Mechanisms Underlying the Anxiolytic Actions of Physical Exercise

Abstract

Exercise reduces anxiety in both humans and rodents. Understanding the mechanisms underlying the anxiolytic actions of exercise may provide clues to novel treatments for individuals with anxiety disorders. To investigate potential mechanisms underlying anxiety, my dissertation focused on the ventral hippocampus, an anxiogenic region that is highly susceptible to neuronal changes due to long-term running. My first series of experiments showed that in sedentary mice, stress activated new and preexisting granule neurons in the ventral hippocampus. Long-term running, which dramatically increases the production of granule neurons in the dentate gyrus of the hippocampus, prevented the stress-induced activation of new and preexisting granule neurons in the ventral hippocampus.

Next, I investigated whether stress alters GABAergic mechanisms differentially in the hippocampus of runner and sedentary mice. I observed that runners have greater stress-induced activation of GABAergic inhibitory interneurons in the ventral hippocampus. I found that runners had greater levels of the presynaptic vesicular GABA transporter and increased GABA release in the hippocampus during stress. These findings suggest that despite having increased numbers of new excitatory neurons in the hippocampus, runners show reduced activation of these cells, most likely because of enhanced activity in local GABAergic interneurons. In addition, direct infusion of the GABA-A receptor antagonist bicuculline into the ventral hippocampus reversed the anxiolytic effect of running in mice, suggesting that GABA signaling mediates the anxiolytic actions of exercise.

Finally, I examined whether gap junctions among GABAergic interneurons in the ventral hippocampus are important for anxiety regulation. I found that gap junction inhibitors injected peripherally and infused directly into the ventral hippocampus reduced anxiety-like behavior. Blocking gap junctions in the ventral hippocampus unilaterally and in the medial prefrontal cortex on the other hemisphere also reduced anxiety-like behavior, suggesting that gap junction-mediated signaling in the ventral hippocampus and medial prefrontal cortex may drive anxiety-like behavior in mice. Running decreased the expression of connexin-36, a critical component of neuronal gap junctions, in hippocampal interneurons, suggesting that reduced anxiety-like behavior in runners may occur through decreased gap junction signaling.

Overall, my results suggest that although running stimulates the proliferation of new neurons in the ventral hippocampus, heightened GABAergic function in runners prevents the activation of these new neurons in response to stress. Increased GABAergic signaling and decreases gap junction-mediated signaling within the ventral hippocampus of runners may mediate running-induced decreases in anxiety-like behavior in mice.