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06-02-2012 | Psychology | Article

Molecular response to stress unraveled

Abstract

Free abstract

MedWire News: Researchers have shed light on the molecular events controlling the release of corticotropin-releasing hormone (CRH) in neurons in response to stress.

"Our study provides pioneering in vivo evidence for a new molecular mechanism of stress adaptation," Gil Levkowitz (Weizmann Institute of Science, Rehovot, Israel) and colleagues write in Neuron.

CRH controls the immediate fight-or-flight response to stress as well as delayed adaptive activation of the hypothalamic-pituitary-adrenal axis. The process requires changes in the transcription of the gene encoding CRH.

"Regulation of the CRH gene is critical for neuronal adaptation to stress," said Levkowitz in a press statement. "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."

The researchers looked at the role of the transcription factor orthopedia, which they say was an "obvious candidate mediator of stress," given its presence in a CRH-positive hypothalamic region crucial for dealing with challenges and regulating homeostasis.

Orthopedia clearly has a vital function; mice lacking the protein die shortly after birth. However, zebrafish have two opt orthologs: opta and optb. Zebrafish with two copies of a mutant opta are viable throughout adulthood and have normal development of hypothalamic neurons and pituitary secretory cells.

But these fish, when exposed to 4 minutes of physical or osmotic stress, did not have the rapid increase in crh expression observed in fish with normal opta. The fish also showed abnormal behavioral responses to stress.

"A major finding of this study is that stress response is modulated by a mechanism that involves activity-dependent alternative splicing," say Levkowitz and team.

When they performed chromatin immunoprecipitation assays, the researchers found that the Opt protein is recruited to the crh promoter, but also to the promoter of a2bp1, which encodes a splicing factor (Ataxin 2-Binding Protein-1) that has been linked to neuronal plasticity.

Mice and zebrafish placed under stress had rapid increases in a2bp1 expression, but this effect was blunted in zebrafish with mutant opta.

Levkowitz et al then looked at the pac1 gene, which encodes the receptor for the pituitary adenylate cyclase-activating peptide and is a known target of the protein product of a2bp1. They show that mice expressed both the short and long splice isoforms of pac1 messenger RNA during the early phase of recovery from stress, but levels of the short isoform declined later in the process, whereas high levels of the long isoform remained.

On further analysis, the researchers found that, in effect, the short isoform of pac1 acted as an "on" switch, promoting transcription of crh, whereas the long isoform had the opposite effect, terminating the stress response.

They note that various components of this signaling pathway have already been implicated with several neurodevelopmental and psychiatric disorders including epilepsy, mental retardation, bipolar disorder, autism, schizophrenia, major depressive disorder, post-traumatic stress disorder, and Rhett syndrome.

By Eleanor McDermid

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