The End of Stage-fright: Scientists identify neurons that initiate urination
By Adam Tozer PhD
The sensation of not being able to ‘go’ when you really need to could soon be a thing of the past as two recent papers describe populations of brain cells important for the control of voluntary urination.
Urination (or micturition) is a natural and necessary process important for removing waste products from our bodies and for maintaining a healthy fluid balance. For animals it is also an important social behaviour necessary for marking territory and attracting potential mates.
Needless to say, the voiding of the bladder and the act of urination needs to be appropriate for the situation and is tightly controlled by the brain. Inappropriate urination could lead to social embarrassment or, in the case of an animal, unwanted attention from predators, for example. Despite this, it is thought that one in three people worldwide suffer from incontinence. And, although we understand a lot about the peripheral mechanisms that lead to bladder voiding, the central control of urination was less understood, until now.
In their recent paper, Yao et al. have identified a subset of layer 5 neurons in the primary motor cortex region of the brain that control the initiation of urination.
They initially identified the neurons by injecting a modified rabies virus encoding a green fluorescent protein (eGFP) directly into the bladder of adult male mice. The pseudo-rabies virus was taken up by neurons innervating the bladder. There, the virus hi-jacked the neuronal cells’ genetic machinery to produce the green protein making them easily identifiable and traceable. After 4.5-5 days, they sacrificed the animals and performed a histological investigation of the brain. Unsurprisingly, they identified lots of green fluorescence in a region of the brainstem previously known to be important for urination, known as the pontine micturition centre (PMC).
However, they also discovered a bilateral expression of GFP in neurons in a specific region of the primary motor (M1) cortex.
Performing three-dimensional reconstruction of the region, they counted around 970 GFP positive neurons in layer 5 of the M1 cortex and a further 643 GFP positive neurons in layer 5 of the primary sensory cortex.
To test if the activity of these neurons coincided with urination, the scientists labelled the neurons with a calcium indicator whose fluorescence increases with cellular activity, enabling them to perform fiber-photometry to record the activity of the neurons as the mouse urinated.
To be sure they captured the neuronal activity in real time with the urination, the scientists made their fiber-photometry measurements whilst filming the mice from beneath as they explored their cage.
Using this setup, the scientists discovered the role of the layer 5 M1 neurons is specifically for the initiation of urination, and drives bladder contraction. They confirmed this by expressing channel rhodopsin in the layer 5 M1 neurons to control urination with light. By measuring muscle contraction in the bladder, they confirmed the activation of the neurons stimulated bladder contraction and voiding.
A network control mechanism
Recent work from the Stower’s lab at the Scripps Research Institute, La Jolla, Ca, identified a subset of neurons in the Barrington’s nucleus region of the brainstem as being important for the control of the urethral sphincter. Indeed, activation of these estrogen receptor-expressing neurons is sufficient to induce bladder voiding.
Whether there is a link between the estrogen receptor-expressing cells in the Barrington’s nucleus of the brainstem and M1 layer 5 neurons of the primary motor cortex remains to be seen. But, together these studies reveal incredible functional insight into the control of urination. And, could possibly one day lead to a therapy that reduces the problem of incontinence or even help people overcome stage-fright at the urinal.