There are an estimated 50,000 people in the UK living with the effects of a spinal cord injury, and around 2,500 new spinal cord injuries every year.
One of the most common impairments after spinal cord injury (SCI) is impairment in urinary function. This is highly debilitating and has been highlighted as a priority by those living with spinal cord injury.
In this project, Professor Rob Brownstone and team will address a key gap in our knowledge of the neural circuits that control bladder function and how these circuits change following spinal cord injury. This will provide foundational knowledge to underpin the development of effective therapies.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to advance knowledge in a field that is high priority for those affected, yet under-researched.
The bladder is a relatively simple organ that expands to store urine and contracts to empty it under voluntary control at a socially convenient time. People with SCI develop urinary problems as a result of a ‘neurogenic bladder’, whereby the normal functioning of the bladder is disrupted. Those affected have reduced awareness of their bladder being full, and reflexes can cause it to empty involuntarily. Bladders also tend to become overactive, meaning that they may contract frequently, with little or no warning. Many people with SCI thus rely on catheters to manage their bladders.
Restoring control of urinary function is consistently emphasised as a major concern for those with SCI. Existing treatments, such as medications and electrical stimulation to facilitate urination, only provide partial relief from the symptoms, and often have side effects and negative health impacts.
A significant challenge in creating new, more effective treatment approaches lies in our limited understanding of the intricate neural circuits of the spinal cord - circuits that coordinate the contractions of various muscles to store urine and to empty the bladder. We also lack a clear understanding of how these neural circuits change following SCI. This knowledge gap hinders the development of new strategies to address neurogenic bladders and enhance urinary function in individuals with SCI. Professor Brownstone and team propose to address this knowledge gap to identify new cellular targets to facilitate recovery of urinary function after SCI.
The process of emptying the bladder is controlled by a combination of brain and spinal cord neurons working together. A group of neurons in the brainstem generates a bladder-emptying (voiding) ‘command’ that is then interpreted by neuronal circuits in the lower spinal cord to coordinate activation of the bladder and sphincter muscles. When the voiding command initiates urinary function, these muscles are activated and inactivated in a coordinated matter to empty the bladder.
After SCI, however, both the brainstem control and the spinal cord coordination are lost, leading to urine retention and a need to catheterise the bladder. In the early phase following injury, the sphincter muscles remain permanently contracted, thus preventing voiding of the bladder. In the later stages, this continuous contraction is relieved by unknown mechanisms, but normal, coordinated voiding does not return.
To understand which neurons are involved in normal urinary function, and how these cells adapt following SCI, the team will perform experiments using a set of approaches ranging from molecular to behavioural tools in mice. They will investigate the cellular properties and anatomical distribution of neurons involved in bladder control, and the organisation of the neuronal circuits that work together to control the process of emptying the bladder. They will then investigate how these circuits are affected after SCI.
Interestingly, mice can regain some of their bladder function within several weeks after spinal cord transection. Thus, the team will use their tools to focus on two important timeframes: the early phase right after the injury, and a later phase when the mice have started to recover some bladder function. By studying the neurons and circuits at these time points, the team aims to uncover the ways these circuits adapt and change during the initial shock of the injury and when some recovery is observed.
This project will provide a detailed characterisation of the local neurons controlling normal bladder function. Moreover, the team will address how these neurons change early after SCI, and how they adapt to the new state of the nervous system at later stages. The identification of cellular and circuit dysfunction will provide foundational knowledge to develop new therapies aimed at these specific targets. Such therapies could include, for example, genetic therapies and functional stimulation.
The project team comprises three scientists. Professor Rob Brownstone is the Brain Research UK Chair of Neurosurgery at UCL Queen Square Institute of Neurology, and is a neurosurgeon-scientist, with expertise in neural circuits and the spinal cord.
On this project he is working with Professor Marco Beato and Dr Görkem Özyurt, neuroscientists who bring complementary skills and expertise, to successfully complete the intricate experiments involved in this project.
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
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