Unraveling a parabrachial circuit for the state-dependent control of rapid breathing - PROJECT SUMMARY Breathing, unlike most motor behaviors, is under automatic control to ensure homeostasis is maintained. This vital physiological regulation of respiratory activity has been the predominant focus of the control of breathing field. However, in awake animals, breathing is also conditionally modified by changes in behavior and emotion, making it highly dynamic. How these state-dependent control mechanisms allow breathing to conditionally dissociate from its underlying physiological regulation remains far less well understood. In mice, this distinction between automatic and state-dependent respiratory control is exemplified by the rapid breathing frequencies that are unique to the awake state. Thus, transgenic mouse lines that allow cell-type-specific manipulations are an excellent model system to unravel the neural circuits and mechanisms that integrate breathing with behavior and emotion. The parabrachial nucleus of the dorsal pons is an integrative hub for many affective states and behaviors, including breathing, and its constituent neurons are similarly diverse in their gene expression and axonal projections. This project characterizes a novel neural circuit in the lateral parabrachial nucleus (PBL) that exerts potent respiratory control specifically in the awake state and can drive rapid breathing frequencies not achievable by known mechanisms of respiratory rhythm generation. By combining modern intersectional transgenic, viral vector, and optogenetic tools, the proposed experiments explore how and when this PBL circuit controls rapid breathing (Aim 1); identify the brain regions downstream of these neurons that mediate their potent respiratory effects and state-dependence (Aim 2); and test whether the canonical medullary site for respiratory rhythm generation, the preBӧtzinger Complex, is also critical for generating the rapid and dynamic breathing patterns that characterize the awake state (Aim 3). These three interactive Aims will provide a comprehensive understanding of the network- and cellular-level mechanisms that mediate the unprecedented state-dependent respiratory control by this PBL circuit. More generally, this project will establish a framework for understanding the conditional control of breathing and significantly expand our basic scientific understanding of how breathing is integrated with behavior and emotion. Insights from these studies may also have significant implications for understanding pathologies associated with dysregulated rapid breathing such as hyperventilation syndrome and panic disorders.
