Stress-Defeating Effects of Exercise Traced to Emotional Brain Circuit

Evidence in both humans and animals points to emotional benefits from exercise, both physical and mental. Now, in recent experiments with mice, scientists have traced the stress-buffering effect of activity to a brain circuit known to be involved in emotional regulation as well as mood disorders and medication effects. The finding is a clue to understanding the neurological roots of resilience, key to developing new means of prevention and treatment for stress-related illness ceus for counselors

Background
In ongoing research, NIMH scientists have used a mouse model that mirrors particularly well the impact of social stress on mood in humans. Male mice are intensely aggressive when housed together; if these mice are placed in conditions that result in defeat by another mouse, they will behave in a way that mimics depression, much like a human might. Previous research demonstrated that mice housed in an environment with plenty of opportunities for exercise and exploration are relatively unfazed by bullying; they are resilient compared to mice housed in more spartan surroundings. The benefits from activity and stimulation depend on the growth of new neurons in the brain in mice (Novel Model of Depression from Social Defeat Shows Restorative Power of Exercise). A next step was to pinpoint where in the brain changes were taking place in response to exercise that resulted in stress resilience.

This Study
Before any mice were exposed to social defeat, all the mice in the study were housed for three weeks in either impoverished housing, with nothing but wood chip bedding; standard housing with a cardboard tube and place for a nest; or "enriched housing," with running wheels and tubes of various shapes and sizes to explore. After three weeks, half of the mice in each type of housing were then placed for two more weeks in close quarters with another mouse, but prevented from fighting by a barrier to prevent injury.

Mice that had been housed in the impoverished or standard housing, and that had been subject to social defeat, reacted to standard behavioral tests in a way that suggests depression; they were measurably passive and cautious, for example, avoiding light-filled spaces and preferring the safety of darkness. Bullied mice that had been housed in enriched environments behaved just like mice that had not experienced social defeat. As in earlier studies, the enriched environment seemed to protect them from the effects of social stress.

The NIMH investigators carrying out this study, Michael Lehmann and Miles Herkenham, then looked within the brain to see what exercise was changing to protect against stress. They focused on a functional circuit of brain centers known to be involved in emotional processing. In mice that had been housed in an enriched environment, levels of a protein that signals the activity level of neurons were increased in cells in the infralimbic cortex (ILC), a part of this circuit. Parts of the brain closely wired to and "downstream" from the ILC, that is, receiving activating signals from it, showed similar elevated activity. If the ILC was inactivated at the beginning of the experiment, environmental enrichment failed to have a positive effect. But if it was inactivated after the first three weeks of housing, environmental enrichment worked; the parts of the brain that receive signals from the ILC remained activated and the mice were stress resilient. The ILC was, in effect, a gateway for the positive activity in these "downstream" parts of the brain. Once these centers were activated by the ILC, it didn't matter if the ILC was still online.

Enrichment had the opposite effect on a part of the brain that is an important trigger for the body's stress response system. So enrichment seemed to enhance positive behavior, while at the same time, dampened activity in an area linked with an increased stress response.

Significance
A central target of research is understanding how stress contributes to mood disorders and why some animals and people seem resilient to the same stresses that can make others ill. Much recent research is aimed at investigating mental processes and disorders in terms of neural circuits. Abnormalities in how the brain deals with fear memories, for example, are thought to play a role in both anxiety disorders and depression. In rats that have been conditioned to fear a particular sound, stimulation of the ILC can dampen the fear reaction. In the study reported here, experience in the environment had the effect of inoculating the mice against a stressor, through changes in this same circuit in the brain.

The areas of the brain examined in this study are analogous to brain regions with altered function in people with disorders like depression and post traumatic stress disorder. Knowledge of the physiological basis of emotional resilience is crucial to developing strategies to help prevent mood disorders; it can also offer targets for the development of new medications for which there remains a pressing need.

Reference
Lehmann, M.I., and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. Journal of Neuroscience 31:6159-6173, 2011.