Whether disappointment is prompted by big setbacks or small mishaps, the feeling originates from within the brain. Now, scientists have identified a part of the brain that controls the processing of sensory and emotive information that results in this feeling.
This discovery could have major implications in the future treatment of mood disorders such as depression, as the researchers’ findings expand upon what is known about how the human body registers negative life events.
“The idea that some people see the world as a glass half empty has a chemical basis in the brain,” said Dr. Roberto Malinow, senior author of the study published in the journal Science. “What we have found is a process that may dampen the brain’s sensitivity to negative life events.”
According to the Centers for Disease Control and Prevention (CDC), an estimated 1 in 10 adults in the US report experiencing depression.
Scientists believe that people with depression process negative experiences more strongly than others, and so the study’s findings could help researchers toward understanding what causes the condition and how it can be treated.
Lateral habenula co-releases excitatory and inhibitory neurotransmitters
Through experiments with rodents, the researchers from the University of California, San Diego, discovered that neurons connecting to an area of the brain called the lateral habenula (LHb) were producing both glutamate and GABA; the former being an excitatory neurotransmitter and the latter being an opposing inhibitory neurotransmitter.
Neuronal firing is promoted by excitatory neurotransmitters and suppressed by inhibitory neurotransmitters. Most neurons produce one or the other — either GABA or glutamate. Only two pathways have been previously identified as having neurons that can release either, and even those remain disputed.
Now, the UC-San Diego team has found 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 lead author Dr. Steven Shabel. “In our case, that pathway is believed to signal disappointment.”
The LHb is a small protrusion located within the epithalamus section of the forebrain, which is in control of processing responses from several larger areas and transmitting messages to the brainstem. In past studies, the LHb has been implicated with the regulation of pain responses, psychosis and a variety of motivational behaviors.
It is known that neurons in the LHb are stimulated by negative experiences, particularly unexpected punishments or the failure to receive some anticipated pleasure (for example, in animal studies, activity within the LHb was noted to increase when a reward was expected by monkeys but not received). Hyperactivity in the LHb is also 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. However, 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. Previous assumptions were that there was a lack of inhibitory neurons in this area of the brain.
The authors of the study hypothesize that this area of the brain may be moderated via this unique co-releasing of both excitatory and inhibitory neurotransmitters. “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 Dr. 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.
Findings also ‘explain antidepressants’
The findings also have implications for the understanding of how antidepressants work. Rodents in which aspects of human depression had been developed were found to produce less GABA in relation to their glutamate levels. When given an antidepressant to boost their serotonin levels, the levels of GABA also increased. Shabel explains:
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.
We may now have a precise neurochemical explanation for why antidepressants make some people more resilient to negative experiences.
Indeed, the GABA neurotransmitter and its receptors are involved in many different brain functions. Past research indicates that imbalances in GABA also are relevant to bipolar disorder, schizophrenia, and anxiety disorder.
Learning more about GABA’s role in the development of depression could also lead to major breakthroughs for patients with depression that does not respond to pharmacological treatments. For instance, evidence suggests that deep brain stimulation could be used to “reset” the balance of inhibitory and excitatory neurotransmitters. In fact, some studies even indicate that the psychological benefits of yoga are actually caused by stimulation of GABA activity.
While further work remains to be done in this line of research, these new findings could be the next step on the road to a true understanding of what is the leading cause of disability worldwide, affecting more than 350 million people across the globe — depression.