Neuronal Activation in the Periaqueductal Gray Matter Upon Electrical Stimulation of the Bladder

Abstract

Reflexes, that involve the spinobulbospinal pathway control both storage and voiding of urine. The periaqueductal gray matter (PAG), a pontine structure is part of the micturition pathway. Alteration in this pathway could lead to micturition disorders and urinary incontinence, such as the overactive bladder symptom complex (OABS). Although different therapeutic options exist for the management of OABS, these are either not effective in all patients. Part of the pathology of OABS is faulty sensory signaling about the filling status of the urinary bladder, which results in aberrant efferent signaling leading to overt detrusor contractions and the sensation of urgency and frequent voiding. In order to identify novel targets for therapy (i.e., structures in the central nervous system) and explore novel treatment modalities such as neuromodulation, we aimed at investigating which areas in the central nervous system are functionally activated upon sensory afferent stimulation of the bladder. Hence, we designed a robust protocol with multiple readout parameters including immunohistological and behavioral parameters during electrical stimulation of the rat urinary bladder. Bladder stimulation induced by electrical stimulation, below the voiding threshold, influences neural activity in: (1) the caudal ventrolateral PAG, close to the aqueduct; (2) the pontine micturition center and locus coeruleus; and (3) the superficial layers of the dorsal horn, sacral parasympathetic nucleus and central canal region of the spinal cord. In stimulated animals, a higher voiding frequency was observed but was not accompanied by increase in anxiety level and locomotor deficits. Taken together, this work establishes a critical role for the vlPAG in the processing of sensory information from the urinary bladder and urges future studies to investigate the potential of neuromodulatory approaches for urological diseases.

The Central Autonomic Network and Regulation of Bladder Function

“…Animal studies, using tract tracing, electrical stimulation, lesioning, and neural recording techniques were instrumental in identifying key subcortical regions important for bladder control, including the PMC which represents the major outflow tract to initiate micturition (Loewy et al, 1979; Holstege et al, 1986; Blok and Holstege, 1997), the pontine continence center (Holstege et al, 1986; Griffiths et al, 1990), the PAG, which receives afferent information about bladder filling and may be significant in switching from storage to voiding mode (Noto et al, 1991; Blok et al, 1995; Liu et al, 2004), and the globus pallidus (Lewin and Porter, 1965; Porter et al, 1971), amongst many others. Of particular relevance to the ANS, the role of the locus coeruleus (LC) in bladder control has been demonstrated (Valentino et al, 1996); the LC is activated along with the PMC, by PAG stimulation (Meriaux et al, 2018) and displays neuronal activity that temporally correlates with the initiation of micturition (Manohar et al, 2017). More recently, newer techniques such as optogenetics and fiber photometry have built on earlier studies to deepen insights into the supraspinal pathways involved in bladder control.…”

Parcellation of human periaqueductal gray at 7‐T fMRI in full and empty bladder state: The foundation to study dynamic connectivity changes related to lower urinary tract functioning

“…The PAG is centrally located in the hierarchical system of micturition control, and is assumed to serve as a relay station projecting afferent information from the bladder to cortical and subcortical brain areas and as a gatekeeper projecting efferent information from these higher areas to the pontine micturition center and ON 2‐4 . The PAG is organized in a symmetrical columnar fashion, and the ventrolateral PAG and dorsolateral PAG are indicated to be involved in the control of voiding and storage of urine respectively 5‐8 . Patients with selective lesions of the PAG are known to present with micturitional disturbances 9‐11 .…”

Choosing to urinate. Circuits and mechanisms underlying voluntary urination

“…PET imaging in humans has found that PAG activity correlates with bladder volume [26]. Histology in the rat has identified a subset of excitatory ventrolateral (vl)PAG neurons that are active in response to bladder stimulation [27,28]. These findings have been supported by single unit recordings in the PAG of anesthetized cats revealing two populations of neurons with tonic activity throughout the cycle, one predominating during urine storage and another with greater activity during discharge [29].…”

“…Electrical stimulation of the bladder muscle also evokes neural activity in the locus coeruleus (LC) [28] (Figure 2b), and LC neurons have been shown to be activated during bladder distention [30]. LC activity is relevant because it houses neurons that release norepinephrine to promote alertness and arousal [31] which is often the perceptual brain state that occurs during the human experience of bladder fullness and urgency to void.…”