Aug. 21, 1998 LEXINGTON, KY (Aug. 19, 1998)--A team of researchers from the University of Kentucky and Marquette University has pinpointed distinct patterns of gene expression that indicate stress causes selective increases in production of an inhibitory transmitter in the brains of laboratory animals. These studies provide evidence for a multi-neuron link between brain regions controlling cognition and those regulating hormonal output of the stress system.
Published in the Aug. 1, 1998, issue of the Journal of Neuroscience, the study's results may lead to the development of future stress intervention strategies.
"The interesting thing about human beings is that we're incredibly good at putting ourselves under situations of prolonged stress," said James Herman, associate professor of anatomy and neurobiology and principal investigator of the study.
"The consequences of prolonged stress can range from general malaise to physical or mental illness. The mechanisms controlling stress remain poorly defined, and our studies aim to establish how the brain controls stress responses."
Herman and colleagues believe the brain's stress circuitry is driven by inhibition 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 prevent generation 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 is O.K.' now has a different message -- 'this is dangerous.' The way it does that is through overcoming the ongoing inhibition of the system."
The delicate balance between stress inhibition and excitation is a survival strategy built into animals through millions of years of evolution, allowing responses to be generated on demand and quickly turned off. Problems arise when the system gets changed to such an extent that the animal no longer is able to activate the inhibition, which means more stress hormones are released into the body and brain.
Based upon earlier studies, the researchers suspected that three main areas were responsible for stress responses:
- The paraventricular nucleus. The PVN is the central core of the body's stress response and is primarily responsible for secretion of stress hormones called glucocorticoids. These chemicals regulate the metabolism of carbohydrates, proteins and fats in the body. It responds to chemical signals sent from other areas.
- 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 of food and water intake, cardiovascular tone, body temperature and hormone release.
- The hippocampus. It is the cognitive area of control. It's where learned stresses, like 'bear in cave' are processed. UK scientists believe that signals sent from this area first have to pass through the hypothalamus before reaching the PVN.
Researchers used snippets of antisense RNA to locate an enzyme called glutamic acid decarboxylase (GAD) in the brain. GAD speeds production of an inhibitory 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 the duration of stress (acute or chronic) applied to rats; these regulators were active only in sections of the brain that the researchers suspected to be control areas.
In the first experiment, rats were placed under short-term restraint to provoke acute stress reactions. There was a significant amount of stress-generated expression of GAD67 in the hippocampus and hypothalamus. The induction was rapid and transient, suggesting an immediate need to manufacture GABA 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 GAD65 expression, indicating that following chronic stress, the animal was attempting to increase the pool of enzyme to attempt to compensate for continual stress exposure.
"It's only in the stress responsive hypothalamic regions of the brain that we're seeing these changes, indicating that stress is activating inhibitory systems," Herman said.
"These studies indicate that signals from higher regions of brain essentially communicate through more primitive regions to influence stress responses, essentially asking neurons controlling the ongoing health status of the animal whether it's OK to mount a stress response. Our results suggest these primitive structures are likely to be a focus of abnormalities seen in stress-related diseases of the brain."
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