Publications by Year: 2026

The periaqueductal gray (PAG) in the midbrain is recognized as a critical relay in lower urinary tract control, integrating ascending bladder signals with descending cortical and subcortical inputs, to coordinate micturition regulation. Animal studies reveal that coordinated pathways within the columnar organization of the PAG converge on the pontine micturition center (PMC), initiating or suppressing micturition. The ventrolateral column, in particular, exhibits robust glutamatergic projections to the PMC that facilitate bladder contractions, whereas local gamma-aminobutyric acid (GABA) interneurons likely modulate this excitatory drive. Recent neuroimaging studies in humans demonstrate that PAG activation correlates with bladder filling and intensifies at the transition from storage to voiding, mirroring findings in preclinical models. Humans, and other species, exert top-down modulation over PAG circuits via forebrain regions responsible for emotion, cognition, and social context, highlighting a multilayered regulatory architecture. Disruptions in these connections, whether through direct lesions, neurodegeneration, or functional connectivity alterations, may manifest as urgency, incomplete voiding, or other lower urinary tract symptoms (LUTS). Refined neuroanatomical methods, advanced imaging at ultra-high field strengths, and targeted manipulations in animal models are likely to further elucidate how discrete PAG subdivisions facilitate maintaining continence. By establishing more precise links between PAG function and higher brain oversight, novel therapeutic strategies for LUTS may emerge, optimizing both diagnostic and treatment paradigms.

Barrington's nucleus (Bar) is a brainstem hub essential for lower urinary tract (LUT) function, yet the molecular identity and functional specialization of its neuronal subtypes remain poorly defined. Here, we construct a single-nucleus transcriptional atlas of the murine Bar and identify an excitatory Penk-expressing population (Bar-Penk) critical for LUT regulation. Bar-Penk neurons are selectively active during voiding, when the external urethral sphincter (EUS) relaxes, and their optogenetic activation elicits time-locked suppression of EUS activity. Chemogenetic activation of these neurons induces a sex-specific, aberrant pattern of micturition, whereas targeted ablation impairs voluntary marking behavior in response to female cues. We observe multiple regions involved in visceromotor regulation and behavioral state control that project to Bar-Penk neurons, supporting their role as integrators of internal state and environmental context that drive urinary output. These findings provide new insights into the brainstem circuits that shape reflexive and voluntary micturition and highlight how discrete neuronal subtypes contribute to sexually dimorphic regulation of LUT function.

Lower urinary tract symptoms (LUTS) are prevalent among the aging population, and current medications offer limited efficacy. Improved therapies require a better understanding of the mechanisms underlying LUTS. Abnormal extracellular ATP levels and altered purinergic contractility have been reported in patients with LUTS, suggesting dysregulation of the purinergic pathways. CD39/ENTPD1 is a major regulator of purinergic metabolism, and patients with ENTPD1 loss-of-function mutations exhibit bladder hypomotility and incontinence, suggesting critical roles for ENTPD1 in bladder function. We have tested this hypothesis in an overexpression mouse model with human ENTPD1 knock-in (hCD39TG), in a hemizygous Entpd1 mouse model (Entpd1+/-) mimicking LUTS patients with impaired ATP hydrolysis, and in a homozygous Entpd1-deleted mouse model (Entpd1-/-) mimicking the complete ENTPD1 loss-of-function observed in patients. We have demonstrated that ENTPD1 dysregulation leads to profound abnormalities in bladder voiding phenotypes and urodynamics, along with impaired BSM contractility and altered purinergic receptor signaling. Furthermore, we have found that modulation of downstream P2Y12/adenosine A2b receptor signaling partially or fully restores normal bladder function. Finally, we have identified expression of ENTPD1 and associated purinergic proteins in human BSM cells, underscoring the critical role of ENTPD1 in human bladder function and highlighting its translational potential for the treatment of LUTS.