Electrical signaling between nerve cells coordinates essential functions of the body. However, neurons face their own regulatory challenges, as they need to produce relatively constant activity patterns as the environment changes. Like homeostatic control that occurs within other organ systems, neural circuits are subject to homeostatic regulation as well, whereby deviations from a set point level of activity elicit corrective responses to maintain circuit output. To achieve this end, neural systems are thought to sense variables that relate to neuronal activity, such as firing rate, ion concentrations, and neuromodulators, to detect when an imbalance in activity occurs. While recording rhythmic motor activity associated with breathing in the American bullfrog, we made the surprising observation that acute cooling to 10°C silenced network activity, but after several minutes, bursting resumed and then overshot baseline frequency upon rewarming. Burst frequency drifted back to the initial value over tens of minutes, consistent with the fast regulation of an activity set point (n=9). Time controls with no temperature changes were stable throughout this period (n=7). Exposing the network to manipulations inducing similar perturbations that silence activity over the same timescale– hypoxia (n=6), glycine (n=6), and tetrodotoxin (n=4)– did not engage feedback regulation. These results suggested that temperature sensing, rather than activity sensing, controls network output. Cation channels activated by cooling in amphibians (TRPM8, n=4; TRPV3, n=4) and L-type Ca2+ channels (n=4) did not contribute to these responses. Experimental activation of the Na+/K+ pump with monensin, which raises intracellular Na+, reduced the compensation response both in the cold (p=0.01, unpaired t-test) and in the overshoot phase following warming, suggesting that cold-dependent inhibition of the Na+/K+ pump enhances network excitability. Finally, NMDA-glutamate receptors played a role in constraining the amount of compensation, as block of NMDARs with D-APV led to compensation that greatly exceeded those observed in the control experiments (n=5, p<0.0001, unpaired t-test), remaining elevated above baseline upon rewarming in all experiments. The cellular mechanisms by which raising intracellular Na+ with monensin and NMDAR signaling influence compensation responses are ongoing. Overall, these results uncover a temperature-sensitive control system that regulates activity in neural circuits. Our results introduce that some neural systems may replace typical activity sensors with regulatory systems that are instead tuned to environmental cues to defend activity set points. R01NS114514, R15NS112920-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Read full abstract