Imaging neuromodulation in the brain

描述（由申请人提供）：唤醒涉及神经活动增强和对环境刺激的阈值敏感性降低的状态。 物质滥用（SA）通常涉及无法控制的自我药物管理，改变唤醒水平. 流行病学和遗传学数据表明SA、睡眠障碍和觉醒/注意力障碍（如ADHD）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。 一个基本的问题是唤醒是否是一个统一的、广义的状态，或者是否存在不同形式的唤醒，控制不同的行为。 与后一种观点相一致的是，唤醒涉及多种神经调节系统，包括生物胺（BA）、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唤醒（睡眠-觉醒与压力诱导）。 这些数据表明，在不同的行为环境中，不同的神经调质作用于影响觉醒的特定神经基质的知识，对于理解觉醒相关疾病（包括成瘾）的电路是必不可少的。 在这个建议中，我们将解决以下问题，使用果蝇作为一个模型系统：1）DA影响其他形式的觉醒，如果是通过什么电路？ 2)还有哪些神经调质影响唤醒，它们控制什么形式的唤醒，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的神经调质受体在体内的激活。 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质调节的神经回路。 如果成功的话，这种方法应该广泛适用于各种遗传可访问的模式生物，并可以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。 公共卫生相关性：多巴胺等神经调节剂在药物滥用、多动症和睡眠障碍中起着关键作用。 所有这些疾病都与唤醒障碍有关。 是否存在不同形式的唤醒，每种唤醒都与不同的行为和行为障碍有关，以及不同的神经调节剂在控制各种形式的唤醒中的作用，目前还知之甚少。 该提案旨在开发新的方法来系统地映射不同神经调质在不同唤醒环境中的作用。

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. PUBLIC HEALTH RELEVANCE: Neuromodulators such as dopamine play a key role in substance abuse, ADHD and sleep disorders. All of these disorders are linked to disturbances in arousal. Whether there are different forms of arousal, each linked to different behaviors and behavioral disorders, and the role of different neuromodulators in controlling various forms of arousal, is poorly understood. This proposal aims to develop new methodology to systematically map the roles of different neuromodulators in different settings of arousal.