Study Finds Evidence Linking The Brain's Cognitive Control Regions With Stress Control Regions

Published in the Aug. 1, 1998, issue of the Journal of Neuroscience, thestudy's results may lead to the development of future stress interventionstrategies.

"The interesting thing about human beings is that we're incredibly goodat putting ourselves under situations of prolonged stress," said James Herman,associate professor of anatomy and neurobiology and principal investigator ofthe study.

"The consequences of prolonged stress can range from general malaiseto physical or mental illness. The mechanisms controlling stress remain poorlydefined, and our studies aim to establish how the brain controls stressresponses."

Herman and colleagues believe the brain's stress circuitry is driven byinhibition of certain chemicals, rather than excitation.

"For instance, say you walk by a cave 50 times, and nothing comes out. It's an innocuous stimulus," Herman said.

"Inhibitory systems engage to preventgeneration of an unneeded, metabolically expensive response. On walk number 51,however, a bear jumps out at you. The part of the brain that says 'this isO.K.' now has a different message -- 'this is dangerous.' The way it does thatis through overcoming the ongoing inhibition of the system."

The delicate balance between stress inhibition and excitation is asurvival strategy built into animals through millions of years of evolution,allowing responses to be generated on demand and quickly turned off. Problemsarise when the system gets changed to such an extent that the animal no longeris able to activate the inhibition, which means more stress hormones arereleased into the body and brain.

Based upon earlier studies, the researchers suspected that three mainareas were responsible for stress responses:

• The paraventricular nucleus. The PVN is the central core of the body's stressresponse and is primarily responsible for secretion of stress hormones calledglucocorticoids. These chemicals regulate the metabolism of carbohydrates,proteins and fats in the body. It responds to chemical signals sent from otherareas.

• The hypothalamus. It is responsible for the body's homeostasis, or balance. It in large part dictates the overall health of the animal through control offood and water intake, cardiovascular tone, body temperature and hormonerelease.

• The hippocampus. It is the cognitive area of control. It's where learnedstresses, like 'bear in cave' are processed. UK scientists believe that signalssent from this area first have to pass through the hypothalamus before reachingthe PVN.

Researchers used snippets of antisense RNA to locate an enzyme calledglutamic acid decarboxylase (GAD) in the brain. GAD speeds production of aninhibitory chemical transmitter called gamma-aminobutyric acid (GABA).

Two forms of the GAD enzyme exist: GAD65, the stored form and GAD67,the rapidly released form. Each form responded differently based upon theduration of stress (acute or chronic) applied to rats; these regulators wereactive only in sections of the brain that the researchers suspected to becontrol areas.

In the first experiment, rats were placed under short-term restraint toprovoke acute stress reactions. There was a significant amount ofstress-generated expression of GAD67 in the hippocampus and hypothalamus. Theinduction was rapid and transient, suggesting an immediate need to manufactureGABA in the acute stress situation.

Other rats were exposed to chronic intermittent stress for two weeks. The stress areas in the brains of the rats showed pronounced increases in GAD65expression, indicating that following chronic stress, the animal was attemptingto increase the pool of enzyme to attempt to compensate for continual stressexposure.

"It's only in the stress responsive hypothalamic regions of the brainthat we're seeing these changes, indicating that stress is activating inhibitorysystems," Herman said.

"These studies indicate that signals from higher regionsof brain essentially communicate through more primitive regions to influencestress responses, essentially asking neurons controlling the ongoing healthstatus of the animal whether it's OK to mount a stress response. Our resultssuggest these primitive structures are likely to be a focus of abnormalitiesseen in stress-related diseases of the brain."