Role of neuromodulators and activity in the regulation of ionic currents and neur

描述（由申请人提供）：众所周知，神经网络活动是由外部神经调节、突触相互作用和网络中每个神经元的内在特性决定的。而内在特性主要是由每个细胞所表达的离子电流决定的。这些过程中的每一个过程的变化和调节导致网络输出的不同曲目。尽管离子电流水平变化很大，神经元和神经网络仍能产生稳定的电活动。然而，如果允许可变性不受控制，这种稳定性可能会受到损害。如果多个离子电流的电导变化相互依赖并得到协调调节，可以降低神经元内整体离子电流的可变性，提高输出稳定性。离子电流水平的调节原则上可以由两类机制控制：1)感知活性偏离给定设定点或范围的机制，触发导致活性恢复的补偿性变化；2)以活性独立的方式稳定活性的机制。甲壳类动物口胃神经节的幽门和胃磨坊网络已被用作模型系统来研究神经调节、突触特性和内在神经元特性在节律性活动产生中的作用。这些网络产生有节奏的活动模式，驱动消化行为。其他产生节律模式的网络驱动对生存至关重要的行为（例如呼吸，运动）或被认为是认知功能（注意力，记忆等）的关键。由于它们的基本性质，可以认为这些节律需要稳定，能够从破坏性扰动中恢复，以最大限度地提高生存能力。幽门网络具有这种强大的行为，将用于研究稳定网络输出的生物物理机制。该建议的指导假设是，神经元和网络活动在两个不同的时间尺度上由两种不同的机制调节：1)通过缓慢作用的神经调节效应控制多种离子电流的水平和相关表达，而这些离子电流并没有被它们剧烈调节；2)通过快速作用的活动依赖机制调节离子电流水平。我建议研究这两个调节过程的作用机制，表征它们在单个神经元中的作用，并研究它们在节律性活动产生和稳定性中的作用。我们将特别关注新的、缓慢的、神经调节剂介导的过程。我们将使用电生理、分子和计算方法。产生稳定的神经元输出并在疾病或创伤后恢复这种输出的能力对于确保行为稳定并最终存活至关重要。这种稳定和功能恢复的机制尚不清楚，对它们的理解可能具有巨大的治疗相关性。神经系统节律的产生对动物的生存至关重要，因为它们涉及生命功能（心跳、呼吸、运动、消化等）的产生，也被认为对许多认知功能（记忆、感知、意识、睡眠/觉醒周期等）的产生至关重要。生物节律受到神经活性物质（如神经调节剂、激素和神经递质）以及自身活动状态的严重调节。在本提案中，我们将研究神经调节剂和神经元网络自身活动在一个简单系统中调节节律模式生成的机制。这些知识对于理解神经系统的正常功能及其对扰动的反应，以及设计对病理状态（如创伤、记忆和睡眠障碍）的有效治疗至关重要。

DESCRIPTION (provided by applicant): It is well known that neuronal network activity is shaped by extrinsic neuromodulation, synaptic interactions and by the intrinsic properties of each neuron within the network. Intrinsic properties in turn are determined chiefly by the ionic currents expressed by each cell. The changes and regulation of each one of these processes results in a diverse repertoire of network outputs. Neurons and networks have been shown to generate stable electric activity despite wide variability in ionic current levels. Such stability could, however, be compromised if variability is allowed to go unchecked. The global ionic current variability in a neuron could be reduced, and output stability enhanced, if the conductance variance of multiple ionic currents depended on each other and were coordinately regulated. Regulation of ionic current levels can in principle be controlled by two classes of mechanisms: 1) mechanisms that sense a departure of activity from a given set point or range that trigger compensatory changes leading to activity restoration, 2) mechanisms that stabilize activity in an activity-independent manner. The crustacean pyloric and gastric mill networks of the stomatogastric ganglion have been used as model systems to study the role of neuromodulation, synaptic properties and intrinsic neuronal properties on the generation of rhythmic activity. These networks generate rhythmic activity patterns that drive digestive behaviors. Other rhythmic pattern generating networks drive behaviors that are also essential for survival (e.g. respiration, locomotion) or are thought to be key in cognitive functions (attention, memory, etc). Because of their basic nature, it could be argued that these rhythms need to be stable and able to recover from disruptive perturbations to maximize survival. The pyloric network has this kind of robust behavior and will be used to examine biophysical mechanisms that stabilize network output. The guiding hypothesis of this proposal is that neuronal and network activities are regulated by two distinct mechanisms at two different time scales: 1) via slow-acting neuromodulatory effects that control the levels and the correlated expression of multiple ionic currents that are not acutely modulated by them, 2) via fast-acting activity-dependent mechanisms that regulate ionic currents levels. I propose to examine the mechanisms of action of these two regulatory processes, characterize their effects in individual neurons, and examine their role on rhythmic activity generation and stability. We will focus especially on the novel, slow, neuromodulator-mediated process. We will use electrophysiological, molecular and computational methods. The capacity to generate stable neuronal output and to recover such output following disease or trauma is crucial to ensure behavioral stability and, ultimately, survival. The mechanisms underlying such stabilization and recovery of function are not well known, and their understanding may be of enormous therapeutical relevance. PUBLIC HEALTH RELEVANCE The generation of rhythms in the nervous system is crucial to the survival of animals since they are involved in the production of vital functions (heart beat, respiration, locomotion, digestion, etc.) and is also thought to be essential for the generation of many cognitive functions (memory, perception, awareness, sleep/wake cycles, etc). Biological rhythms are heavily regulated by neuroactive substances such as neuromodulators, hormones and neurotransmitters, as well as by their own state of activity. In this proposal we will examine the mechanisms by which neuromodulators and the neuronal networks own activity regulate rhythmic pattern generation in a simple system. This knowledge is essential to understand the normal function of the nervous system, its response to perturbations, and to design effective treatments of pathological states, such as trauma, memory and sleep disorders.