Social mammals—for example, rats and humans—learn to control necessary bodily functions, such as urination (a.k.a. micturition), to keep their living quarters clean or to avoid social faux pas. As a bladder fills with fluid, stretch receptors send nerve impulses to the spinal column, signaling smooth muscle in the bladder wall to contract—a process known as the micturition reflex. Ordinarily the brain overrides the impulse to urinate until an appropriate opportunity arises, but the signaling loop can fail, leading to incontinence.
It is well known that the neurotransmitter gamma-aminobutyric acid (GABA) is involved in micturition, but exactly which part of the brain controls the micturition response has been hard to pin down. Searching for the brain’s urination control switch, University of Birmingham’s Thelma Lovick took a close look at a region of the midbrain called the periaqueductal grey (PAG). This tubular area, only about 2 mm wide by 3.5 mm long in the rat, is involved in a number of different functions, which include modulating the sensation of pain and mediating “fight, flight, or freeze” defensive or attack behavior, as well as its attendant increases in heart rate, breathing rate, and muscle tone. Lovick’s lab was able to identify exactly where in the PAG the control of urination resided.
The PAG contains a high proportion of GABA receptors, leading many researchers to suspect that there had to be a urination switch in the region, according to Lovick. But nobody “had put two and two together and got exactly four.” Lovick is interested in knowing how the brain controls bodily sensations—the urge to urinate and the feeling of pain, for example—which in general seem to be seated in the PAG. So, knowing that changing levels of GABA in the PAG are associated with control of bladder emptying, Lovick and her collaborators decided to measure bladder emptying following injection of drugs that either mimic or inhibit GABA’s action into localized regions of the PAGs of anesthetized rats.
First, they fed a steady stream of saline directly into the bladders of the rats, forcing them to reflexively urinate at regular intervals, about every minute. Then they injected 50 nanoliters of a solution of muscimol—a psychoactive compound from Amanita mushrooms that activates GABA receptors—into small, defined sites 0.2–0.8 mm apart. Such a tiny volume does not diffuse very far through the tissue, and so affects only a hundred or so neurons. Lovick’s team found that at most locations in the PAG there was no effect. At seven places, in a very small area of the PAG, however, injection of muscimol either temporarily reduced the frequency of urination by about a third or stopped it completely—and as saline continued to flow into the bladder, the rats eventually developed overflow incontinence and steadily leaked urine.
Then Lovick’s lab examined the effect of bicuculline (BIC), a plant-derived alkaloid which blocks GABA receptors and can be used to experimentally induce epilepsy. They injected the same PAG sites where muscimol inhibited micturition, and discovered that BIC increased frequency of urination—to three or four times a minute. The region of the PAG responsible for controlling urination, narrowed down in this way, turned out to be very small. “We could move our [needle] half a millimeter and not get the effect,” Lovick says.
Interestingly, in 2004 Ichiro Yabe and colleagues at Hokkaido University in Japan reported the case of a patient who was suddenly unable to urinate. An MRI scan of the patient’s brain revealed a small tumor in his PAG. Steroid treatment reduced the size of the lesion, and the man was able once more to urinate.
“The most exciting part,” Lovick says, was realizing that her team had found this “switch that determines whether you wee or whether you don’t.” She adds that manipulating the switch, either pharmacologically or electrically (by deep brain stimulation), could be the basis of new treatments for urge incontinence. She is collaborating with a team of neurosurgeons at Oxford University whose patients already have electrodes inserted into their PAGs for pain relief, to establish whether deep brain stimulation can treat urge incontinence in this way. Lovick says that the results from these studies are still preliminary, but are “looking very encouraging.”
Another approach is to design drugs that could interfere with the GABA signaling pathway in the PAG. This would require identifying precisely which neurotransmitters, apart from GABA, are involved in synaptic transmission, so her lab is also injecting different pharmacological agonists and antagonists into this tiny region of the PAG to chart their effects on bladder function.
A Hidden Jewel refers to an article, published in a specialist journal, which has been evaluated in Faculty of 1000, a post-publication peer review service of the Science Navigation Group. Read the evaluation of Lovick’s article.