GABAA δ receptors in vagal motor neurons play a role in the influence of high fat diet on cardiac function
Authors: Strain Misty M. , Espinoza Liliana , Fedorchak Stephanie , Boychuk Carie R. 
Published: May 2022

Central vagal circuitry plays a key role in cardioinhibition and is critical to cardiac homeostasis. Long‐term high fat diet (HFD) is associated with decreased vagal drive, which is linked to increased cardiovascular morbidity and mortality. However, recent evidence suggests that HFD elicits changes in central circuits during early consumption (days). This study tested the hypothesis that decreased central vagal regulation contributes to poor cardiac regulation during the first two weeks of HFD. C57/Bl6 mice were examined for changes in autonomic regulation of HR both at rest and during reflex challenges using chronically implanted telemetry devices. Metabolic parameters were examined throughout all experiments. HFD fed mice exhibited a resting tachycardia throughout the two weeks of HFD (669 ± 20 bpm) compared to NFD (606 ± 20 bpm; p=0.03). Using pharmacological manipulations at Day 15, animals given HFD showed lower resting HR responses to intraperitoneal injection of the parasympathetic antagonist, methyl‐scopolamine, (68 ± 8 bpm) compared to NFD (104 ± 15 bpm; p=0.03). To determine if HFD also influenced homeostatic regulation of HR, animals were tested for capsaicin‐ and phenylbiguanide (PBG)‐mediated cardiopulmonary reflexes. In these animals, HFD blunted capsaicin‐mediated cardiopulmonary reflex at day 15 of HFD (‐19 ± 7 bpm), compared to NFD (‐45 ± 3 bpm; p=0.01). The HFD‐induced blunting of capsaicin‐mediated bradycardia continued throughout testing (60 days; ‐22 ± 5 bpm in HFD). No changes were seen in PBG‐mediated bradycardias (p=0.86). Previous work from our lab indicates that vagal motor neurons after metabolic challenges express large GABAergic currents mediated by GABAA receptors expressing the δ‐subunit, GABAA(δ)R. Since GABAergic neurotransmission is critical to both resting HR and reflex responses, we generated a novel bi‐transgenic mouse line using a floxed GABAA(δ)R and ChATcre mouse line (ChAT‐ δnull) to knock out the expression of δ‐subunit in vagal motor neurons. Examination of resting HR after HFD and NFD in ChAT‐ δnull showed no differences between diets (p=0.68). Pharmacological manipulations of HR in ChAT‐δnull mice with methyl‐scopolamine also showed no differences in HR responses between the diets (p=0.34). In addition, ChAT‐ δnull mice on HFD (61 ± 9 bpm) no longer showed a significant blunting of capsaicin‐mediated bradycardia compared to NFD (39 ± 5 bpm; p=0.10). Together, this study showed that HFD induces lasting changes in central circuitry within 15 days after consumption. In addition, this study found that parasympathetic dysfunction contributes to early HFD‐induced changes in HR and autonomic reflexes. This is important, as most pharmaceutical treatments currently available to patients target the sympathetic hyperactivity, and not parasympathetic hypoactivity. Finally, increased GABAA(δ)Rs likely mediate decreased vagal output after HFD. Therefore, more research is needed to determine mechanistic underpinning(s) of increased GABAA(δ)R activity and parasympathetic dysfunction to lead to better treatment options for cardiovascular disease associated with high fat diet consumption.