Neuromodulators constrain the activity of neurons and neuronal networks by restricting their parameter space

神经元被组织成网络和电路。当神经元和神经元回路受到创伤、生长或疾病的干扰时，神经元的活动和所谓的神经调节剂的释放就会受到影响。然而，在扰动后的延迟后，由于神经活动的变化和/或神经调节剂的作用所触发的机制，活动通常会恢复。这些机制尚不清楚，特别是神经调节剂的作用和机制。在这个项目中，神经调节剂在决定单个神经元表达的蛋白质星座中所起的作用将被研究，重点是在神经元细胞膜中构成通道并影响神经活动的蛋白质。目的是确定在神经网络受到严重扰动后激活的机制，从而导致神经元正常活动的恢复。为此，我们使用了螃蟹的一个小型神经网络，因为这种网络的神经元成分很少，非常为人所知，并且在实验中相对容易获得。各个层次（从高中到博士生）和不同背景的学生将参与一个协作和高度互动的实验室环境。通过代谢受体作用的神经调节通常被认为是通过调节离子电流、突触和转运体来快速和短暂地改变和扩大神经元和神经元网络的输出库。在这个项目中，假设被检验，在长时间尺度上（≥小时），相反的情况可能发生：神经调节剂将神经元和网络限制在决定其活动的参数空间的限制区域，这种影响可能会阻碍神经元的可塑性和从扰动中恢复的能力。通过减少神经元和神经网络可以占据的参数空间区域，神经调节剂被认为可以塑造系统所需的活动模式，以服务于特定功能，类似于发育过程中发生的事情。然而，这种假设的神经调节剂的雕刻作用也可能限制对侮辱、损伤或其他持续扰动作出适应性反应所需的可能的神经活动模式。了解网络可以用来维持其功能活动或在受到干扰后恢复其功能的各种机制，将扩大我们对网络如何具有弹性的理解。本研究利用蟹的幽门网络这个简单、易接近且特征明确的模型，对神经调节剂在定义神经元元素（神经元、离子电流）中的作用进行了机械理解，这些神经元元素指定了成体的活动模式，并在大时间尺度上控制了它们的功能可塑性。通过使用已经定义良好的系统和计算方法，将采取一种相对简单的途径来理解神经调节剂的作用，然后可以在更复杂的系统中应用和测试。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Neurons are organized into networks and circuits. When neurons and neuronal circuits are perturbed by trauma, growth, or disease, the activity of neurons and the release of so-called neuromodulators is affected. However, after a delay following the perturbation, activity often is restored thanks to mechanisms triggered by changes in neural activity and/or effects of the neuromodulators. These mechanisms are not well understood, especially not the role and mechanisms of the neuromodulators. In this project, the role that neuromodulators play in determining the constellations of proteins expressed by individual neurons will be studied, with an emphasis on proteins that constitute channels in the cell membrane of neurons and that affect neural activity. The objective is to identify the mechanisms activated after severe perturbation of the neural network that lead to the recovery of the neurons’ normal activity. For this purpose, a small neural network from crabs is used because this networks’ neuronal components are few, very well known, and relatively accessible experimentally. Students of all levels (from high school to doctoral student) and diverse backgrounds will participate in a collaborative and highly interactive lab environment. Neuromodulation through metabotropic receptor action is commonly thought to rapidly and transiently modify and expand the output repertoire of neurons and neuronal networks by regulating ionic currents, synapses, and transporters. In this project, the hypothesis is examined that, over long time scales (≥ hours), the opposite may happen: neuromodulators constrain neurons and networks into restricted regions in the parameter space that determines their activity, and this effect may hinder the neurons’ plasticity and ability to recover from perturbations. By reducing the region of parameter space that neurons and networks can inhabit, neuromodulators are thought to sculpt patterns of activity required by the system to serve specific functions, analogous to what happens during development. However, this hypothesized sculpting role of neuromodulators may also limit the possible neural activity patterns needed to respond adaptively to insults, damage, or other persistent perturbations. Understanding the various mechanisms that a network can use to maintain its functional activity, or restore it after it has been perturbed, will broaden our understanding of how networks can be resilient. Here the simple, accessible and well-characterized pyloric network of the crab is used to reach a mechanistic understanding of the role of neuromodulators in defining the neuronal elements (neurons, ionic currents) that specify adult patterns of activity, and control their functional plasticity over large time scales. By using an already well-defined system and computational approaches, a relatively simple path to understanding the role of neuromodulators will be taken, which can then be applied and tested in more complex systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.