Scientists explain how chronic stress activates behavioural problems like loss of pleasure, depression result

Chronic stress clearly has an influence on human behaviour, resulting in issues such as sadness, decreased interest in formerly pleasurable activities, and even PTSD.

Scientists now have evidence that persistent stress causes a group of neurons in a bow-shaped region of the brain to become hyperactive. These kinds of behavioural issues arise when these POMC neurons become overly active, and when scientists lower their activity, the behaviours disappear, according to a study published in the journal Molecular Psychiatry.

Scientists at the Medical College of Georgia at Augusta University looked in the hypothalamus, key to functions like releasing hormones and regulating hunger, thirst, mood, sex drive and sleep, at a population of neurons called the proopiomelanocortin, or POMC, neurons, in response to 10 days of chronic, unpredictable stress. Chronic unpredictable stress is widely used to study the impact of stress exposure in animal models, and in this case that included things like restraint, prolonged wet bedding in a tilted cage and social isolation.

They found the stressors increased spontaneous firing of these POMC neurons in male and female mice, says corresponding author Xin-Yun Lu, MD, PhD, chair of the MCG Department of Neuroscience and Regenerative Medicine and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.

When they directly activated the neurons, rather than letting stress increase their firing, it also resulted in the apparent inability to feel pleasure, called anhedonia, and behavioral despair, which is essentially depression. In humans, indicators of anhedonia might include no longer interacting with good friends and a loss of libido. In mice, their usual love for sugar water wains, and male mice, who normally like to sniff the urine of females when they are in heat, lose some of their interest as well.

Conversely when the MCG scientists inhibited the neurons’ firing, it reduced these types of stress-induced behavioral changes in both sexes.

The results indicate POMC neurons are “both necessary and sufficient” to increase susceptibility to stress, and their increased firing is a driver of resulting behavioral changes like depression. In fact, stress overtly decreased inhibitory inputs onto POMC neurons, Lu says.

The POMC neurons are in the arcuate nucleus, or ARC, of the hypothalamus, a bow-shaped brain region already thought to be important to how chronic stress affects behavior.

Occupying the same region is another population of neurons, called AgRP neurons, which are important for resilience to chronic stress and depression, Lu and her team reported in Molecular Psychiatry in early 2021.

In the face of chronic stress, Lu’s lab reported that AgRP activation goes down as behavioral changes like anhedonia occur, and that when they stimulated those neurons the behaviors diminished. Her team also wanted to know what chronic stress does to the POMC neurons.

AgRP neurons, better known for their role in us seeking food when we are hungry, are known to have a yin-yang relationship with POMC neurons: When AgRP activation goes up, for example, POMC activation goes down.

“If you stimulate AgRP neurons it can trigger immediate, robust feeding,” Lu says. Food deprivation also increases the firing of these neurons. It’s also known that when excited by hunger signals, AgRP neurons send direct messages to the POMC neurons to release the brake on feeding.

Chronic stress, according to their findings, alters the yin-yang equilibrium between these two neuronal groups. Although AgRP projection to POMC neurons is certainly necessary for their firing activity, Lu believes that the intrinsic mechanism is most likely the primary mechanism behind chronic stress-induced hyperactivity of POMC neurons.