Vagal control of the brain-esophagus axis ameliorates stress-induced esophageal motility dysfunction in male mice

Mental stress serves as a major contributor to a spectrum of esophageal motility disorders, including distal esophageal spasm (DES), a condition marked by premature contractile activity of the lower esophageal sphincter (LES). These spasms are often exacerbated by psychiatric conditions such as distress, anxiety, and depression. This study investigates the impact of mental stress on LES contractile function in mice. Chronic unpredictable mild stress (CUMS) was observed to reduce food intake, prolong esophageal emptying time, and increase LESP, along with elevated levels of inflammatory factors, IL-1β and TNFα in mice. Retrograde viral tracing identified a neuronal projection from the hypothalamus paraventricular nucleus (PVN) to the LES via the dorsal motor nucleus of the vagus (DMV) and the vagus nerve. Optogenetic activation of the PVN-DMV-vagus pathway increased the frequency and amplitude of LES electromyogram signals in mice, an effect negated by vagotomy or acetylcholine receptor antagonists. Conversely, chemogenetic inhibition of the PVN-DMV-vagus pathway alleviated CUMS-induced LES contraction abnormalities. High-throughput RNA sequencing revealed an upregulation of myosin binding protein C2 (MYBPC2) in the gastroesophageal junction (GEJ) following sustained activation of the PVN-DMV-vagus pathway. Similarly, cultured GEJ cells exposed to acetylcholine exhibited increased MYBPC2 levels. Notably, downregulation of MYBPC2 expression in the GEJ restored normal function in mice with PVN-DMV-vagus-acetylcholine pathway activation. In summary, this study demonstrates that mental stress induces LES contraction disorders through a PVN-DMV-vagus dependent pathway, which drives an increase in MYBPC2 expression in the GEJ.