Chronic stress, be it from the covid pandemic, conflict in the Middle East, burnout from work, or any number of reasons, is a leading trigger for mental health issues, like anxiety and depression. Yet, it’s unclear how some people manage to buck stress’ ill effects and are impervious of its insidious influence. Researchers at the Princeton Neuroscience Institute might now have the answer: what dictates whether a person will thrive or succumb to psychological pressure may be due to a pea-size brain region called the lateral habenula.

According to new results in mice from the labs of Ilana Witten, Ph.D. and Annegret Falkner, Ph.D., the lateral habenula, a brain area crucial for processing bad experiences, was more active in mice who were more vulnerable to stress compared to their resilient cage mates from day-one.

The teams’ findings, which were published October 10 in the journal Neuron, may have promising implications for a new understanding of where to target treatment to quash stress in its tracks and prevent burn out, or other unwanted stress-induced side effects.

To stress mice out, the team set up a harrowing ten-day mouse “fight club”, during which, a small mouse received a daily five-minute pummeling by a bigger, more aggressive mouse. 

Prior studies from the Witten and Falkner labs found that that dopamine brain networks are more active when resilient mice fight back, while susceptible mice tend to escape, suggesting these mice adopt different strategies that are more rewarding to them. These differences, however, only gradually emerge over the ten days of repeated wallops. Whether other brain regions exhibit early differences in activity from the very start of a stress marathon was unknown.

“Lateral habenula suppresses dopamine responses and has been implicated in stress and depression, so it was a logical region to investigate,” said Anna Zhukovskaya, Ph.D., the lead author of the study who is now a postdoctoral researcher at Columbia University. 

Zhukovskaya and her colleagues then used a genetic tweak to make brain cells light up when they fire to visually track lateral habenula activity. After ten days of getting beat up, 20% more habenula cells were activated when susceptible mice interacted with bigger mice compared to more resilient rodents. As these differences were present from the first day of the stress marathon, it suggests that lateral habenula activity can reliably predict which mice will buckle under stress. 

If mice with more lateral habenula activity are vulnerable to stress, Zhukovskaya then reasoned she could make resilient mice susceptible just by dialing up their habenula activity during a scuffle. Sure enough, when previously resilient mice had their lateral habenula cells activated during a fight, it made them less social and more anxious in the boxing ring. This suggests that the elevated lateral habenula activity is not only associated with, but indeed causes future susceptibility to stress.

Since dialing up habenula activity made previously stress-free mice wig-out, Zhukovskaya then silenced the same region in stress-susceptible mice to see whether they could weather the wallops better. While reducing habenula activity was unable to entirely reverse their stress response, the mice were slightly more resilient than their unmanipulated counterparts.

Taken together, Witten and Falkner now plan to test if resilience and susceptibility are dictated by partially distinct brain pathways. Previous work from the team found that activating the dopamine reward pathway promotes resilience, whereas their new findings show that activating the lateral habenula promotes susceptibility.

Though it’s early days, the results suggest it may one day be possible for people to receive treatment that quiets or stimulates a part of the brain to better endure a stressor.

“Our results suggest that deep-brain stimulation of the habenula and other interventions early on during a period of chronic stress may help to prevent depression”, Zhukovskaya said.
 

CITATION: “Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility,” Anna Zhukovskaya, Christopher A. Zimmerman, Lindsay Willmore, Alejandro Pan-Vazquez, Sanjeev R. Janarthanan, Laura A. Lynch, Annegret L. Falkner, Ilana B. Witten. Neuron, December 4, 2024. DOI: 10.1016/j.neuron.2024.09.009