UC San Diego

Scent marking behavior in male mice can simultaneously address two important gaps in neuroscience: (1) the need for a simple and ethologically relevant output to make sense of the neural activity driving it, and (2) the need for better models of voluntary urination to take us beyond a coarse understanding of prevalent medical issues. Uncontrolled urination, or incontinence, is a common problem that stems from disruption at the two main muscles responsible, the bladder wall and external urethral sphincter (EUS). Lesion studies have shown that these muscles switch from urine storage to release via control from a small region in the brainstem known as Barrington’s nucleus (Bar). Although we know some cellular details of bladder control, specific neurons that relax the EUS and ultimately enable urine flow are unknown, partly because this is a voluntary, striated muscle, and adequate animal models of voluntary urination do not exist. Here we establish a scent marking assay in which male mice rapidly urinate when presented with female odor. This allows measurement and manipulation of neural activity in Bar while quantifying voluntary urination, and led us to identify a small subset of novel Bar neurons that control the EUS. These excitatory neurons express estrogen receptor 1 (BarESR1), project to sphincter-relaxing interneurons in the spinal cord, and have increased activity during natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of voluntary urination and its dysfunction, as well as a tractable anchor from which to study upstream control. Because scent marking behavior is regulated by age, sex, competing interests, and learning, this paradigm provides a powerful avenue for future studies examining more general mechanisms of behavioral control in mammals.