LEVERAGING A NOVEL HYPOTHALAMUS-BRAINSTEM NEUROCIRCUIT FOR URINARY AND FECAL INCONTINENCE

Urinary and fecal incontinence are direct consequence of pathological conditions of the lower urinary tract (LUT), the colon, and their neural innervation, disproportionately affecting the elderly population. Understanding how the brain communicates with and controls LUT and gut function is key to properly addressing this health concern. 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 VMHvl^ERα/MC4R and the major micturition center in the brain, the Barrington’s nucleus (Bar). Stimulatory and inhibitory chemogenetic manipulations unveiled a powerful role for VMHvl^ERα/MC4R neurons in suppressing urine and fecal release while driving physical activity. Chemogenetic activation of the VMHvl^ERα/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 VMHvl^ERα/MC4R stimulation. Finally, we confirmed that changes in urination triggered by VMHvl^ERα/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 place the VMHvl-Bar neurocircuit as a new, potent suppressor of bladder voiding and defecation, with therapeutic potential for alleviating incontinence.