Wednesday, June 04, 2014

Mice, learned helplessness, navy seals, depression (in no particular order)

This morning Tord Helsingeng in Norway posted an interesting piece to the Dermoneuromodulation group on Facebook:

Stress and the susceptible brain(1), by Bethany Brookshire, aka Scicurious, about a paper(2).

Here's the story:
1. The objective is to unravel depression.
2. Mice were put into cages with floors that shocked they little tiny tender feets, randomly, for an hour. They had to endure this for two days straight. Then they were allowed a place to escape to.
3. Eighty percent (80%) of the mice dove for the escape route; 20% didn't bother. These ones also lost weight and didn't appear to have much fun anymore.
4. The 80% that escaped were considered "resilient", i.e., could "still change their behaviors in response to stress", while the 20% that didn't bother were considered "susceptible", and a model for depression.
5. Here is the abstract:
When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical–genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.

Tord wondered why. Excellent question. Why would susceptibility/depression/failure to run away from an obvious stressor be associated with stronger synaptic activity in the medial prefrontal cortex?

When I went to look up medial prefrontal cortex, I found this:

Though depression involves an overall reduction in brain activity, some parts of the brain are more affected than others. In brain-imaging studies using PET scans, depressed people display abnormally low activity in the prefrontal cortex, and more specifically in its lateral, orbitofrontal, and ventromedial regions. And the severity of the depression often correlates with the extent of the decline in activity in the prefrontal cortex.

Wait... my bold. Isn't "low" the opposite of "stronger"? 
Or maybe: if the synapses are stronger, they don't have to be as active to ferry around the same amount of information. So the brain can make do with less activity and still know what it's doing.
Also this:
One of the regions of the prefrontal cortex that is most affected both by depression and by the manic phase of manic depression is the ventromedial cortex (also known as the subgenual cortex, because it sits beneath the genua, or knee, of the corpus callosum). This area deep inside the frontal lobes, on either side of the centre line separating the two hemispheres, lets us switch from one kind of affect to another. It is also heavily involved in feelings of pleasure and positive reinforcement.

Wait... pleasure?
Isn't this a contradiction? Would the 20% of mice who grimly stuck out the foot shocks be enjoying it?

I couldn't find anything about a dorsomedial prefrontal cortex in Brain from Top to Bottom, so I googled.. found this:

The PFC can be divided into ventromedial and dorsolateral regions, each of which is associated with posterior and subcortical brain regions. The ventromedial PFC (vmPFC) has reciprocal connections with brain regions that are associated with emotional processing (amygdala), memory (hippocampus) and higher order sensory processing (temporal visual association areas), as well as with the dorsolateral PFC (dlPFC). The dlPFC has reciprocal connections with brain regions that are associated with motor control (basal ganglia, premotor cortex, supplementary motor area), performance monitoring (cingulate cortex) and higher order sensory processing (association areas, parietal cortex). The vmPFC is well suited to support functions involving the integration of information about emotion, memory and environmental stimuli, and the dlPFC to support the regulation of behaviour and control of responses to environmental stimuli....

According to the SEC framework, counterfactual reasoning about action versus inaction preferentially recruits the dorsomedial PFC (dmPFC). Several neuroscience studies have implicated the dmPFC in the continuous internal monitoring of action (Botvinick et al. 2004). Barch et al. (2001) report an extensive meta-analysis of functional imaging studies that included data from a broad range of action monitoring tasks (e.g. involving the inhibition of prepotent responses) that recruited the dmPFC. Along the same lines, Waltonet al. (2004) observed activity in the dmPFC when participants monitored the outcome of self-selected actions. These findings suggest that the dmPFC is critical for monitoring the addition versus subtraction of actions for counterfactual reasoning. 

So... trying to figure out the mice business, none of the authors are clear about which bit, ventral or dorsal, they are examining. Maybe in mice there isn't enough in there to subdivide. Or maybe there is and they didn't. 

I have yet to fathom all that, but in the back of my mind I keep thinking about Navy Seals, what they have to go through in their training, how the situation is designed to weed out anyone who caves to the stress, who can't take the combination of socially imposed stress and physical stress.

"If you want to change the world, start by making your bed."

(Then, find people to help you paddle, measure people by the size of their heart, not their flippers, get over being a sugar cookie, don't be afraid of circuses, learn to slide down an obstacle head first, punch sharks right in the nose, don't lose it in the darkest moment, when you're up to your neck in mud, sing, and don't ever ever ring the bell.)

Maybe those little mice were doing their own version of navy seal training. Maybe they were inhibiting their own behaviour because that way, they could "enjoy"(if that's the right word..) maintaining an internal locus of control. 
Maybe the mice that headed off for the escape hatch were being driven to it by the external locus of control, handlers, which in human terms might be the equivalent of external "society" - an Other-Determined locus of control. Maybe the 20% who stayed put were thinking, screw you, I'm going to stay right here - this isn't so bad, I'm used to it now. Those jerks think they can make me go toward that spot where 80% are going, but I'll show them I'm different/I'm tough/ I'm an individual/I'm no sissy/I can take whatever they dish out/eff them - how much worse could it get?

Speaking of mouse handlers, it has come up that mice respond to the sex of the handler. If the handler is male, mice will not exhibit the same sorts of behaviours as when the handler is female. I.e., they don't exhibit "pain" behaviours. Even their chemistry (descending modulation) is different. 
So there is another twist. We don't know what sex the handler is in the "depression model" study, not from the abstract at least..


1. Brookshire B; Stress and the susceptible brain. Scicurious ScienceNews blog June 3/2014

2. Wang M, Perove Z, Arenkiel BJ, Li, B; Synaptic Modifications in the Medial Prefrontal Cortex in Susceptibility and Resilience to Stress. The Journal of Neuroscience, 28 May 2014, 34(22): 7485-7492

5. Parrish S; 10 Life Lessons From a Navy Seal. Farnam Street blog, May 27/2014

6. Brookshire B; You smell, and mice can tell. Scicurious ScienceNews blog May 2/2014

7. BIM: Of Mice and Men - Jeff Mogil on Grimacing, BodyInMind blog May 21/2014

8. Robert E Sorge, Loren J Martin, Kelsey A Isbester, Susana G Sotocinal, Sarah Rosen, Alexander H Tuttle, Jeffrey S Wieskopf, Erinn L Acland, Anastassia Dokova, Basil Kadoura, Philip Leger, Josiane C S Mapplebeck, Martina McPhail, Ada Delaney, Gustaf Wigerblad, Alan P Schumann, Tammie Quinn, Johannes Frasnelli, Camilla I Svensson, Wendy F Sternberg, & Jeffrey S Mogil; Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature Methods 11, 629–632 (2014)

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