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尚不清楚。雌激素被认为是调节大脑学习和编码新记忆能力的潜在候选者。雌激素在雌性和雄性大鼠以及非人灵长类动物的海马中均可诱导脊髓发生和突触增强。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。虽然雌激素诱导的脊柱形成已经研究了几十年，但尚未对新出现的脊柱进行实时成像和表征。在这里，我建议结合双光子成像和电生理记录在成年大鼠急性海马切片来检查这些新棘的功能特性。我的主要假设是，雌激素在成年海马中诱导了更“年轻”的形态和电生理特征，具有高度可塑性的新棘和沉默突触的增加；然而，这些变化是允许的，因为在没有“稳定”刺激（如LTP的诱导）的情况下，新的脊髓和突触消失了。本实验对雌激素在成人中枢神经系统中的功能研究具有重要意义

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.