Stress Hormone ‘Switch’ Could Improve Some Neurological Disorders

In reaction to a threat, our brains set off a chain of biochemical reactions that result in the release of cortisol — the body’s stress hormone — from the adrenal glands.

Researchers have now discovered a switch in the brain for regulating this process, which could hold great promise for people suffering from stress-related neurological disorders.

Corticotropin releasing hormone, or CRH, is manufactured and stored in special neurons in the hypothalamus region of the brain. When that area senses danger, it goes into stress-response mode, and the CRH-containing neurons begin producing the hormone — and even when it’s depleted, those neurons are already receiving the directive to produce more.

The new research, conducted on zebrafish, found that a protein called Otp is involved in several stages of CRH production. It doesn’t just directly activate the genes encoding CRH, it also regulates the production of two different receptors on the neurons’ surface for receiving and relaying CRH production signals — in other words, “on” and “off” switches, which are both encoded in a single gene.

Otp regulates a gene-editing process known as alternative splicing, allowing some of the elements in a gene’s encoded sequence to be “cut and pasted” to make slightly different “sentences.” In this case, it generates two variants of a receptor called PAC1, with the short version producing the “on” receptor and the long version with the extra sequence encoding the “off” receptor.

Scientists found that as a threat passes and the supply of CRH was replenished, the ratio between the two types receptors on the neurons’ surface gradually changed from more “on” to mostly “off.”

Faulty switching mechanisms may be partially responsible for a number of stress-related disorders, and the action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder, schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder and autism.

The latest research, published in Neuron, was conducted by Dr. Gil Levkowitz and a team in the Molecular Cell Biology Department at the Weizmann Institute of Science in Rehovot, Israel.