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

项目摘要 很明显，睡眠和清醒状态对皮质的可塑性有深远的影响，而且它们是 是许多形式的功能性学习和记忆所必需的；它们也代表着不同的大脑状态，在 哪种感觉驱动、神经调节和活动模式是截然不同的。考虑到 这表明，神经调节剂是多种形式的可塑性和皮质活动模式的强大调节器。 睡眠或醒来，通过特定的神经调节器，可能选择不同的可塑性机制。这种状态- 具体选择塑性机制具有显著的潜在好处；例如，至关重要的是 Hebbian(正反馈调节)和稳态(负反馈调节)塑性机制 有效地合作，保持复杂的大脑回路的可塑性和稳定性，并避免晕厥或癫痫 各州。事实上，这两种类型的可塑性具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，许多研究都观察到了睡眠的作用 和尾迹状态在不同形式的可塑性中的功效，但结果缺乏任何解释 可能会发生特定于状态的塑性选择。我们的实验室已经开发出一种强有力的方法来研究这一点。 通过持续收集行为数据和跟踪来自视觉皮质的单个单位的基本问题 (V1)在公认的单眼剥夺(MD)范式中自由行为的大鼠。多发性硬化导致 在头两天(MD1-2)，通过类似Hebbian LTD的机制强烈抑制V1的激发，这 诱导动态平衡机制，在接下来的两天内使放电率恢复到基线水平(MD3-4) 尽管MD仍在继续。使用这个范例，我们已经证明了这个反弹，称为射击率 动态平衡(FRH)，仅发生在活动觉醒期间(AW；Hengen等人，2016)。在这里，我将调查 AW如何具体实现向上的FRH。AW(当FRH向上时)V1的主要差异 睡眠和安静觉醒(QW)状态(当它被抑制时)都是胆碱能(ACh)水平 去甲肾上腺素(NE)输入。ACh和NE对AW特定的皮质活动模式有很大贡献，是关键 调节多种形式的学习，并已知在V1中引起各种调制效应，允许 对于突触效能的广泛变化。此外，我的初步数据证实，对ACh神经元的抑制 基底前脑(BF)是新皮质ACh的主要来源，在AW时使V1 LFP活动 更像是慢波睡眠。因此，我将检验V1中向上的FRH由AW选通的假设- 特定的神经调节输入。我将测试BF ACh和LC NE神经元在使FRH上升中的作用 在AW期间，既使用慢性全局手法(DREADD)，也使用急性局部手法(光遗传 方法)。不管结果如何，这些实验将提供对行为方式的重要洞察 国家可以选择性地协调体内不同的可塑性机制，并告知未来关于 状态特异性控制可塑性的分子靶标和作用机制。

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.