ASTROCYTE-NEURONAL INTERACTIONS IN THE VISUAL CORTEX

摘要 星形胶质细胞是脑中的主要细胞类型，与所有其他神经细胞类型密切相关，具有 广泛的神经递质受体，响应神经元活动，并释放神经活性分子; 尽管如此，我们对这些细胞在生理、行为或疾病中的作用知之甚少。一个主要 这一领域的局限性在于缺乏研究神经系统中星形胶质细胞功能的模型 在活体动物的感官刺激后。迄今为止，几乎所有的星形胶质细胞功能的研究都依赖于 药理学方法来激活或抑制这些细胞中的信号传导，并记录它们的作用。 在体外或原位对周围细胞的活性。我们认为，在这方面取得进展需要一个模范制度 其中：1）活体动物的感觉输入可用于激活星形胶质细胞信号传导，2）行为 读数可用于确定体内星形胶质细胞信号传导的功能结果。为此我们 我建议使用小鼠中枢视觉通路来研究星形胶质细胞信号级联在 突触传递和可塑性以及视觉。在特定目标1中，我们将使用特征良好的切片 的初级视觉皮层检查的途径和机制调节星形胶质细胞信号原位。在 具体目标2：我们将使用体内成像来确定星形胶质细胞的钙反应是否是空间限制性的 并且在局部控制血管张力中很重要。在具体目标3中，我们将使用体内成像和遗传学- 改良小鼠研究星形胶质细胞在视觉可塑性中的作用。在第四章中，我们将... 研究星形胶质细胞在视觉中的作用，这是一种感觉输入的行为读出， 视觉皮层总的来说，这些研究的结果应该澄清的条件下，感觉输入导致 星形胶质细胞信号的激活以及星形胶质细胞信号在突触传递和视觉中的作用。

ABSTRACT Astrocytes are the predominate cell type in brain, closely associate with all other neural cell types, exhibit a wide array of neurotransmitter receptors, respond to neuronal activity, and release neuroactive molecules; in spite of this, we know very little about the role of these cells in physiology, behavior, or disease. A major limitation in this area is the lack of models that permit the study of astrocyte function in neural systems following sensory stimulation in living animals. To date, nearly all studies of astrocytic function have relied on pharmacological approaches to activate or inactivate signaling in these cells and to record the effects of their activity on surrounding cells in vitro or in situ. It is our view that progress in this area requires a model system where: 1) sensory input in living animals can be used to activate astrocytic signaling and, 2) behavioral readouts are available for determining the functional outcome of astrocytic signaling in vivo. To this end, we propose to use the mouse central visual pathway to investigate the role of astrocytic signaling cascades in synaptic transmission and plasticity as well as in vision. In Specific Aim 1 we will use well-characterized slices of primary visual cortex to examine the pathways and mechanisms regulating astrocytic signaling in situ. In Specific Aim 2 we will use in vivo imaging to determine if astrocytic calcium responses are spatially-restricted and important in the local control of vascular tone. In Specific Aim 3 we will use in vivo imaging and genetically- modified mice to investigate the role of astrocytes in visual plasticity. Finally, in Specific Aim 4 we will genet- ically engineered mice to investigate the role of astrocytes in vision, a behavioral readout of sensory input into the visual cortex. Overall, the results of these studies should clarify the conditions where sensory input leads to the activation of astrocytic signaling and the role of astrocytic signaling in synaptic transmission and vision.