Midbrain dopamine systems and control of bladder function

Urinary Urge Incontinence (UUI): ?a sudden compelling desire to pass urine which is difficult to defer? is a widespread clinical problem that especially the elderly in whom an incidence of 12-17% is reported. The latest available figures (from 1997) estimated a cost to the UK health budget of #536 million, yet despite its enormous socioeconomic impact UUI is still not managed effectively. Normally, adult humans are able to inhibit their bladder from emptying, even when it is full, until they find themselves in a safe and socially acceptable place such as a bathroom. With UUI the ability to defer bladder emptying is lost. Current drug treatments target the bladder muscle, with the aim of reducing its excitability. However, the primary cause may lie not in the bladder itself, but in the central control pathways that regulate bladder filling and emptying. At present the precise location of these pathways in the brain and the chemical neurotransmitters employed by the nerve cells to communicate with each other are not fully understood. A clearer understanding of the normal function of the bladder control circuitry is essential before any new treatment for UUI can be developed. The current proposal, which uses a mouse model, has been designed to provide a fuller understanding of these brain circuits in normal animals. The aim is to combine a powerful new method called ?optogenetic? (activation/inactivation of neurons by light), a virus-based neuron connectivity mapping tool with classical physiological measurements to study brain circuitry that controls bladder function. The new data from the study will provide the essential information needed for developing new drugs that act to ?normalise? the activity of the bladder control circuits in those individuals with UUI in whom the control has been lost.

Even when the bladder is full, adult humans and many socialised species of animal are able to defer micturition until they find themselves in a safe and socially acceptable place. With urge urinary incontinence (UUI) this control is lost. Current drug treatments for UUI target the bladder muscle, with the aim of reducing its excitability. However, the primary cause may lie not in the bladder itself, but in the central control pathways that regulate bladder filling and emptying. At present, the precise location of these pathways and the neurotransmitters employed are not fully understood. Clearly a full understanding of the central control of the bladder is essential before any new treatment for UUI can be developed.
Our recent studies on rats suggest that the neuronal ?switch? that controls bladder activity is located in the caudal ventrolateral periaqueductal grey (cvlatPAG) in a region that contains a cluster of dopaminergic neurones. In the proposed study we will investigate the role of these cells in controlling micturition. Using a mouse model we will investigate the effect on bladder function, assessed by bladder cystometry, of selectively lesioning these neurones firstly in urethane-anaesthetised mice and then in conscious mice with indwelling bladder catheters. We will then take advantage of the availability of a mouse strain that has been genetically engineered to express Cre protein in the dopamine-expressing neuronal population. By injecting an adeno-asociated virus expressing rhodopsins to the cvlatPAG and hyperpolarize or depolarize the dopaminergic cell population by laser light initially in acute urethane-anaesthetised mice and then in chronically instrumented animals we will investigate the function of dopaminergic neurons on micturition. In the final part of the study transynaptic viral tracing combined with immunohistochemistry will enable us to investigate synaptic connectivity of the dopaminergic cell group within the micturition control pathway. The new data from the project will provide essential information on central control, which could form the basis for development of new drugs that act to ?normalise? the activity of the bladder control circuits in those individuals with UUI in whom the control has been lost.