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 成体星形胶质细胞，分布在大脑的几个区域。这让我们假设，除了它的 NFIA在星形胶质细胞发育中起关键作用，也可能有助于星形胶质细胞在 成年人。这一假说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”，即 调控成年星形胶质细胞功能的转录机制尚不清楚。 NFIA是否有助于成熟星形胶质细胞的功能，我们创造了新的转基因小鼠 在成年星形胶质细胞中专门消除它的线条。对这些小鼠的初步研究 显示缺乏NFIA的星形胶质细胞在形态上表现出区域特异性的变化，即 再加上钙离子活性受损。星形胶质细胞功能的这些变化直接影响 神经元生理学，由于突触活动受损和长时程增强的诱导 (LTP)被抑制。因此，LTP的这种抑制与学习和学习障碍相对应 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的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，基于这些初步数据的力量，我们提出如下建议 明确的目标。在特定的目标1中，我们将确定NFIA的缺失如何影响星形胶质细胞 在一系列时间点上，不同大脑区域的形态和功能， 删除NFIA后。功能研究将包括评估星形胶质细胞膜 使用遗传编码的GCaMP报告的电导和钙反应。具体而言 目标2，我们将重点放在海马体上，并确定星形胶质细胞中NFIA的丢失 影响神经生理学、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。在特定的目标3中，我们已经确定了一组候选的NFIA靶基因，我们将 在功能上验证，并在这个目标的第二部分将确定NFIA目标基因网络在 星形胶质细胞，跨越不同的大脑区域，以解码NFIA丢失的区域特异性脆弱性 成人的大脑。

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.