ASTROCYTE-NEURONAL INTERACTIONS IN THE VISUAL CORTEX

摘要 星形胶质细胞是大脑中最主要的细胞类型，与所有其他神经细胞类型密切相关，表现出 广泛的神经递质受体，对神经元活动做出反应，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。一位少校 这一领域的局限性是缺乏允许研究神经系统中星形胶质细胞功能的模型。 在活着的动物身上进行感官刺激。到目前为止，几乎所有的星形细胞功能研究都依赖于 激活或失活这些细胞中的信号并记录其作用的药理学方法 在体外或在体上对周围细胞的活性。我们认为，在这一领域取得进展需要一个示范系统 其中：1)活体动物的感觉输入可以用来激活星形胶质细胞信号，2)行为 读数可用于确定星形细胞信号在体内的功能结果。为此，我们 建议使用小鼠中央视觉通路来研究星形细胞信号级联在 突触传递和可塑性以及视觉。在具体目标1中，我们将使用具有良好特征的切片 以研究星形胶质细胞信号的调节通路和机制。在……里面 特定目标2我们将使用活体成像来确定星形胶质细胞钙反应是否受空间限制 在局部控制血管张力方面也很重要。在特定的目标3中，我们将使用活体成像和遗传学- 改良小鼠以研究星形胶质细胞在视觉可塑性中的作用。最后，在具体目标4中，我们将产生- 用基因工程小鼠研究星形胶质细胞在视觉中的作用，这是一种感觉输入到视觉的行为读数 视觉皮质。总体而言，这些研究的结果应该澄清感官输入导致 星形胶质细胞信号的激活和星形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.