These diaries on post-traumatic stress disorder have obvious interest to some folks who either have PTSD or know someone who has PTSD, which I take extremely seriously, so I would like to offer a few caveats. First, it's difficult to avoid evocative subject-matter when discussing stress. These diaries are meant to educate, not inflame or offend. Second, I am not a clinician. While I do stress-related research, these are my opinions on PTSD, as I indicated in my very first diary on the subject "Compound F’s theory of PTSD." I try to keep my opinions in the mainstream of published research. One opinion that is not mainstream: I find it questionable to call PTSD a "disorder," because natural selection would suck to allow organisms to forget traumatic experiences easily. One could make a strong argument that remembering the situations, causes, and evocative stimuli related to trauma according to its severity is quite adaptive. Finally, people sometimes goof off in threads to decompress, but not usually out of disrespect for the subject matter. Comments on topic are great, but goofing about is also healthy. I have yet to see anyone on this site show disrespect for victims of trauma, and I am sure it won’t be tolerated. Caveat lector!
Previously, I bored you to tears with an extremely tedious piece on associative learning, and in particular, some key neural pathways mediating value-laden, or emotional memories, a piece so intensely dull that I’m sure it has been entirely forgotten. In this diary, we will amplify that tedium to unbearable, near-doldrum-like levels, hopefully punctuated with little moments of memorable excitement. In particular, we will discuss how stress-related molecules amplify the formation of memories for emotional, but not non-emotional events.
Adrenaline
Brainstem adrenergic and noradrenergic (e.g., adrenaline) systems are critically activated by emotionally arousing events and play a key role in emotional memory formation. To demonstrate this in humans Cahill et al (1994) gave normal human volunteers one of two stories to read, a run-of-the-mill non-emotional narrative and a matched, similar but emotional (and somewhat graphic!) narrative. In addition, half of each group was given adrenergic blockade (propanolol) or a placebo tablet prior to reading the story. Below are the matched sentences of each narrative for your perusal. The first sentence in each pair is the sentence from the emotionally neutral story, while the second is from the emotionally charged story. Notice that, in the beginning and the very end, the sentences are perfectly matched, whereas in the middle they differ primarily in their emotional impact.
A mother and her son are leaving home in the morning.
A mother and her son are leaving home in the morning.
She is taking him to visit his father’s workplace.
She is taking him to visit his father’s workplace.
The father is a laboratory technician at Victory Memorial Hospital.
The father is a laboratory technician at Victory Memorial Hospital.
They check before crossing a busy road.
They check before crossing a busy road.
While walking along, the boy sees some wrecked cars in a junk-yard, which he finds interesting.
While crossing the road, the boy is caught in a terrible accident, which critically injures him.
At the hospital, the staff are preparing for a practice disaster drill, which the boy will watch.
At the hospital, the staff prepare the emergency room, to which the boy is rushed.
An image from a brain scan machine used in the drill attracts the boy’s interest.
An image from a brain scan machine used in a trauma situation shows severe bleeding in the boy’s brain.
All morning long, a surgical team practiced the disaster drill procedures.
All morning long, a surgical team struggle to save the boy’s life.
Make-up artists were able to create realistic-looking injuries on actors for the drill.
Specialized surgeons were able to re-attach the boy’s severed feet.
After the drill, while the father watched the boy, the mother left to phone her other child’s pre-school.
After the surgery, while the father stayed with the boy, the mother left to phone her other child’s pre-school.
Running a little late, she phones the pre-school to tell them she will soon pick up her child.
Feeling distraught, she phones the preschool to them she will soon pick up her child.
Heading to pick up her child, she hails a taxi at the number nine bus stop.
Heading to pick up her child, she hails a taxi at the number nine bus stop.
About a week after reading these stories, the human subjects were given a recall test for items in their respective stories. The vertical axis shows percent recall, whereas the horizontal axis shows memory for different parts (beginning, middle, or end) of the story. The first graph shows memory for the boring neutral story:
Recall is moderate, and there is no effect of the beta-adrenergic blockade on recall for any portion of the story. Now, look at recall for the arousing story. Note that the placebo group shows enhanced recall of only the portion of the story that crossed into emotionality, and that this effect was blocked by gumming up the adrenergic receptors. In addition, it didn't impair recall of the un-emotional parts of the story, so the effect was specific to emotion, not a general effect.
This is just the type of mechanism one would like to see in a well-designed organism: A mechanism for creating arousal for emotional events is also working to enhance encoding of that event in long-term memory. From rat studies we know that the locus of this enhancement is the amygdala, a major repository of value-laden associations. Some studies suggest that peripheral adrenaline release that gives one "butterflies" may also activate the sensory vagus nerve, which then stimulates the ascending noradrenergic bundle in brainstem to release adrenaline into the amygdala. It's also worth pointing out that stimuli used in this memory experiment were fairly benign and vicarious compared to true traumatic experience, but it nonetheless illustrates the point that mechanisms of arousal and memory formation are intimately related.
Corticotropin Releasing Factor
Another system activated by stressors is the brain CRF networks controlling anxiety, including CRF in the central nucleus of the amygdala. Among other CRF networks, amygdala CRF promotes activity in brain arousal systems, as well. Not surprisingly, CRF not only promotes anxiety and arousal, it is also involved in the formation of emotional memories.
One way to study this system in rats is to force them to associate a context with an acute stressor, such as putting them into a specific context and giving them a brief electrical shock to the foot. The diagram below depicts a two-compartment apparatus having a bright compartent and a dark compartment. Rats naturally prefer darkness. In training (top panel), as soon as they step from the light to dark, they receive a brief footshock. Two days later, memory is tested (lower panel) by placing the rat into the bright compartment. The time it takes for them to step into the dark compartment (without shock) is used as a measure of memory, with longer latencies suggesting stronger associations between the dark compartment and the stressor.
Here's a cartoon of data from Roozendaal et al (2002) showing what happens to memory for stressful experience when the CRF molecule is prevented from activating its receptor by infusing a receptor blocker into the cortical amygdala. The saline infusion (lavender) shows the normal hesitation rats show in stepping back into the stressful context under conditions of a low footshock (left panel) and a high footshock (right panel). Clearly, the magnitude of the stress alters the strength of memory.
The green bars show what happens when escalating doses (shown on the horizontal axis in micrograms) of the CRF receptor blocker are infused into the cortical amygdala immediately after training. Under both low and high footshock, increasing doses of CRF blockade cause the animal to seemingly forget about the association between the context and the shock, as they show much reduced hesitation to step back into the dark compartment. Once again, a neuromodulator that is acutely elevated by stress also plays a role in encoding the memory for that event. This effect receptor blockade is specific to the cortical amygdala, not the central nucleus.
I know what you're going to say: "Compound F, quit twisting my knickers! It's the central nucleus that produces the CRF, and its projections to the cortical aspect are extremely sparse. How does the CRF get into the cortical part of the amygdala?" Bascially, while the brain has tons of wiring to direct specific substances to very specific places, it also acts like a soup: Passive diffusion.
"Horsefeathers, Compound F, because why doesn't the antagonist also diffuse into cortical amygdala, thus making the effect not-detectable as specific to the cortex?" The antagonist is less soluble, and just doesn't diffuse as easily as the endogenous molecule. Good question, though.
Glucocorticoids
Finally, a discussion of stress-induced memory would not be complete without looking at the effects the adrenal steroids on the formation of emotional memories.
There have been many demonstrations of positive effects of elevated steroid on emotional memory. In this study (Thompson et al 2004) gave rats twice-daily injections of steroid to keep levels artificially elevated, or they gave them vehicle injections. You'll recall that chronically elevated steroid mounts central stress networks with some lasting effects. Immediately after the first injection on the sixth day, rats were placed in a box a received a single footshock. About a week later they were tested for how well they remembered the box by measuring how much they froze during testing. They subtracted freezing during the test from the amount of freezing in the immediate aftermath of shock to show the decrement in freezing. The greater the decrement, the more forgetting was assumed to have occurred during the week, whereas the smaller the decrement, the stronger the memory for stress. Here are the results:
Rats that were treated with steroid show much smaller changes in freezing behavior than rats treated with vehicle. So, once again stress hormones elevated in the the aftermath of stress facilitate the formation of emotional memories. And where is the likely site of action? You guessed it: the amygdala. Below are autoradiographs showing CRF mRNA in the central nucleus of the amygdala in control (top panel) and steroid-treated animals (bottom panel). There is no contest: Steroid treated animals show a massive upregulation of CRF mRNA, which is the template that produces the protein that causes anxiety, stimulates arousal systems, and helps promote the formation of emotional memories. The image has been inverted so you can see how the amygdala "lights up!" with stress.
The point is that all these systems can not only independently influence the formation of memory in parallel, they can mutually stimulate one another serially, as well, thus causing synergistic amplifications of emotional memory. Sure, it's a little more complicated than that, but that's the basic take home message.
Oh. Reading can be relaxing.