Brainstem cold-defense circuitry

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ABSTRACT As warm-blooded (endothermic) animals, our survival requires neurons that detect cold temperatures and initiate adaptive responses. These vital “cold-defense” adaptations allow us to inhabit diverse climates. Cold- defense responses are a set of motivated behaviors and autonomic changes that help us avoid the cold while generating and retaining heat. Often, however, these responses are impaired by aging, disease, drugs, or neurologic injury. Many patients suffer from chronic cold intolerance, and accidental hypothermia remains a significant public health concern, but our ability to investigate the underlying mechanisms is constrained by an inability to selectively target central cold-defense neurons. Closing this knowledge gap is the primary objective of this project. Successful completion of the proposed work will provide information that opens opportunities for progress in translational research on cold intolerance, as well as thermogenic treatments for obesity and improved protocols for therapeutic hypothermia. We begin by observing that cold-activated neurons in a specific region of the brainstem known as the parabrachial nucleus (PB) may represent a vulnerable bottleneck in this circuit. Neurons in this region collect input from the entire body surface, relayed via neurons at every level of the spinal cord, and they use this information to activate target sites in the forebrain. Cold-activated PB neurons are an accessible entry point, but they intermingle with other, diverse populations of PB neurons, and their molecular identity remains uncertain. We hypothesized that surviving at a cold ambient temperature requires a specific subset of neurons in this location, which promote cold-defense behaviors and activate autonomic responses. In our preliminary experiments, eliminating glutamatergic PB neurons did not alter body temperature or arousal at room temperature. However, cold exposure caused core body temperature to plummet in these PB-ablated mice, at ambient temperatures that do not cause decompensation in PB-intact control mice. These preliminary findings suggest that PB neurons are not only involved in, but necessary for cold-defense responses. In the proposed studies, we will use a rigorous and systematic approach to determine the identity of PB neurons required for cold defense. We will also determine the behavioral and autonomic changes produced by activating these neurons. Finally, we will determine which PB-activated behavioral and autonomic responses are required to sustain core body temperature during prolonged cold exposure. Successful completion of the proposed expeirments will determine the neurons and neural circuit mechanisms that allow mammals to survive in the cold. In addition to fundamentally advancing our understanding of this life- critical neural circuit, this work will improve our understanding of the genetically defined connections and functions of intermingled neuronal subpopulations in the PB. Our results will have broader impact by opening opportunities to engineer new methods of inducing and sustaining therapeutic hypothermia for critical care, field medicine, organ transplant, and someday, perhaps, spaceflight.