Defining Roles for Astrocyte Subpopulations in the Aging Brain

摘要 星形胶质细胞是中枢神经系统中含量最丰富的神经胶质细胞，在急性淋巴细胞白血病中起着至关重要的作用 大脑生理学的各个方面。我们实验室最近的研究确定了五个分子和 大脑中不同功能的星形胶质细胞亚群。其中一个亚群是 由细胞表面标志物CD51特异性标记，被赋予增强的 突触生成功能，使我们假设CD51+星形胶质细胞发挥重要作用 在正常运作的大脑回路中。为了确定CD51+星形胶质细胞如何参与电路功能， 我们创造了一种CD51-FLP小鼠品系，它允许我们有选择地标记和操纵 大脑中星形胶质细胞的数量。破译调控CD51+的机制 星形胶质细胞，我们发现转录因子Sox9在这个亚群中富含。 对一种新产生的小鼠品系的初步研究，该品系特异性地消除了Sox9在 星形胶质细胞发现，这种转录因子选择性地调节星形胶质细胞的形态和 海马体和嗅球中的电路功能与衰老有关。一起， 这些新的小鼠品系将使我们能够揭示CD51+星形胶质细胞是如何调节大脑回路的 并揭示了Sox9在控制星形胶质细胞多样性和衰老过程中的功能方面的新角色。 基于这些初步观察的证据，我们提出如下建议 明确的目标。在具体目标1中，我们将定义解剖、形态和生理 脑老化过程中CD51+和CD51-星形胶质细胞的特性及其作用机制 影响到海马体和嗅球的回路功能。在具体目标2中，我们将使用我们的 星形胶质细胞特异性Sox9基因敲除小鼠破译其如何调节星形胶质细胞功能 以及星形胶质细胞的这些变化如何影响海马区和 嗅球。在特定的目标3中，我们将确定Sox9如何调节星形胶质细胞在 并将我们的发现与Sox9芯片-序列整合，以破译Sox9靶基因网络。

Summary Astrocytes are the most abundant type of glial cell in the CNS and play vital roles in all facets of brain physiology. Recent studies from our lab identified five molecularly and functionally distinct astrocyte subpopulations in the brain. One of these subpopulations is specifically labeled by the cell surface maker CD51 and is endowed with enhanced synaptogenic function, leading us to hypothesize that CD51+ astrocytes play an important role in functioning brain circuits. To determine how CD51+ astrocytes contribute to circuit function, we created a CD51-FLP mouse line that allows us selectively label and manipulate this population of astrocytes in the brain. To decipher the mechanisms that regulate CD51+ astrocytes, we found that the transcription factor Sox9 is enriched in this subpopulation. Preliminary studies in a newly generated mouse line that specifically eliminates Sox9 in astrocytes revealed that this transcription factor selectively regulates astrocyte morphology and circuit function in the hippocampus and olfactory bulb in an aging-dependent manner. Together, these new mouse lines will enable us to uncover how CD51+ astrocytes regulate brain circuits and reveal novel roles for Sox9 in controlling astrocyte diversity and function during aging. Based on the strength of these preliminary observations, we propose the following specific aims. In specific aim 1, we will define the anatomical, morphological and physiological properties of CD51+ and CD51- astrocytes in the aging brain and decipher how they contribute to circuit function in the hippocampus and olfactory bulb. In specific aim 2, we will use our astrocyte-specific Sox9 knockout mouse to decipher how it regulates astrocyte function in the aging brain and how these changes in astrocytes impact circuit function in the hippocampus and olfactory bulb. In specific aim 3 we will determine how Sox9 regulates astrocyte diversity during aging and integrate our findings with Sox9 ChIP-Seq to decipher Sox9 target gene networks.