Stress management.

Everyone faces stress occasionally, whether in school, at work, or during a global pandemic. However, some cannot cope as well as others. In a few cases, the cause is genetic. In humans, mutations in the OPHN1 gene cause a rare X-linked disease that includes poor stress tolerance. Cold Spring Harbor Laboratory (CSHL) Professor Linda Van Aelst seeks to understand factors that cause specific individuals to respond poorly to stress. She and her lab studied the mouse gene Ophn1, an analog of the human gene, which plays a critical role in developing brain cell connections, memories, and stress tolerance. When Ophn1 was removed in a specific part of the brain, mice expressed depression-like helpless behaviors. The researchers found three ways to reverse this effect.

To test for stress, the researchers put mice into a two-room cage with a door in between. Normal mice escape from the room that gives them a light shock on their feet. But animals lacking Ophn1 sit helplessly in that room without trying to leave. Van Aelst wanted to figure out why.

Her lab developed a way to delete the Ophn1 gene in different brain regions. They found that removing Ophn1 from the prelimbic region of the medial prefrontal cortex (mPFC), an area known to influence behavioral responses and emotion, induced the helpless phenotype. Then the team figured out which brain circuit was disrupted by deleting Ophn1, creating overactivity in the brain region and ultimately the helpless phenotype.