Rat brain’s executive hub quells alarm center if stress is controllable

Treatments for mood and anxiety disorders are thought to work, in part, by helping patients control the stresses in their lives. A new study in rats by National Institutes of Health (NIH) grantees provides insight into the brain mechanisms likely involved. When it deems a stressor controllable, an executive hub in the front of the brain quells an alarm center deep in the brainstem, preventing the adverse behavioral and physiological effects of uncontrollable stress.

“It’s as if the prefrontal cortex says: ’Cool it, brainstem! We have control over this and there is no need to get so excited’,” quipped Steven Maier, Ph.D., University of Colorado, whose study was funded by the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA). Maier and colleagues posted their findings online in Nature Neuroscience, February 6, 2005.

Lack of control over stressful life experiences has been implicated in mood and anxiety disorders. Rats exposed to uncontrollable stress develop learned helplessness, a syndrome similar to depression and post traumatic stress disorder (PTSD). They lose the ability to learn how to escape stressors. Activation of a brainstem area (dorsal raphe nucleus) has been implicated in such reactions. But this area is too small and lacks the proper sensory inputs to judge whether a stressor is controllable. Many of its inputs come conspicuously from the mid-prefrontal cortex area (medial prefrontal cortex), seat of higher order functions, such as problem-solving and learning from experience. These signals are sent via the chemical messenger serotonin, which is involved in mood regulation and in mediating the effects of the most widely prescribed antidepressants. The medial prefrontal cortex has also been implicated as the source of an “all clear” signal that quells fear in rats.*

To find out the role of the medial prefrontal cortex, Maier’s team chemically inactivated it in rats that were learning to control a stressor. The animals showed the same brainstem activation and, eventually, the same behaviors characteristic of depression (failure to learn to escape) and anxiety (exaggerated fear conditioning) as rats exposed to uncontrollable stress.

“If an organism can cope behaviorally with an event, there’s no need for intense physiological adaptation. It has been assumed that when stressors are uncontrollable the organism learns this, and that it is this uncontrollability that sets off the neural cascade,” explained Maier. “However, our data suggest that instead it is control that is the active ingredient. If the organism has control and can cope behaviorally, this is detected by the cortex, which then sends inhibitory signals to the brainstem.”

In PTSD, which is triggered by uncontrollable stress, medial prefrontal cortex activity is reduced. Proposing an analogous mechanism, Maier speculated that loss of inhibition from the medial prefrontal cortex may explain increased activity of the amygdala (a fear hub) in PTSD.

Also participating the study were: Drs. Jose Amat, Erin Paul, Sondra Bland, Linda Watkins, and Michael Baratta.

Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005 Feb 06; [Epub ahead of print].