Mammals depend on thermosensation to detect changes in core temperature and mount compensatory responses. Many species demonstrate a hyperthermic ventilatory response to dissipate heat and maintain acid-base balance until slower cooling mechanisms (e.g., sweating, vasodilation) are activated. Thus, the respiratory system must function across a wide range of temperatures, leading to the hypothesis that at least some elements of the brainstem respiratory network are intrinsically heat-sensitive. We combined electromyography (EMG), electroneurography (ENG) and whole-cell patch clamp electrophysiology to investigate mechanisms underlying hyperthermic respiratory responses in vivo, at the circuit level, and in individual motoneurons. Experiments were performed in typically developing (control) and nicotine-exposed (DNE) Sprague Dawley rat pups aged 1-10 days. Here, DNE refers to nicotine exposure throughout gestation and postnatal development. First, we recorded breathing-related EMG activity from the genioglossus (GG) and diaphragm muscles, which function to maintain airway patency and inflate the lungs, respectively. After baseline data collection at normal body temperature (36-37°C), measurements were repeated at a core temperature of 39-40°C. Respiratory frequency during eupnea increased with heat in both groups, and this heat-frequency relationship was unaffected by DNE in vivo. At normal body temperature, both groups increased GG and diaphragm EMG amplitude in response to a brief hypoxic hypercapnia challenge. Under thermal stress, this response was enhanced in controls, and blunted in DNE animals (n=24, 6/sex/group). Next, we recorded rhythmic cervical phrenic rootlet activity in the isolated brainstem-cervical spinal cord preparation in vitro. Burst frequency increased with warming in both groups, and this effect was slightly but significantly attenuated in DNE preparations, which also showed more variable burst patterns. Because the brainstem-cervical spinal cord preparation does not include the hypothalamus, these results suggest that rhythm-generating neurons within the medullary respiratory network are intrinsically heat sensitive (n=28, 7/sex/group). Last, whole-cell patch-clamp recordings in hypoglossal motoneurons (XIIMNs) revealed steeper frequency-current relationship curves, and the appearance of excitatory post synaptic potentials, at high temperatures. These responses to heat dramatically increased the excitability of control XIIMNs, but were attenuated in DNE XIIMNs (n=24, 6/sex/group). We propose that similar ionic and synaptic mechanisms confer heat-sensitivity throughout the brainstem respiratory network and modulate the rate and depth of breathing to accommodate fluctuating thermal and metabolic conditions, while simultaneously modulating excitatory drive to upper-airway motor pools to restore or enhance airway patency. We also found that DNE, a prevalent teratogen, reduces neural sensitivity and resilience to heat, creating intrinsic vulnerabilities in affected offspring This work was funded by NIH 5R01DC020889-03; NIH T32HL007249; Arizona Biomedical Research Commission, RFGA 2023-008-29. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Frazure et al. (Fri,) studied this question.