ASTROCYTE-NEURONAL INTERACTIONS IN THE VISUAL CORTEX

描述(申请人提供)：星形胶质细胞是大脑中的主要细胞类型，与所有其他神经细胞类型密切相关，展示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。这一领域的一个主要限制是缺乏允许研究神经系统中星形胶质细胞在活体动物感觉刺激后的功能的模型。到目前为止，几乎所有关于星形胶质细胞功能的研究都依赖于药理学方法来激活或停用这些细胞中的信号，并在体外或原位记录它们的活动对周围细胞的影响。我们认为，这一领域的进展需要一个模型系统，其中：1)活体动物的感觉输入可以用来激活星形细胞信号，2)行为读数可以用来确定活体星形细胞信号的功能结果。为此，我们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中的作用。在特定的目标1中，我们将使用特征良好的初级视皮层切片来研究星形胶质细胞信号原位调控的途径和机制。在特定的目标2中，我们将使用体内成像来确定星形胶质细胞的钙反应是否在空间上是受限的，并且在局部血管张力控制中是重要的。在特定的目标3中，我们将使用体内成像和转基因小鼠来研究星形胶质细胞在视觉可塑性中的作用。最后，在特定的目标4中，我们将对小鼠进行基因工程，以研究星形胶质细胞在视觉中的作用，视觉是一种感觉输入到视觉皮质的行为读数。总体而言，这些研究的结果应该澄清感觉输入导致星形细胞信号激活的条件，以及星形细胞信号在突触传递和视觉中的作用。 公共卫生相关性：星形胶质细胞是大脑中的主要细胞类型，与所有其他神经细胞类型密切相关，显示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。了解星形胶质细胞在视觉皮质中扮演的角色可能会导致视觉障碍的新治疗方法。

DESCRIPTION (provided by applicant): 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 genetically 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. PUBLIC HEALTH RELEVANCE: 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. Understanding the role that astrocytes play in the visual cortex could lead to new therapeutic treatments of visual disorders.