Phenotypic Shifts in Neurons of the Dorsal Motor Nucleus of the Vagus Resulting from Chronic Cardiac Ischemia

Abstract

AbstractHeart disease remains the number one cause of mortality in the world in spite of significant efforts aimed at treatment. The use of vagal stimulation in the treatment of heart failure has shown mixed successes (Dicarlo et al. 2013; Zannad et al. 2015), suggesting that the treatment has potential, but that the mechanism incompletely understood. Vagal activity confers a robust cardioprotective effect in both humans and animal models, preferentially originating specifically from the dorsal motor nucleus of the vagus (DMV) and deriving a significant benefit from intact gut projections, not just cardiac (Shinlapawittayatorn et al. 2013; Mastitskaya et al. 2012; Basalay et al. 2012). In order to examine the DMV response to heart failure, myocardial infarction was induced in male Sprague Dawley rats. DMV neurons were isolated in small pools of single cells using laser capture microdissection 1 week and 3 weeks after infarction and their gene expression assayed. The results show a transcriptional shift towards a neurosecretory phenotype starting at 1 week and increasing in recruitment of neurons to 3 weeks. The LAD ligation shift appears mediated in part by upregulation of Pax4a, a transcription factor most active during stem cell development of neurosecretory cells during embryonic development. This phenotype is characterized by upregulation of Cacna1d (Cav1.3) and Hcn2 along with increased expression of Cck and Sst. This work suggests that the neurons of the DMV adaptively respond to the dynamics present in the periphery, elucidating the means by which the nature of vagal activity responds to heart failure.Significance StatementThe autonomic nervous system plays a significant role in the pathogenesis of cardiovascular disease. Through demonstration of shifting neuronal phenotypes in central neurons in response to peripheral stimuli, we suggest that neuron peptide or neurotransmitter phenotypes are not static in adult rodents. This suggests that even “reflexes” are modifiable dynamic systems. With such plasticity in the transcriptional programming existing in autonomic brain regions there can be new potential therapeutic interventions for cardiovascular disease aimed at leveraging the autonomic nervous system.