The periaqueductal gray and its role in the neural control of lower urinary tract function

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.