The origins of respiratory motor neurons (MNs) and the genetic programs that underlie the formation of the respiratory motor circuit remain poorly defined, though recent work from our lab and others suggests that they all emerge from the hypaxial motor column (HMC). It is not yet known how the respiratory MNs are organized in the developing spinal cord molecularly and functionally, particularly in terms of inspiratory and expiratory functions. To begin addressing this question, my research seeks to define first the genetic program associated with HMC/respiratory MN development and their subdivision into inspiratory and expiratory subgroups. This will be accomplished by mapping the expression of a collection of genes that I have found are selectively expressed in HMC MNs, and evaluating the function of one gene, Pou3f1, which is associated with the formation of the inspiratory subgroup. In parallel, I will investigate the logic by which these respiratory MN groups are selectively innervated by descending premotor inputs originating in the brainstem. To understand this logic, I will characterize the anatomical, electrophysiological, and behavioral aspects of this connection when the number or position of HMC MNs has been altered. Through this research plan, I will provide novel insights into the molecular and functional organization of the respiratoy MNs and how this arrangement is the critical layout for the proper assembly of the respiratory motor circuit.
This proposal will examine how the cells of the central nervous system develop and connect to control muscles that are used in breathing. The ways in which the components of the nervous system organize and form a functional circuit to achieve respiratory muscle control have not been understood. The knowledge from the proposed studies can be applied for the development of new therapeutic means to repair injured or diseased respiratory motor circuits.
