Live-imaging and characterization of estrogen-induced dendritic spines

描述（由申请人提供）：成人神经可塑性的机制知之甚少。雌激素已经成为一种潜在的候选者，可以调节大脑在一生中学习和编码新记忆的能力。雌激素已被证明在雌性和雄性大鼠以及非人类灵长类动物的海马中诱导棘发生和突触增强。此外，雌激素与多种神经可塑性改变的疾病有关，如阿尔茨海默病、帕金森病、抑郁症和精神分裂症。虽然雌激素诱导的棘发生已经研究了几十年，但尚未对新出现的棘进行实时成像和表征。在这里，我建议使用双光子成像和电生理记录在成年大鼠的急性海马脑片的组合，以检查这些新的棘的功能特性。我的主要假设是，雌激素诱导更多的“年轻”的形态和电生理的档案在成年海马，高度可塑性的新的棘和沉默的突触增加;然而，这些变化是允许的，在没有“稳定”的刺激，如诱导LTP，新的棘和突触消失。本实验对研究雌激素在成年人中枢神经系统中的作用具有重要意义 以及一般成年人的脊髓和突触发生的功能。公共卫生相关性：大脑学习和形成新记忆的能力在许多疾病中受损，如阿尔茨海默病，帕金森病，抑郁症和精神分裂症。雌激素已被证明可以增加突触的数量，突触是脑细胞之间的交流场所。因此，更好地了解雌激素的作用机制具有巨大的潜力， 临床应用。

DESCRIPTION (provided by applicant): The mechanisms underlying adult neural plasticity are poorly understood. Estrogen has emerged as a potential candidate to mediate the brain's ability to learn and encode new memories throughout life. Estrogen has been shown to induce spinogenesis and synaptic potentiation in the hippocampus of both female and male rat, and in non-human primates. In addition, estrogen has been implicated in a wide variety of disorders in which neural plasticity is altered, such as Alzheimer's Disease, Parkinson's Disease, depression, and schizophrenia. Although estrogen-induced spinogenesis has been studied for decades, live imaging and characterization of the newly emerged spines has not yet been performed. Here, I propose to use a combination of two-photon imaging and electrophysiological recording in acute hippocampal slices of adult rat to examine the functional properties of these new spines. My main hypothesis is that estrogen induces more "youthful" morphological and electrophysiological profiles in the adult hippocampus, with highly plastic new spines and an increase in silent synapses; however, these changes are permissive in that in the absence of "stabilizing" stimulus such as induction of LTP, the new spines and synapses disappear. The proposed experiments will be important for both investigations of estrogen's functions in the adult CNS as well as the functions of spino- and synaptogenesis in the adult in general. PUBLIC HEALTH RELEVANCE: The brain's ability to learn and form new memories is impaired in many disorders, such as Alzheimer's Disease, Parkinson's Disease, depression, and schizophrenia. Estrogen has been shown to increase the number of synapses, the sites of communications between brain cells. Thus, a better understanding of the mechanisms of estrogen's actions holds great potential for far-reaching clinical applications.