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

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.