(PTSD: post-traumatic stress disorder)
In a previous diary I briefly discussed how stress can leave physical, sometimes permanent marks on organisms. Then I started at the beginning to discuss the core components of the HPA axis, the function of the daily rhythms of stress hormones, and how normal functioning of this axis in the absence of a stressor, even while providing stress levels of steroid to brain on a daily basis, does not feel stressful. In this diary, I want to move on to the stress response as most people think about stress, as resulting from an acute, salient, and negatively perceived threat. Harry Whittington's shot in the face was a real, life-threatening insult, and the stress response was signaled by damaged tissue in a reactive "bottom up" fashion. The beauty of brains sitting on top of all that peripheral machinery of the body is that response systems can be signaled proactively in advance of actual damage. Simply anticipating getting shot in the face by a predator is a sufficient to raise stress levels in plasma and brain to promote the appropriate avoidance or aggressive responses. That proactive, anticipatory signaling changes depending on how often one is threatened, and how much over-exposure one receives from elevated stress steroids.
Like most males, I’ve had my share of agonistic confrontations with other males. Few have led to physical combat, but the escalation itself is quite stimulating and stressful. In one somewhat traumatic episode, I was taking a crowded Muni train downtown when I see these two young bucks aggressively flirting with and then frankly harassing a young woman. They sat next to her, began touching her, literally falling from the aisle onto her bodily, having a grand old time terrorizing her. She swatted and pushed back at and cowered. Typically, but always amazingly, everyone else on the train looked straight ahead, which further set my teeth on edge, so I got up and got into it. "Get off her!" They turned on me immediately, outraged: "Mother fucker this, mother fucker that. Who the fuck are you? I’m gonna knock you out...." Either one probably could have zonked me, and that would have been it, but it seldom happens that way. Male aggression always starts with displays of toe-to-toe, in your face, yelling and escalation, displays used to size-me-up. It’s perfectly natural to fear losing a tooth, an ear, an eye, even if you’re big and tough. For my part, I anti-displayed, giving them as little information as possible about my potential for danger. Like those guys who play in poker tournaments, the dark sunglasses were helpful. Then the taller buck takes a different tack: "A mother fucker can get killed for coming between a man and his girlfriend." His friend echoes him. It was a bullshit ruse, and I called him on it. "Is he your boyfriend?" She was frozen. Again: IS HE YOUR BOYFRIEND? No, she said. THAT"S IT. SHE IS NOT YOUR GIRLFRIEND. END OF STORY. Then the portly one starts his own tack, jaw-boning about how much danger I was in, and I turned toward him, which was not a great move, because it left the other one at my back with an open shot, but I stuck with facing down the jabbering chubsteak, just hoping I didn’t get clocked or worse from behind. I was in a very bad position, and at this point my stress hormones were raging behind my eyeballs, on a knife’s edge of fear and aggression. That little eternity came to an abrupt end when the train stopped, and they decided they had enough, and walked off, not, of course, without turning and spitting on the back of my jacket as I walked off the other way down the platform. I began to turn back, but then thought better about it, and let that one go. No one got hurt, but it took hours to decompress, and simply recalling it now raises my blood pressure. In this diary, let's follow the critical transformations in the stress response and brain when such stressful encounters happen repeatedly.
The Acute Stress Response
(all images have been redrawn and adapted from originals for illustrative purposes)
Whether a stressor is signaled by bodily reactions or through an increase in threat perception, the final common pathway is:
hypothalamic CRF --> pituitary ACTH --> adrenal steroids --> body & brain.
The following shows ACTH and steroid responses to a non-physical, psychogenic threat in the rat. In this case, the rat is placed into a tube and not allowed to escape. Such restraint is considered to be a psychogenic stressor because it doesn't physically hurt the animal. In fact, rats are natural tunnelers and initially view the tube as a safe harbor. You put the tube in front of its nose, goose him on the hindquarters, and the rat jumps right into the tube. Only after jumping in does he realize he can't get out. That lack of control is the stressor.
Rapid sampling of blood shows how rapidly the brain responds to this perceived threat, with ACTH responses being stimulated in minutes, and the steroid (in rats it's compound B, or corticosterone) being stimulated by ACTH at the adrenal cortex is right on its heels. This neuroendocrine response is slower than adrenaline response that comes in the first heart-beat, but as we will see later, it is critical. Also notice how when the steroid reaches peak levels the ACTH begins to shut off. This is the inhibitory feedback action of the steroid in brain. Of two steroid receptor sub-types in the brain, one receptor has a high-affinity for the steroid and is mostly occupied at all times, whereas the other receptor has a low affinity for the steroid, and only becomes occupied under stress concentrations of the hormone. It is primarily the second receptor that mediates effects of stress as we think of it, and it is the one involved in shutting off the system to avoid excess, prolonged exposure to the steroid. This is the "classic" acute stress response that occurs when, say, two males are escalating threats in a bar without actually fighting.
Changes in Stress Responses after Repeated Stress
If you repeat this process with the same rat, he comes to the realization that, while the experience is unpleasant, nothing truly awful results from being in the tube and the size of the response to that stimulus wanes over subsequent days. Does this habituation of the stress response mean that the rat is over it? He may be getting over that particular stressor, but something has changed in the brain. If you give that same animal a novel stressor, for example, placing him in a new, bright, open space without places to hide (which rats don't care for) the stress response will be instantly renewed, and in some cases will be facilitated, even bigger than before, even bigger than in a naive rat who goes into the bright open space for the first time in the absence of the prior stress. There is something about repeated, chronic stress that changes stress responsiveness.
Facilitation of Stress Responses by Chronic Stress
Here's the first clue. Say you take one group of rats and pump steroid into its brain to elevate the steroid chronically in the absence of stress, but high enough to occupy the low affinity receptor. Another group gets a saline pumped into the brain as a control. Then after several days of elevated steroid you stress them a few times, and look at what happens to activity in the HPA axis:
(adapted from Laugero et al, 2001b)
Recall that after a single episode of stress, elevated steroid in brain shuts off further activity in the HPA axis. However, when the steroid is chronically elevated in brain, activity in the stress axis is now facilitated. Activity in the CRF motorneurons driving the ACTH response is also elevated.
Recruitment of Central Chronic Stress Response Networks
What’s really interesting to me is what happens when stress hormones enter the brain. Let’s look at what happens in brain with acute, short-term elevations of glucocorticoids in the brain. In this case, sheep were exposed to a barking dog, and CRF efflux was measured in the central nucleus of the amygdala, along with venous cortisol (the sheep and human steroid). First, a 20 minute, unstressed baseline is recorded; then the sheep is exposed to the barking dog (a psychogenic threat).
When the dog is introduced there is an immediate rapid increase in CRF efflux in the amygdala that is neurally mediated. This is followed by a slower rise in venous cortisol. Notice that there is a second wave of CRF efflux that parallels plasma (and brain) concentrations of the steroid. In this case, the elevation of steroid in brain is driving the prolonged efflux (as can be shown by similar experiments wherein the experimenter puts steroid into the animal intravenously).
What is the Relevance of Steroid Driving Amygdala CRF?
First, whereas some parts of brain are rather "cold and computational," the amygdala is part of the brain associated with value-laden experiences, and CRF is the neuromodulator that is first and foremost associated with the negative valence, anxiety, edginess, depression, and so forth. Behaviorally, CRF administered in the brain decreases eating and sexual behavior, while increasing freezing, startle and defensive responses, conditioned aversions, and even seizures at high doses. It also increases heart rate, blood pressure, and breathing. In short, CRF is the anxiety attack of neuromodulators.
Finally let's look at what happens to the long-lasting recruitment of amygdala CRF by chronically elevated steroid. In the lower panels, sheep were once again exposed to barking dogs, except this time on repeated occasions over a one week period. During exposure to the dogs, they were either allowed to escape (walk away) or not Then, in testing they were given new type of stressor, an electric shock to the foreleg, and amygdala CRF efflux was measured. Note how in the escape condition, the CRF efflux is reduced, because having control over stressors reduces the perception of threat. Not having control, on the other hand, increases both the neurally mediated phase of the response, and the protracted phase mediated by steroids.
(last two images adapted from (C. Cook 2002, 2004)
Now look at the right panel. In this case, the animals were allowed to escape or not as before, but in addition, during the time they were being chronically stressed by the dog, they were given a drug to prevent the elevated steroid from "unlocking" the receptors in brain. Thus, when they brains were protected from steroid during the original chronic stressor, they were unable to show facilitated CRF efflux in later testing with a new stressor. This pretty thoroughly implicates chronic elevations of stress steroids in brain in the change in brain from normal, acute stress responses to facilitated stress responses following chronic exposure to stressors.
This facilitation and recruitment of central stress networks by chronically elevated steroid is, in my opinion, the critical event in the path to post-traumatic stress disorder (PTSD). There's more, much much more to come. But this is the core event. In later diaries, we'll explore the role of the stress steroid and CRF in driving other critical neuromodulatory systems related to the constellation of PTSD symptoms.