A pathway in the brain has been found to act in a way seldom seen before, operating both excitation and inhibition. The discovery helps explain why some people are resilient to setbacks that leave others emotionally devastated and suggests opportunities to better target drugs to enhance this resilience.
The neurotransmitter glutamate is responsible for exciting many parts of the brain, while GABA has the opposite effect, damping down responses. Most neurons produce one or the other, with only two pathways previously identified having neurons that can release either, and even those remain disputed.
A team from the University of California, San Diego, report in Science that the lateral habenula (LHb) is a third region occupied by neurons capable of releasing both types of transmitters. "Our study is one of the first to rigorously document that inhibition can co-exist with excitation in a brain pathway," says first author Dr. Steven Shabel.
The LHb is a small protrusion on the epithalamus section of the forebrain that processes responses from several larger areas and transmits messages to the brainstem. It is known that the neurons are stimulated by negative experiences, particularly unexpected punishments or the failure to receive some anticipated pleasure.
Unsurprisingly, hyperactivity in the LHb—a part of the brain linked with disappointment—is associated with depression. Deep brain stimulation of the LHb, which can dampen down excitation, has been shown to lessen depressive symptoms in rats.
Neuroscientists have been able to see how painful events or chemical imbalances can overstimulate the LHb, leading to depression. Until now, it has been more challenging to explain why some people are resilient, bouncing back from events that might send others into a depressive spiral. After all, there appeared to be very few inhibitory neurons to damp down the excitation.
"The take-home of this study is that inhibition in this pathway is coming from an unusual co-release of neurotransmitters into the habenula," says Shabel. He admits it is still not clear why the LHb has combined the two functions when most brain parts separate them, but speculates it may offer finer control, at least in healthy people.
The paper also reports that both rats and mice showing signs of depression produced more glutamate and less GABA in the LHb than those who appeared happy. Administration of antidepressants restored the balance.
"Our study suggests that one of the ways in which serotonin alleviates depression is by rebalancing the brain's processing of negative life events vis-à-vis the balance of glutamate and GABA in the habenula," Shabel says. "We may now have a precise neurochemical explanation for why antidepressants make some people more resilient to negative experiences." It is hoped that this understanding will help the design of drugs that can perform the same function more effectively.
