Disinhibition of the medial prefrontal cortex increases cardiorespiratory output and firing rate of neurons in the ventral respiratory column in anesthetized mice

Abstract

During wakefulness, breathing is frequently voluntarily modulated to facilitate various behaviors including vocalization, feeding, and whisking. Breathing also correlates highly with changes in behavioral arousal such as during sleep ( Physiol 36: 203, 2021) , periods of high emotionality ( Neuroimage 134: 305, 2016), or recovery from anesthesia ( Curr Biol 28: 2145, 2018). The medial prefrontal cortex (mPFC) alters voluntary executive function ( Brain Stimul 13: 582, 2020) and arousal ( Trends Neurosci 45: 722, 2022). Additionally, previous studies have shown that the mPFC has the capacity to modulate breathing ( Resp Physiol Neurobiol 303: 103924, 2022). This modulation occurs via top-down influence of cortical and subcortical nuclei and hinges on a balance of excitatory and inhibitory activity within the mPFC ( Int Rev Neurobiol 158: 337, 2021). Furthermore, there are direct and indirect connections from the mPFC to the pontine and ventral respiratory column (VRC) neurons that control breathing ( J Comp Neurol 492: 145, 2005). Taken together, these data suggest a tripartite relationship among the mPFC, behavioral arousal, and breathing, however, the exact neuronal mechanisms underlying the mPFC modulation of breathing are unknown. To address this gap, this study is testing the hypothesis that administration of the GABAA receptor antagonist gabazine into the mPFC of mice increases breathing and heart rate, as well as neuronal activity of the respiratory neurons in the VRC. All procedures were reviewed and approved by the SCRI Institutional Animal Care and Use Committee and adhered to the ARRIVE guidelines. We recorded diaphragmatic activity and heart rate in response to unilateral microinjection (50.6nL) of gabazine (0.13nmol, 47ng) into the mPFC of female and male, urethane (1.5mg/kg) anesthetized mice (n = 5, mean age: 20wks). In 1 of the 5 mice, a Neuropixel high-density electrode was inserted into the VRC along the rostro caudal axis to simultaneously record neuronal activity. Paired, two-tailed t-test revealed gabazine delivered to the mPFC significantly (p<0.05) increased respiratory rate and heart rate. Firing rate of the neurons in the VRC also significantly increased as confirmed by a Wilcoxon Rank-Sum test. These data indicate that blocking inhibitory neurotransmission in the mPFC increases cardiorespiratory output and neuronal activity in the VRC. This result is consistent with data from rats ( J Physiol 591: 6069, 2013) and supports the interpretation that the mPFC participates in the neurobehavioral control of breathing. Ongoing studies are increasing sample size and phenotyping specific populations of mPFC neurons that modulate breathing and heart rate. This work is funded by the National Institutes of Health R01-HL151389, R01-HL126523, R01-HL144801, P01-HL090554 This is the full abstract presented at the American Physiology Summit 2023 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.