Breathing behavior in humans, and all mammals, emanates from rhythmic activity in brainstem respiratory neurons. The key population of rhythm-generating neurons is contained in the preBotzinger complex (preBotC) of the ventral medulla. Neurons in the preBotC form excitatory networks and synchronously discharge bursts during the inspiratory phase of network activity. The intrinsic properties of preBotC neurons are hypothesized to function synergistically with glutamatergic synapses during inspiratory burst generation. This project aims to discover these integrated functions at the cellular and synaptic level, by studying preBotC neurons actively engaged in rhythm generation in brainstem slices from neonatal mice that retain the ability to generate inspiratory motor output in vitro. Critical questions regard the burst-generating role of the Ca2+-activated nonspecific cationic current (ICAN), which is putatively expressed in preBotC neuron dendrites and is activated by glutamatergic synaptic inputs. This project will examine the role of ICAN, discover its molecular identity, and characterize how the glutamate receptors cause Ca2+ influx and activate ICAN. Experimental data will be used to create a realistic mathematical model of preBotC neurons, which will be assembled into a network model that simulates respiratory rhythm generation. The overall framework for analysis is that preBotC neurons have active dendritic properties that are maximally evoked in the context of synaptically coupled network activity, which can explain how very small numbers of preBotC neurons generate neural rhythms that are robust and resilient. The new knowledge obtained will be of general interest in neuroscience and biology because respiratory regulation is a critical brain function that must operate continuously to sustain life and homeostasis in all mammals. This project is a model of interdisciplinary research that addresses an important biological problem at several levels of analysis from the cellular/molecular level to the system/behavior level, and employs powerful tools from mathematical modeling to advance understanding. The research will be integrated with computational biology and neuroscience instruction at The College of William and Mary to promote interdisciplinary education and research training at the graduate and undergraduate level.
