Mechanism sheds light on how the brain adapts to stress

January 25, 2012

Scientists now have a better understanding of the way that stress impacts the brain. New research, published by Cell Press in the January 26 issue of the journal Neuron, reveals pioneering evidence for a new mechanism of stress adaptation and may eventually lead to a better understanding of why prolonged and repeated exposure to stress can lead to anxiety disorders and depression.

Most stressful stimuli cause the release of corticotropin-releasing hormone (CRH) from neurons in the brain. This is typically followed by rapid changes in CRH gene expression. In more practical terms, as soon as the CRH-containing neurons run out of CRH, they are already receiving directions to make more. CRH controls various reactions to stress, including immediate "fight-or-flight" responses as well as more delayed adaptive responses in the brain. Regulation of CRH activity is critical for adaptation to stress, and abnormal regulation of CRH is linked with multiple human .

"Despite the wealth of information regarding the physiological role of CRH in mediating the response to stress, the that regulate expression of the CRH gene, and thereby CRH synthesis, have remained largely elusive," explains senior study author, Dr. Gil Levkowitz, from the Weizmann Institute of Science in Israel. "In our study, we used mouse and model systems to identify a novel intracellular signaling pathway that controls stress-induced CRH gene expression."

Dr. Levkowitz and colleagues discovered that the protein Orthopedia (Otp), which is expressed in associated with stress adaptation, modulated CRH 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.

"This regulation of the CRH gene is critical for neuronal adaptation to stress. Failure to activate or terminate the CRH response can lead to chronic over- or under-activation of stress-related brain circuits, leading to pathological conditions," concludes Dr. Levkowitz. "Taken together, our findings identify an evolutionarily conserved biochemical pathway that modulates adaptation to stress."

Explore further: Novel mechanism regulating stress identified

More information: Amir-Zilberstein et al.: “Homeodomain protein Otp and activity-dependent splicing modulate neuronal adaptation to stress.” Neuron, January 26, 2012.

Abstract
Regulation of corticotropin-releasing hormone (CRH) activity is critical for the animal’s adaptation to stressful challenges, and its dysregulation is associated with psychiatric disorders in humans. However, the molecular mechanism underlying this transcriptional response to stress is not well understood. Using various stress paradigms in mouse and zebrafish, we show that the hypothalamic transcription factor Orthopedia modulates the expression of CRH as well as the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1). We further show that the G protein coupled receptor PAC1, which is a known A2BP1/Rbfox-1 splicing target and an important mediator of CRH activity, is alternatively spliced in response to a stressful challenge. The generation of PAC1-hop messenger RNA isoform by alternative splicing is required for termination of CRH transcription, normal activation of the hypothalamic-pituitary-adrenal axis and adaptive anxiety-like behavior. Our study identifies an evolutionarily conserved biochemical pathway that modulates the neuronal adaptation to stress through transcriptional activation and alternative splicing.

Related Stories

Novel mechanism regulating stress identified

December 13, 2011
Neuroscience researchers from Tufts have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that ...

Control of fear in the brain decoded

September 6, 2011
When healthy people are faced with threatening situations, they react with a suitable behavioural response and do not descend into a state of either panic or indifference, as is the case, for example, with patients who suffer ...

Scientists find missing link in regulation of glucose

December 22, 2011
(Medical Xpress) -- A team led by USC neuroscientist Alan Watts identified for the first time a biochemical signal that helps regulate the amount of glucose in the blood.

Study finds two genes affect anxiety, behavior in mice with too much MeCP2

January 8, 2012
The anxiety and behavioral issues associated with excess MeCP2 protein result from overexpression of two genes (Crh [corticotropin-releasing hormone] and Oprm 1 [mu-opioid receptor MOR 1]), which may point the way to treating ...

Recommended for you

'Residual echo' of ancient humans in scans may hold clues to mental disorders

July 26, 2017
Researchers at the National Institute of Mental Health (NIMH) have produced the first direct evidence that parts of our brains implicated in mental disorders may be shaped by a "residual echo" from our ancient past. The more ...

Laser used to reawaken lost memories in mice with Alzheimer's disease

July 26, 2017
(Medical Xpress)—A team of researchers at Columbia University has found that applying a laser to the part of a mouse brain used for memory storage caused the mice to recall memories lost due to a mouse version of Alzheimer's ...

Cellular roots of anxiety identified

July 26, 2017
From students stressing over exams to workers facing possible layoffs, worrying about the future is a normal and universal experience. But when people's anticipation of bad things to come starts interfering with daily life, ...

Cognitive cross-training enhances learning, study finds

July 25, 2017
Just as athletes cross-train to improve physical skills, those wanting to enhance cognitive skills can benefit from multiple ways of exercising the brain, according to a comprehensive new study from University of Illinois ...

Brain disease seen in most football players in large report

July 25, 2017
Research on 202 former football players found evidence of a brain disease linked to repeated head blows in nearly all of them, from athletes in the National Football League, college and even high school.

Zebrafish study reveals clues to healing spinal cord injuries

July 25, 2017
Fresh insights into how zebrafish repair their nerve connections could hold clues to new therapies for people with spinal cord injuries.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.