Imaging neuromodulation in the brain

描述（由申请人提供）：觉醒涉及一种神经活动增强和对环境刺激敏感度降低的状态。药物滥用（SA）通常包括无法控制的自我给药，从而改变觉醒水平。流行病学和遗传数据表明，SA、睡眠障碍和觉醒/注意力障碍（如多动症）之间存在联系。因此，对控制觉醒的遗传和神经回路水平机制的理解可能有助于深入了解SA的病理生理学和遗传学。一个基本问题是，唤醒是一种统一的、广义的状态，还是存在不同形式的唤醒，控制着不同的行为。与后一种观点一致的是，唤醒涉及多种神经调节系统，包括生物胺（BAs）、乙酰胆碱（ACh）、激素和神经肽（如食欲素）。此外，我的实验室最近的数据表明，在果蝇中，即使是单一的神经调节剂（多巴胺；DA）也可以通过不同的神经回路，以相反的方向影响不同形式的觉醒（睡眠-觉醒vs压力诱导）。这些数据表明，了解不同神经调节剂在不同行为环境下影响觉醒的特定神经基质，对于理解觉醒相关疾病（包括成瘾）的回路至关重要。在这个提议中，我们将以果蝇作为模型系统来解决以下问题：1)DA是否会影响其他形式的唤醒，如果会，通过什么回路影响？2)哪些其他神经调节剂影响觉醒，它们控制什么形式的觉醒，它们通过哪些回路起作用？为了解决这些问题，我们将开发一种通用的方法来可视化特定神经回路上的内源性配体对神经调节剂受体的激活。我们将使用这种方法来可视化受唤醒影响的不同行为范式中由不同神经调节剂调节的神经回路。如果成功，这种方法应该广泛适用于各种遗传可接近的模式生物，并可能改变神经调节及其在SA，成瘾，注意力和多动障碍以及睡眠障碍中的作用的研究。

DESCRIPTION (provided by applicant): Arousal involves a state of heightened neural activity and lower threshold sensitivity to environmental stimuli. Substance abuse (SA) often involves the uncontrollable self- administration of drugs that alter levels of arousal. Epidemiological and genetic data suggest a linkage between SA, sleep disturbances and arousal/attentional disorders such as ADHD. Thus an understanding of the genetic and neural circuit-level mechanisms that control arousal may lend insight into the pathophysiology and genetics of SA. A fundamental question is whether arousal is a unitary, generalized state, or whether there are different forms of arousal, controlling different behaviors. Consistent with the latter view, multiple neuromodulatory systems have been implicated in arousal, including biogenic amines (BAs), acetylcholine (ACh), hormones and neuropeptides such as orexin. Furthermore, recent data from my laboratory have shown that in Drosophila, even a single neuromodulator (dopamine; DA) can influence different forms of arousal (sleep-wake vs. stress-induced) in opposite directions, by acting through different neural circuits. These data suggest that a knowledge of the specific neural substrates on which different neuromodulators act to influence arousal, in different behavioral settings, will be essential for understanding the circuitry of arousal-related disorders, including addiction. In this proposal, we will address the following questions, using Drosophila as a model system: 1) Does DA influence other forms of arousal, and if so through what circuits? 2) Which other neuromodulators influence arousal, what form(s) of arousal do they control and through which circuits do they act? To address these questions, we will develop a general method to visualize the activation of neuromodulator receptors on specific neural circuits by their endogenous ligands in vivo. We will use this method to visualize the neural circuits that are regulated by different neuromodulators in different behavioral paradigms that are influenced by arousal. If successful, this method should be broadly applicable to a variety of genetically accessible model organisms and could transform studies of neuromodulation and its role in SA, addiction, attentional and hyperactivity disorders, and sleep disturbances.