Transcriptional Control of Gliogenesis in the CNS

我们对成人大脑星形胶质细胞多样性的研究表明，NFIA在成人大脑中高度表达。 成年星形胶质细胞，跨越几个大脑区域。这使我们假设，除了它的 在星形胶质细胞发育中起关键作用，NFIA也可能有助于星形胶质细胞功能， 成年人了这一假设解决了我们对星形胶质细胞生物学知识中的一个关键“空白区域”， 调节成体星形胶质细胞功能的转录机制尚不清楚。 无论NFIA是否有助于成熟的星形胶质细胞功能，我们产生了新的转基因小鼠， 在成年星形胶质细胞中特异性消除它。对这些小鼠的初步研究 显示缺乏NFIA的星形胶质细胞表现出区域特异性的形态学变化， 再加上受损的Ca 2+活性。星形胶质细胞功能的这些变化直接影响 神经元生理学，因为突触活动受损和长时程增强的诱导 (LTP)被抑制了。因此，LTP的这种抑制对应于学习缺陷， 记忆行为总之，这些观察揭示了一种新的转录机制， 调节成年星形胶质细胞功能和相关的神经元回路，同时也定义了一种新的 NFIA在大脑中的作用。 因此，根据这些初步数据的强度，我们提出以下建议 明确的目标。在具体目标1中，我们将确定NFIA的缺失如何影响星形胶质细胞 在一系列的时间点上， 删除NFIA后。功能研究将包括评估星形胶质细胞膜 电导和钙响应使用遗传编码的GCaMP报告。在特定 目的2，我们将重点放在海马，并确定如何损失NFIA在星形胶质细胞 影响神经元生理、电路功能和相关行为。这些研究将 利用基础生理学研究评估基础和诱发/可塑性反应， 神经元在具体目标3中，我们已经鉴定了一组候选NFIA靶基因， 功能验证，并在第二部分，这一目标将确定NFIA靶基因网络， 星形胶质细胞，在不同的大脑区域解码区域特定的脆弱性，以NFIA损失， 成人大脑

Our studies on astrocyte diversity in the adult brain, revealed that NFIA is highly expressed in adult astrocytes, across several brain regions. This led us to hypothesize that, in addition to its pivotal role in astrocyte development, NFIA may also contribute to astrocyte function in the adult. This hypothesis addresses a key “gap area” in our knowledge of astrocyte biology as the transcriptional mechanisms that regulate adult astrocyte function are unknown.To ascertain whether NFIA contributes to mature astrocyte function, we generated new transgenic mouse lines that specifically eliminates it in adult astrocytes. Preliminary studies with these mice revealed that astrocytes lacking NFIA exhibit region-specific changes in morphology, that are coupled with impaired Ca2+ activity. These changes in astrocyte function directly impact neuronal physiology, as synaptic activity is impaired and the induction of long term potentiation (LTP) is inhibited. Accordingly, this inhibition of LTP corresponds with deficits in learning and memory behaviors. Together, these observations reveal a novel transcriptional mechanism regulating adult astrocyte function and associated neuronal circuits, while also defining a new role for NFIA in the brain. Therefore, based on the strength of these preliminary data, we propose the following specific aims. In specific aim 1, we will determine how loss of NFIA influences astrocyte morphology and function across a diverse range of brain regions, over a series of timepoints, post-deletion of NFIA. Functional studies will include assessing astrocyte membrane conductance and calcium responses using genetically encoded GCaMP reporters. In specific aim 2, we will focus on the hippocampus and determine how loss of NFIA in astrocytes influences neuronal physiology, circuit function, and associated behaviors. These studies will make use of basic physiological studies to assess basal and evoked/plasticity responses in neurons. In specific aim 3, we have identified a set of candidate NFIA target genes that we will functionally validate and in the second part of this aim will identify NFIA target gene networks in astrocytes, across diverse brain regions to decode region specific vulnerabilities to NFIA loss in the adult brain.