Feeling anxious? Run it out!

When life isn’t going well, I go for a run. I’ve always found running soothing. Maybe it’s due to “runner’s high”, the burst of endorphins that dampen physical pain and elevates mood. Maybe it’s because running increases the generation of new neurons in the brain (of mice), which we think is protective against depression.

Or maybe, as this new study shows, it’s because running tweaks the brain’s inhibitory circuits to directly dampen anxiety.

Schoenfeld et al. (2013) Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus" J. Neurosci. 33(18):7770-7777

Let’s first zoom in on the ventral hippocampus deep within the brain. This is one of the areas that process emotions, and is implicated in stress and anxiety regulation*. Increased activity in the ventral hippo is correlated (but not causative of) with anxious behaviour. Since running decreases anxiety, researchers wanted to know if runners’ ventral hippo respond differently to stress than sedentary people, in such a way that dampens anxiety.

(* You might remember the hippocampus is important for learning and memory – you’re right! However, increasing evidence is pointing to the dorsal hippo as the processing power behind memory. The hippo is quite a multitasker!)

Elevated plus maze. I even find it scary! Source: http://www.cidd.unc.edu/

Since directly monitoring brain activity at the single neuron level from people is impossible, scientists turned to mice. If you ever had a pet hamster, you know that rodents love to run – give them a wheel and they’ll go at it for hours. After 6 weeks of voluntary running, scientists placed these mice onto an elevated maze with two dark closed arms and two light open arms (imaging a cross-like mountain with cliffs at the ends, pic left). Runners showed significantly less anxiety as they explored the open “cliffs” than their sedentary peers. They also had more newly born neurons in their brains.

So running decreases anxiety, but is it through lowering hippocampus activation? To tackle this question, scientists exposed the mice to cold water. If you’ve ever tried a New Years polar bear swim, you’ll know that swimming in cold water is very stressful. Indeed, in sedentary mice, cold-water stress caused a spike in neuronal activity in the ventral hippo, as measured by a set of genes that transiently and rapidly get turned on in response to neuron activation. These immediate-early genes act as messengers to tell the neuron to start making proteins to adapt to the stimulus, and are a reliable sign of recent neuron activity.

As you can see below, couch-potato mice showed a spike in neuronal activity (Sed, black bar with a star), as measured by immediate-early genes c-fos and arc. This response was almost completely wiped out in the runners (Run, black bar with no stars). So running decreases ventral hippo’s willingness to react to stress, leading to less anxious behaviors. But how?

The activity of neuronal circuits is mainly balanced by two antagonistic neurotransmitters: glutamate-mediated excitation and GABA-mediated inhibition. Most anti-anxiety meds right now work by increasing GABA signaling. Researchers found that runners had significantly more GABA neuron activation when exposed to cold-water stress. These mice also released more GABA neurotransmitter, especially during the period of stress (see the peak in the black line below?). So maybe increased GABA in runners is enough to increase inhibition and dampen ventral hippo activity?

One way to test this is to block GABA signaling and see how these runner mice behave. To test for anxiety, researchers brought back the elevated plus maze. As you may remember, this maze has two dark, chill closed arms, and two brightly lit open arms. Usually mice prefer to spend more time in the closed “safe” arms, and this is indeed the case with sedentary mice (white bar). However, runners showed increased exploration of the open “cliff” arms of the elevated maze just like before (black bar). They were way less anxious about the light and openness of those cliff-like arms.

Now, if you block GABA signaling with a chemical called bicuculine in runners, these mice (grey bar above) behaved just like sedentary mice (white bar). Their anxiety returned! Bicuculine only worked when given to the ventral hippo; if you block GABA in the dorsal hippocampus – important in learning and memory but not mood – it didn’t affect the runners’ anxiety levels. These results tell us that increased GABA signaling lowers ventral hippo activation, and this leads to decreased anxiety.

Overall the researchers pretty convincingly show that running reduces anxiety through activating GABA signalizing in the ventral hippocampus. It would’ve been nice to see how runner vs sedentary mice behaved in the maze AFTER cold-water exposure, ie if running can “immunize” mice against stress-induced anxiety as well. It would also be interesting to see how long this anti-anxiety change lasts once the runners stopped running – does GABA signaling go back or does it stay responsive for a long time?

Regardless, this study gives you another reason to go out for a run and keep running. Try it for three weeks (how much the mice ran) and see if it helps with stress and anxiety. Science says it does.

Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, & Gould E (2013). Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (18), 7770-7 PMID: 23637169