Study Title:

Stress Blunts Relaxing Nerves

Study Abstract

In mammals, stress elicits a stereotyped endocrine response that requires an increase in the activity of hypothalamic parvocellular neuroendocrine neurons. The output of these cells is normally constrained by powerful GABA-mediated synaptic inhibition. We found that acute restraint stress in rats released the system from inhibitory synaptic drive in vivo by down-regulating the transmembrane anion transporter KCC2. This manifested as a depolarizing shift in the reversal potential of GABAA-mediated synaptic currents that rendered GABA inputs largely ineffective. Notably, repetitive activation of GABA synapses after stress resulted in a more rapid collapse of the anion gradient and was sufficient to increase the activity of neuroendocrine cells. Our data indicate that hypothalamic neurons integrate psychological cues to mount the endocrine response to stress by regulating anion gradients.

From press release:

Chronic stress takes a physical and emotional toll on our bodies and scientists are working on piecing together a medical puzzle to understand how we respond to stress at the cellular level in the brain. Being able to quickly and successfully respond to stress is essential for survival.

Using a rat model, Jaideep Bains, PhD, a University of Calgary scientist and his team of researchers at the Hotchkiss Brain Institute have discovered that neurons in the hypothalamus, the brain’s command centre for stress responses, interpret ‘off’ chemical signals as ‘on’ chemical signals when stress is perceived. “It’s as if the brakes in your car are now acting to speed up the vehicle, rather than slow it down.” says Bains.

This unexpected finding is being published in the March 1st online edition of Nature Neuroscience.

Normally, neurons receive different chemical signals that tell them to either switch on or switch off. The off signal or brake only works if the levels of chloride ion in the cells are maintained at a low level.

This is accomplished by a protein, known as KCC2. What Bains and colleagues have shown is that stress turns down the activity of KCC2, thus removing the ability of the brake, a chemical known as GABA, to work properly. A loss of the brain’s ability to slow down may explain some of the harmful, emotional consequences of stress.

While the findings provide a new mechanistic explanation of how the brain interprets stress signals, "there is still much work needed in the basic science of this phenomenon before there are any new advances in the medical treatment of stress," says Bains.

“This opens entirely new and quite unexpected avenues for controlling stress responses” says Yves De Koninck, PhD, president-elect of the Canadian Association for Neuroscience and professor of Psychiatry at Laval University.

“I was fascinated when I learned of this work. It has not been clear till now how the neuroendocrine stress response was activated by external stressors. Bains’ work shows a complex, yet elegant solution, involving a switch from inhibition to excitation.” says Jane Stewart, PhD a behavioural neuroscientist from Concordia University, “these findings may lead to a better understanding of the changes in sensitivity to stress that result from chronic exposure.”

The research was supported by the Canadian Institutes of Health Research. Bains is an Alberta Heritage Foundation for Medical Research scholar, an associate professor in the Department of Physiology and Biophysics and a member of the Hotchkiss Brain Institute in the Faculty of Medicine at the University of Calgary.

Study Information

Sarah A Hewitt, Jaclyn I Wamsteeker, Ebba U Kurz & Jaideep S Bains
Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis
Nature Neuroscience
2009 March
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

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