An estrogen-responsive hypothalamus-brainstem neurocircuit for urinary and fecal incontinence

Understanding how the brain communicates with and controls the lower urinary tract (LUT) and bowel function is key to properly addressing urinary and fecal incontinence, pathological conditions affecting a broad population, particularly during aging. Here, we focused on the anatomical and functional dissection of a novel, estrogen-sensitive hypothalamus-brainstem circuit that overrides the urge to urinate and defecate in young and aged mice. Using anterograde trans-synaptic tracing, we mapped the synaptic afferents from the Esr1/Mc4r-expressing neurons in the ventrolateral ventromedial hypothalamus (VMHvl) into the brainstem, uncovering a direct connection between the VMHvlERα/MC4R and the major micturition center in the brain, the Barrington’s nucleus (Bar). Stimulatory and inhibitory chemogenetic manipulations unveiled a powerful role for VMHvlERα/MC4R neurons in suppressing urine and fecal release while driving physical activity. Chemogenetic activation of the VMHvlERα/MC4R node completely blocked micturition and defecation for at least 2 h, even when mice were preloaded with saline to induce a physiological need to urinate, and delayed colonic transit time by 40-fold. Cystometry studies clearly revealed a strong suppression of bladder contraction and voiding following VMHvlERα/MC4R stimulation. Finally, we confirmed that changes in urination triggered by VMHvlERα/MC4R neurons occur via their connection to Bar by using a new, trans-synaptic multi-vector payload delivery system to specifically manipulate the activity of VMHvl-targeted Bar neurons. Altogether, our data contribute to emerging work on brain-body physiology and place the VMHvl-Bar neurocircuit as a new, potent suppressor of bladder voiding and defecation, with therapeutic potential for alleviating incontinence. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.