Behavioral State Gating of Neuroplasticity: The Role of State-Specific Neuromodulators in Firing Rate Homeostasis

项目摘要 很明显，睡眠和清醒状态对大脑皮层的可塑性有着深远的影响， 它们是许多形式的功能性学习和记忆所必需的;它们也代表了不同的大脑状态， 其中感觉驱动、神经调节和活动模式是截然不同的。鉴于 神经调质是许多形式的可塑性和皮层活动模式的强调节剂，这表明 通过特定的神经调质，睡眠或清醒可以选择不同的可塑性机制。这个州- 具体选择塑性机制具有显著的潜在益处;例如， Hebbian（正反馈介导）和稳态（负反馈介导）可塑性机制 有效地协同工作，以保持复杂的大脑回路的可塑性和稳定性，并避免僵硬或癫痫 states.事实上，这两种类型的可塑性有一些相同的分子效应器，这意味着它们可以 如果没有适当的隔离，就会相互干扰。事实上，许多研究已经观察到睡眠 和唤醒状态在不同形式的可塑性的功效，但结果缺乏任何解释， 可能正在发生特定于状态的可塑性选择。我们的实验室已经开发出一种强大的方法来研究这一点 通过持续收集行为数据和跟踪视觉皮层的单个单元， (V1)自由行为的大鼠在良好的单眼剥夺（MD）范式。MD导致A 前两天（MD 1 -2）通过Hebbian LTD样机制强烈抑制V1放电， 诱导稳态机制，使放电率在接下来的两天内恢复到基线水平（MD 3 -4） 尽管继续MD。使用这种范例，我们已经表明，这种反弹，称为射击率， 内稳态（FRH）仅发生在主动觉醒期间（AW; Hengen等人，2016）。在这里，我将调查 AW是如何具体实现向上FRH的。AW之间V1的主要差异（当向上FRH为 启用）以及睡眠和安静清醒（QW）状态（当它被抑制时），是胆碱能（ACh）的水平 和去甲肾上腺素能（NE）输入。ACh和NE对AW特异性皮层活动模式有很大贡献，是关键 调节多种形式的学习，并已知引起V1的各种调节作用， 突触功效的广泛变化。此外，我的初步数据证实，抑制乙酰胆碱神经元， 基底前脑（BF）是ACh向新皮层的主要来源，在AW时产生V1 LFP活性 更像是慢波睡眠因此，我将检验V1中向上的FRH由AW门控的假设- 特定的神经调节输入。我将测试BF ACh和LC NE神经元在使向上FRH中的作用 在AW期间，使用慢性全局操作（DREADD）和急性局部操作（光遗传学 方法）。不管结果如何，这些实验将提供重要的洞察力，了解行为如何 状态可以选择性地协调体内不同的可塑性机制，并为未来的假设提供信息， 分子目标和可塑性的状态特异性控制的作用机制。

Project Summary It is clear that sleep and wake states have a profound influence on cortical plasticity and they are necessary for many forms of functional learning and memory; they also represent distinct brain states, during which sensory drive, neuromodulation, and activity patterns are dramatically different. Given that neuromodulators are strong regulators of many forms of plasticity and cortical activity patterns, this suggests that sleep or wake, via specific neuromodulators, may select for distinct plasticity mechanisms. This state- specific selection of plasticity mechanisms has significant potential benefits; for example, it is critical that Hebbian (positive feedback-mediated) and homeostatic (negative feedback-mediated) plasticity mechanisms work together efficiently to keep complex brain circuits plastic and stable, and to avoid cataleptic or epileptic states. The fact that the two types of plasticity have some of the same molecular effectors implies they could interfere with each other if not appropriately segregated. Indeed, many studies have observed roles for sleep and wake states in the efficacy of different forms of plasticity, but the results lack any explanation for how state-specific plasticity selection may be occurring. Our lab has developed a robust way to study this fundamental question by continuously collecting behavioral data and tracking single units from the visual cortex (V1) of freely behaving rats during the well-established monocular deprivation (MD) paradigm. MD causes a strong suppression of V1 firing via Hebbian LTD-like mechanisms over the first two days (MD1-2), which induce homeostatic mechanisms that bring firing rates back to baseline levels over the next two days (MD3-4) despite continued MD. Using this paradigm, we have already shown that this rebound, termed firing rate homeostasis (FRH), occurs exclusively during active wake (AW; Hengen et al., 2016). Here, I will investigate how AW specifically enables upward FRH. The major differences in V1 between AW (when upward FRH is enabled) and both sleep and quiet wake (QW) states (when it is suppressed), are levels of cholinergic (ACh) and noradrenergic (NE) input. ACh and NE contribute strongly to AW specific cortical activity patterns, are key regulators of multiple forms of learning, and are known to cause a variety of modulatory effects in V1, allowing for broad changes in synaptic efficacy. Further, my preliminary data confirms that inhibition of ACh neurons in the basal forebrain (BF), which are the main source of ACh to neocortex, makes V1 LFP activity during AW more like slow-wave-sleep. Therefore, I will test the hypothesis that upward FRH in V1 is gated by AW- specific neuromodulatory inputs. I will test the role of BF ACh and LC NE neurons in enabling upward FRH during AW using both chronic, global manipulations (DREADDs) and acute, local manipulations (optogenetic approaches). Regardless of the outcome, these experiments will provide important insight into how behavioral states can selectively coordinate distinct plasticity mechanisms in vivo and inform future hypotheses regarding molecular targets and mechanisms of action for state-specific control of plasticity.