the initial phases of the project. These studies will provide an integrated view of cellular mechanisms that mediate song expression and the associated seasonal neuroplasticity and will contribute to an understanding of whether brain changes can be mediated via changes in behavioral expression.