Estrous cycle modulates inhibition of dorsal vagal motor neurons
Authors: Boychuk Carie Renee , Littlejohn Erica , Espinoza Liliana 
Published: June 2021

Neurons in the dorsal motor nucleus of the vagus (DMV) comprise the preganglionic parasympathetic motor output to much of the viscera and critically contribute to autonomic regulation of energy homeostasis. Gamma‐aminobutyric acid (GABA) is the main inhibitory neurotransmitter mediating both tonic (extrasynaptic) and phasic (synaptic) inhibition to the DMV. A small body of evidence suggests that GABAA receptor activity throughout the brain exhibits sexually dimorphic regulation. Some of the differences between the two sexes may arise through estrous cycle‐dependent hormone changes and occur even in brain regions with no direct role in reproduction. Therefore, it is possible that DMV neurons may express estrous cycle‐dependent modulation of GABAergic inhibition. Since females demonstrate changes in autonomic function and energy homeostasis ‐ both normally and after disease‐ differently from males, modulation of GABAergic inhibition may account for some of these sex differences. This study investigated the effect of sex and estrous cycle on both tonic and phasic modalities of GABAA receptor‐mediated inhibition in the DMV using whole‐cell patch‐clamp recordings in mice. Males and females demonstrated no large differences in GABAA receptor electrophysiology. However, in several parameters, including GABAA receptor tonic current, females had significantly more variance from the mean. Additional experiments were then run to determine if estrous cycle influences these parameters, and therefore could contribute to the increased variability in recorded responses. No differences were determined in the synaptic parameters between DMV neurons from females in estrus or diestrus. This included frequency, amplitude, or decay time. However, DMV neurons from females in diestrus demonstrated significantly more GABAA receptor tonic current than neurons from females in estrus. Interestingly, this was not accompanied by a change in the transcriptional expression of the delta‐subunit of the GABAA receptor that is thought to prominently carry this current. Female mice were then ovariectomized (OVX) and whole‐cell patch‐clamp experiments were again compared to males. OVX‐ed females did not demonstrate a significant difference in GABAA receptor current variance compared to males, suggesting that estrous cycle modulation of DMV neurons in females 1) does occur and 2) contributes to changes in inhibitory responses. Taken together, these experiments confirm that a non‐reproductive brain region, the DMV, can be modulated by differences in sex hormones. Results suggest that plasticity of GABAA receptor‐mediated signaling related to changes in receptor subunit composition accompanies fluctuations in sex hormones across the estrous cycle. These altered GABAA receptor currents in female mice could contribute to male‐female differences in autonomic and metabolic dysfunction in disease.Support or Funding InformationAHA 16SDG26590000This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.