After learning about PTSD last week, I found myself thinking about how people with PTSD react to stressful and traumatic situations if they experience these events again, or just how they deal with stress if they are already in a depression. So I found this article that by Izquierdo, Wellman, & Holmes (2006) on the effects of stress on dendritic retraction in mice after they have gone fear conditioning and fear extinction training. The fear conditioning/extinction is supposed to mimic the traumatic event/therapy. Previous research has shown that the medial prefrontal cortex (mPFC) is implicated in fear conditioning, and that it is activated in both humans and rats during fear extinction. Previous research has also shown that lesions to the mPFC cause a deficit in extinction learning, and that stimulation of the mPFC mimics the effects of extinction learning through neural outputs to the amygdala. As such, the researchers wer looked to see if stress-induced changes in mPFC function would impair fear extinction. In relation to PTSD, patients have been found to have smaller mPFC volumes as well as a mPFC that is less activated during fear extinction than normal controls.
First they performed an uncontrollable stress paradigm, forced swim test for 10 minutes either 3 consecutive days, 1 day, or no days (control). Then, 24 hours after the force swim, they were subjected to the fear conditioning paradigm, using footshock. Then, 24 hours later, mice were subjected to fear extinction, in which they are placed in a novel context compared to the conditioning paradigm. The extinction process was 40 footshocks (the conditioned stimulus). Another 24 hours later they were tested for context recall, and then killed for brain retrieval.
They found that there was no effect on the fear conditioning no matter what type of stress they had undergone (0,1, or 3 days). However they found that freezing behavior during extinction was significantly effected by stress. It also took mice who had 3 days of stress significantly longer to reach criterion of extinction conditioning then the other 2 conditions. They also found in the infralimbic cortex that stress significantly decreased the length in the apical branches of the pyramidal neurons in that area.
this is a golgi staining, and the thick vertical dendrite that extends vertically upwards is the apical branch (thought I’d give you a visual). This study showed that exposure to uncontrollable stress before fear conditioning impaired fear extinction in mice, meaning that stress produces a selective deficit in fear extinction instead of effecting fear conditioning (aka impairing learning and memory). They further suggested that:
the finding that even brief exposure to a sufficiently stressful event can cause resistance to fear extinction provides a novel model of stress-induced psychopathology in neuropsychiatric conditions characterized by impaired extinction, such as PTSD.
4 thoughts on “PTSD: lots and lots of STRESS!!!”
Hey Natasha! I think that this is a really cool article. It sounds like chronic stress will make it difficult to unlearn negative associations. I also like the inclusion of the mPFC lesions, but I wonder if all of this relates to the amygdala and the hippocampus as well. Specifically, a lesion of the mPFC might make it more difficult to extinguish the negative association; however, would a lesion of the amygdala paired with a mPFC lesion ameliorate such deficits? The amygdala helps encode emotional memories and plays a large role in emotional processing. Without the amygdala, negative associations may be harder to learn and easier to forget because the brain will no longer be able to pair emotional salience with the stimulus. Just a thought for future directions…
The interaction between the mPFC and amygdala is likely mediated by hippocampal processing of memory. The interactions between these structures are complex. There is a timing issue as mPFC lesions prior to a conditioning-extinction paradigm have little effect on the later development of extinction; however, mid-point lesions impair the development of extinction.
To further complicate interpretation of the the research, the extent of lesioning of the mPFC will also affect the development of extinction. Extinction is dependent on the most ventral portion of the anterior cingulate; fear expression is dependent on more dorsal areas of the same structure.
And there are two more variables, developmental stage and genetic vulnerability. Infants of any species are more vulnerable to stress as they are not yet wired to cope with stressors (and more vulnerable to developing childhood symptoms of stress, e.g. ADHD). Some individuals are born with polymorphisms in their 5-HT and DA systems that when stressed allow expression of conditions like PTSD. Seeing and understanding the whole picture is quite a challenge.
But yes, I think that we can conclude that PTSD is a failure of the development of extinction of overwhelming stress. Fortunately prolonged exposure therapies help to facilitate hippocampal memory processing and the eventual extinction of overwhelming responses to stressful experiences.
It would be interesting to look at this on a more behavioral level as well. I hate to keep going back to the stereotypical war vet PTSD, but I think that people going to war could potentially be a good subject pool because there are so many of them. Assessments of previous life stressors/overall stress level could be administered prior to deployment, and then correlated with PTSD levels when those individuals return from war, whenever that may be.
In line with the suggestion that prior experience of chronic stress makes it difficult to unlearn negative associations could be a possible explanation based on neural plasticity, or lack there of. It is possible that this chronic stress reduces both behavioural and neural plasticity. Because the brain is now less capable of being flexibly resilient to the effects of subsequent stress, the negative associations made thereafter are more permanently ‘fixed’in the brain. These eventually reflect in behaviour too. Thus the decrease in neural plasticity is what serves as the basis of resistance to the eradication of the fear response.