Mechanisms that regulate microglial dynamics in the context of plasticity

发育过程中视觉经验对皮层网络的重建依赖于突触的快速变化 结构和功能。这些活动驱动的突触变化的精致特异性回避了一个问题 它们是如何实施的。令人惊讶的是，我们最近表明，大脑的免疫细胞小胶质细胞 在这一过程中至关重要。然而，只有极少数有助于可塑性的小胶质细胞机制 都被描述过。这些通路最初被研究在神经炎性反应中的作用，它是 越来越清楚的是，这种机制也用于健康大脑的小胶质功能。去甲肾上腺素 已知通过小胶质肾上腺素能受体的信号在病理环境中影响小胶质细胞的功能。 但小胶质细胞在去甲肾上腺素对可塑性的影响中所起的作用尚未得到研究。肾上腺素能信号是 一个特别耐人寻味的候选者，因为它直接反对我们认为的小胶质细胞中的嘌呤能信号通路 表明小胶质细胞中的肾上腺素能信号对可塑性至关重要，这表明肾上腺素能信号也可能影响突触 改建。此外，肾上腺素能信号调节睡眠和清醒之间的全局状态变化， 我们最近发现，觉醒会改变小胶质细胞的动力学，这对小胶质细胞至关重要-- 突触相互作用。因此，在这个提议中，我们将检验这样一个假设，即去甲肾上腺素通过 小胶质细胞肾上腺素能受体改变小胶质细胞的功能，从而影响可塑性。严谨地 研究去甲肾上腺素如何影响生理性小胶质细胞，我们将首先研究肾上腺素能信号如何 在体内影响小胶质细胞动力学、监测和损伤反应(Aim1)。然后我们将研究如何 小胶质细胞中的肾上腺素能信号影响视皮质的活动依赖性可塑性(目标2)和 小胶质细胞在可塑性过程中的相关功能(目标3)。我们将使用药理学方法来改变 肾上腺素能信号，同时监测小胶质细胞和视觉反应，我们将确定是否影响 利用条件性小胶质细胞特异性敲除β2基因对小胶质细胞中肾上腺素能信号的特异性 肾上腺素能受体(β-2-AR)，在小胶质细胞中高水平表达。这些研究将提供 对小胶质细胞与突触相互作用时使用的分子机制的重要见解 对于理解小胶质细胞如何促进突触可塑性至关重要。因为突触的可塑性受到影响 在大量的神经发育和神经障碍中，其中许多也与 异常的肾上腺素能信号，我们的工作将为干预提供潜在的靶点，恢复适当的 这些疾病的可塑性改变和症状的改善。

Remodeling of cortical networks by visual experience during development relies on rapid changes in synaptic structure and function. The exquisite specificity of these activity-driven synaptic changes begs the question of how they are implemented. Surprisingly we have recently shown that microglia, the brain’s immune cells, are critical in this process. However, only a handful of the microglial mechanisms that contribute to plasticity have been described. These pathways were initially studied for their roles in neuroinflammatory responses and it is becoming clear that such mechanisms are also used in microglial function in the healthy brain. Norepinephrine signaling through microglial adrenergic receptors is known to affect microglial function in pathological settings but microglial contributions to norepinephrine’s effects on plasticity are as yet unstudied. Adrenergic signaling is a particularly intriguing candidate as it directly opposes the purinergic signaling pathway in microglia that we showed to be critical for plasticity, suggesting that adrenergic signaling in microglia could also impact synaptic remodeling. Additionally, adrenergic signaling modulates global state changes between sleep and wakefulness, and we have recently discovered that arousal changes microglial dynamics, which are critical to microglia- synapse interactions. Therefore, in this proposal we will test the hypothesis that norepinpehrine acting through microglial adrenergic receptors alters microglial function thereby affecting plasticity. To rigorously investigate how norepinephrine affects physiological microglia, we will first examine how adrenergic signaling affects microglial dynamics, surveillance and injury response in vivo (Aim1). We will then examine how adrenergic signaling in microglia affects activity-dependent plasticity in the visual cortex (Aim 2) and the associated functions of microglia during plasticity (Aim 3). We will use pharmacological approaches to alter adrenergic signaling while monitoring microglia and visual responses, and we will determine whether effects are specific to adrenergic signaling in microglia using conditional microglia-specific knock-out of the beta 2 adrenergic receptor (β2 AR) which is expressed at high levels within microglia. These studies will provide important insight into the molecular mechanisms used by microglia when interacting with synapses which is critical for understanding how microglia contribute to synaptic plasticity. Because synaptic plasticity is affected in a large number of neurodevelopmental and neurological disorders, many of which are also associated with aberrant adrenergic signaling, our work will provide potential targets for intervention to reinstate appropriate plastic changes and ameliorate symptoms in these diseases.