New Insight About Why Mild Stress Can Trigger Extreme Responses in PTSD and Other Disorders

New Insight About Why Mild Stress Can Trigger Extreme Responses in PTSD and Other Disorders

Posted: December 8, 2015

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Researchers have uncovered new details about what happens in the brain when a mild source of stress generates an extreme response, disproportionate to the stress. Their findings identify possible targets for new medications to treat the debilitating stress responses that define post-traumatic stress disorder (PTSD) and other illnesses.

People develop PTSD after experiencing severe trauma, which in turn makes them hypersensitive to stress even in situations completely unlike the original trauma. This hypersensitivity has been linked to two specific kinds of mental processes. The first is an unusually strong reflexive reaction, known as the “startle response,” to a sudden event in the environment. The second, a phenomenon called “prepulse inhibition” (PPI), takes the form of a relative insensitivity to weak stimuli that normally reduce startle responses, including those that indicate the perception of threat associated with an event.  Increased startle and decreased PPI responses are seen in PTSD and also have been observed in other disorders, including schizophrenia.

Publishing their findings online October 21 in The Journal of Neuroscience, a research team used a rat model of PTSD behavior to study both startle and PPI in relation to specific brain cells, which may be targeted in future drug development.  The team was led by NARSAD 2003 and 2007 Young Investigator grantee Vaishali P. Bakshi, Ph.D., and included 2002 NARSAD Young Investigator grantee Brian A. Baldo, Ph.D., both of the Department of Psychiatry at the University of Wisconsin-Madison.

Drs. Bakshi, Baldo and graduate student Abha Rajbhandari induced the equivalent of trauma in rats by exposing them to ferrets, a natural rat predator. The exposed rats later showed extreme reactions — both high startle and reduced PPI — to small amounts of norepinephrine, a chemical that triggers stress response, after its injection into a part of the brain called the amygdala, crucial in fear processing. Experiments showed that this overreaction to norepinephrine could be stopped by blocking the activity of receptors, or docking ports, on nerve cells for a stress hormone called corticotropin-releasing factor, or CRF.  

The scientists found that injecting CRF into the rats’ amygdalae (every brain has two, one in each hemisphere) had the same effect as putting the rats close to ferrets, by exaggerating their reactions to subsequent norepinephrine. These findings pointed to CRF as the key player in making the amygdala oversensitive to norepinephrine.

The researchers also found receptors for norepinephrine and CRF on the same neurons within the amygdala, further evidence that their activity is linked. Importantly, these receptors were found to be on the neurons that send projections from the amygdala to other brain regions that are important for drug abuse, so this new finding could also help to explain the high incidence of alcoholism in PTSD, according to Dr. Bakshi.  Together, these findings provide the first evidence of a specific mechanism involving CRF and norepinephrine that leads to the extreme stress responses following trauma seen in PTSD and other illnesses.

New drugs, the researchers say, may prevent the development of extreme stress responses by targeting brain chemicals that “transfer” information about the trauma from the CRF receptor to the norepinephrine receptor and render that latter receptor supersensitive to subsequent mildly stressful situations. They suggest that future work should examine the relationship between CRF and norepinephrine in models of other illnesses besides PTSD that are exacerbated by stress, such as schizophrenia and anxiety disorders.

Read the paper.

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