Neural mechanisms for metabolic-ventilatory coupling during thermogenesis

The National Heart, Lung, and Blood Institute awarded the University of Virginia $760,156 for Project Grant R01HL179001 on July 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837).

The award funds investigation of neural mechanisms underlying metabolic-ventilatory coupling during thermogenesis. The research addresses how metabolic rate and ventilation coordinate during cold exposure—a three-to-five-fold increase in both without disrupting blood gas homeostasis—using a validated mouse model of cold-induced ventilatory stimulation. The principal investigator applies genetically targeted optogenetics, single-photon in-vivo imaging of retrotrapezoid nucleus (RTN) activity, and transgenic knock-out models to determine whether increased RTN neuron activity drives the ventilatory response to cold exposure and to elucidate the central mechanisms by which hypothalamic thermogenic neurons, cold-stimulated arousal-related inputs, and counter-regulatory chemical feedback integrate within RTN chemoreceptors to mediate metabolic-ventilatory coupling. This work addresses a gap in understanding respiratory dysfunction in co-morbid metabolic and respiratory diseases including COPD, obesity-hypoventilation syndrome, thyroid disorders, and heart failure.

Performance of research occurs in Charlottesville, Virginia, with a period of performance from July 1, 2026, through March 31, 2030. The assistance type is a Project Grant. This is a Project Grant (R01), the standard NIH research grant mechanism for independent investigation.

Abstract

CO-morbid metabolic and respiratory dysfunction is a hallmark of prevalent human diseases such as copd, obesity-hypoventilation syndrome, thyroid disorders, and heart failure. Despite this well-established association, IT remains unclear whether metabolic rate directly contributes to respiratory pathophysiology, in part because the mechanisms underlying metabolic-ventilatory coupling are poorly understood. This GAP in knowledge hinders the development of treatments for respiratory dysfunction associated with metabolic disorders. We address this GAP in knowledge by elucidating the central mechanisms responsible for metabolic- ventilatory coupling during cold exposure, which leads to a three-to-five-fold increase in both metabolic rate and ventilation without disrupting blood gas homeostasis. Crucially, as arterial PCO2 and PO2 are unchanged during cold exposure, this suggests that conventional respiratory chemoreflexes are unlikely to mediate the elevation in central ventilatory drive during cold exposure. How then is this homeostatic ventilatory response coordinated? Our central proposal is that metabolic-ventilatory coupling is a homeostatic mechanism mediated by central respiratory chemoreceptors in retrotrapezoid nucleus (RTN) involving the integration of inputs from hypothalamic thermogenic neurons, cold-stimulated arousal-related inputs, and counter-regulatory chemical feedback. We address this issue using a validated model of cold-induced ventilatory stimulation in mice in which we apply genetically targeted optogenetics, single-photon in-vivo imaging on RTN activity, and transgenic knock-out models, supported by complementary neuroanatomical approaches. In aim 1, we extend these preliminary results showing that an increase in RTN neuron activity drives the ventilatory response to cold exposure using optogenetics and in-vivo imaging calcium imaging with fiber photometry to establish the functional requirement of RTN neurons in the ventilatory response to graded cooling. Aim 2 of this project is to identify the physiological mechanisms that mediate the increase in ventilation during cold exposure, focusing on: [a] inputs to RTN neurons from thermogenic neurons in the hypothalamus; [b] behavioral thermoregulation and arousal; and [c] chemical feedback mediated RTN proton-sensing. These experiments will define the neural circuitry and molecular mechanisms involved in ventilatory- metabolic coupling during cold exposure and will reveal connections between the hypothalamus and brainstem that contribute to central ventilatory drive. Considering the overlapping hypothalamic circuitry involved in the autonomic effects of energy homeostasis, psychological stress, the febrile response, and exercise, the mechanisms we identify here may be relevant in several physiological and pathophysiological conditions. As such, this fundamental research lays a foundation for understanding metabolic-ventilatory coupling across physiological and pathophysiological conditions.