Excessive dietary intake of fat exacerbates the progression of a broad spectrum of cardiovascular diseases (CVDs) like cardiac arrhythmias. Still, the obesity-independent mechanisms through which HFD contributes to the pathogenesis of cardiac arrhythmias are poorly understood. A wealth of preclinical and clinical data has conclusively linked decreased vagal parasympathetic tone to CVDs. Studies suggest that HFD has the potential to reduce cardiac parasympathetic activity, suggesting HFD-induced reductions in cardiac parasympathetic tone are a promising candidate of research. This proposal will determine obesity-independent effects of HFD on vagal parasympathetic tone and identify their role in cardiac arrhythmogenesis. Cardiac vagal innervation originates from two neuronal populations in the brainstem: the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DMV). Cardiac NA neurons have received significant attention, given their dense projections to the sinoatrial node of the heart. Contrastingly, cardiac DMV neurons are understudied. This represents a significant knowledge gap, considering cardiac DMV neurons are uniquely dysregulated, and their selective activation has been shown to improve cardiac outcome measures in animal models of CVD. Preliminary data confirms that HFD decreases indices of cardiac parasympathetic activity and increases gamma-aminobutyric acid (GABA) inhibitory current in DMV neurons, suggesting decreased cardiac DMV neuron activity is a potential mechanism for HFD-induced cardiac arrhythmias. This proposal will test the overarching hypothesis that HFD increases GABAergic inhibition in cardiac DMV motor neurons, leading to decreased cardiac vagal tone, and ultimately--in the absence of concurrent cardiac sympathetic responses to HFD--tachycardia.In addition to providing the first assessment of the obesity-independent effects of HFD on cardiac parasympathetic neurons, this proposal will determine the role of the delta subunit-containing GABAA receptors in HFD regulation of cardiac vagal tone. We propose that HFD increases GABAergic inhibition in cardiac DMV motoneurons by increasing the expression of delta subunit-containing GABAA receptors. This proposal will assess the therapeutic potential of targeting the expression of delta subunit-containing GABAA receptors by selectively knocking down delta subunit gene expression and determining if HFD-induced increases in GABAergic inhibition and heart rate can be prevented.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|