Proper urinary function requires that the brain process sensory information from the bladder and respond by initiating signals that coordinate bladder activity with appropriate cognitive and behavioral responses so that micturition occurs in an appropriate and safe environment and remains separate from other behaviors. Disordered central processing of bladder information can result in voiding dysfunctions as well as sensations of urgency and pain as is seen with interstitial cystitis. Despite the importance of understanding how the brain processes bladder information to achieve these functions, research in this area has been limited. The overall goal of this research is to elucidate how the brain processes bladder information and coordinates the visceral and cognitive/behavioral aspects of micturition. This will be done using state-of-the- art neuronal recording techniques that can directly quantify activity of neurons in a pontine micturition circuit along with cortical electroencephalographic (EEG) activity and determine how neuronal activity corresponds with urodynamic measures using in vivo cystometry in unanesthetized rats. Multichannel electrodes will record single unit activity from neurons in Barrington's nucleus (the pontine micturition center) and/or the locus coeruleus (LC), a brain region that is thought to initiate arousal in response to bladder pressure increases via its cortical projections. Cortical EEG will be simultaneously recorded with activity from these neurons during cystometric measures of urodynamic endpoints such as bladder pressure and micturition.
Aim 1 will determine how Barrington's nucleus neuronal activity, LC neuronal activity and cortical EEG co-vary with bladder pressure and micturition under normal conditions.
Aim 2 will examine this in 3 models of urinary dysfunction a) partial bladder outlet obstruction, b) social stress-induced voiding dysfunction and c) a neurogenic model of interstitial cystitis.
Aim 3 will test the hypothesis that corticotropin-releasing factor (CRF) and/or glutamate neurotransmission in the LC are integral for relaying bladder information to the cortex in normal and/or pathological conditions. Although it is well recognized that the brain regulates visceral and behavioral components of the micturition reflex and can play an integral role in diseases of urinary function, this will be the irst study to elucidate the precise relationship between brain neuronal activity and bladder activity in unanesthetized rats in normal and disease states. As such, this research will lead to new perspectives on the etiology of urinary disorders and guide novel therapeutic directions.

Public Health Relevance

This research will reveal how the brain neurons process information from the bladder to coordinate bladder activity and behavior. The research has important implications for understanding urinary disorders that are characterized by disordered processing of bladder sensory information such as nocturnal enuresis, overactive bladder and interstitial cystitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Hoshizaki, Deborah K
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Children's Hospital of Philadelphia
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Valentino, Rita J; Guyenet, Patrice; Hou, Xun Helen et al. (2017) Central Network Dynamics Regulating Visceral and Humoral Functions. J Neurosci 37:10848-10854
Manohar, Anitha; Curtis, Andre L; Zderic, Stephen A et al. (2017) Brainstem network dynamics underlying the encoding of bladder information. Elife 6: