When we sense threat, our brain center goes into gear, setting off a chain of biochemical reactions leading to the release of cortisol – a hormone produced by the adrenal glands. However, prolonged cortisol secretion, which may be due to chronic stress for example, can lead to various physical and mental health problems.

Israeli researchers from Weizmann Institute of Science say they have found a new kind of “ON/OFF” switch in the brain, which can help regulate the body’s response to stress. The research was conducted on zebrafish and its results were published in the journal Neuron.

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How our body adapts to stress

In response to stressful conditions, a hormone called Corticotropin-releasing hormone (CRH) is released from neurons in the brain. This process, in turn, stimulates cortisol release in the body.

The release of CRH is typically followed by rapid changes in CRH gene expression: as soon as the CRH-containing neurons run out of the hormone, they are already receiving directions from the brain to produce more of it.

Regulation of CRH activity is critical for adaptation to stress and abnormal regulation of CRH is linked with multiple human psychiatric disorders.

Co-researcher Dr. Gil Levkowitz tells NoCamels: “We decided to conduct this research because my lab has a long-standing interest in studying the hypothalamus – a brain region that regulates, among other things, metabolism and emotional and physical stress.”

Understanding the mechanism

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Despite the wealth of information regarding the physiological role of CRH in mediating the response to stress, the molecular mechanisms that regulate expression of the CRH gene have remained largely elusive. “Our manuscript now shows a new molecular switch mechanism that modulates stress-induced CRH levels,” says Dr. Levkowitz.

Dr. Levkowitz and his colleagues discovered that the protein Orthopedia (Otp), which is expressed in parts of the brain associated with stress adaptation, modulated CRH gene expression and was required for stress adaptation.

The researchers went on to show that Otp regulates production of two different receptors on the neurons’ surface. The receptors, which receive and relay CRH production instructions, essentially function as “ON” and “OFF” switches.

Levkowitz’s team found the same kind of switch in mice. They concluded that this conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain. In other words, the findings identify an evolutionarily conserved biochemical pathway that modulates animals’ adaptation to stress.

Faulty switching mechanisms might play a role in a number of stress-related disorders. The findings on CRH regulation might be useful for the understanding of pathological states of chronic stress – that lead to anxiety disorders and depression.

Dr. Levkowitz added that “as often happens in science, our recent findings raise many more questions that we will certainly like to further explore.”

The research, started about four years ago, was headed by Dr. Liat Amir-Zilberstein together with Dr. Janna Blechman, Dr. Adriana Reuveny, Dr. Natalia Borodovsky and Dr. Maayan Tahor.

Photo by Hank Grebe