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Chapter 8:  What is causing brain atrophy in depression?
The role of stress hormones
(Updated 12/2005)

Summary:   Stress hormones, including cortisol in particular and probably CRH as well, lead directly to the cellular atrophy we have been looking at in the last two chapters.  This chapter shows you (or reminds you) where these hormones come from and how they are controlled:  the hypothalamus, the pituitary, and the adrenal gland (sometimes called the HPA axis).  

Acknowledgement:  This 12-chapter series began with a quote ("findings such as these support the frequent uphill battle ... convincing others this is a real biological disorder") from Robert Sapolsky.  He is one of the main researchers who developed the story presented in this brief chapter.  He wrote a great book (also in plain English) about all this, entitled Why Zebras Don't Get Ulcers, updated in 1998.  As you can tell, he has a great sense of humor as well as one of the greatest understandings of "chronic stress" effects of anyone on the planet.  The story told here has unfolded from his basic research on African baboons and other creatures not as stressed as we humans.

Link to Chapter 9


Perhaps we better start by defining "stress?"  Nahh... Too boring, and you already know two main types.  First, there's sudden emotional stress:  someone runs out into the street from behind a parked car, right in front of you.  You jam on the breaks, almost hitting him.  A second or two later, knowing that everyone is all right, you feel your heart pounding hard, and fast; you feel jittery, and your hands almost tremble; and you have this rushing feeling in your head -- right?  Maybe you've had this with a near-accident on your bike; or a next to a rushing subway car.  But you can imagine that you'd surely have such a reaction if you were charged by a grizzly bear, towering nearly twice your height.  You'd coil up ready to slug him right in the chops, right?  Well, okay, maybe you'd be more like me, looking for any place you could run.  

You know the "a rush of adrenalin" feeling I'm talking about.  This is a well-known type of stress: sudden, brief, then resolved (hopefully with all limbs intact). 

The second kind of stress is rather the opposite:  slow, sustained, unresolving.  A job you can't afford to quit, where you get yelled at no matter how hard you try to do it right; a loved one who is suffering, and there's nothing you can do to fix it; a relationship that could fall apart at any moment, where you can't seem to make things more stable; or more responsibilities than you can possibly keep up with, yet people are counting on you not to fail them, and you don't want to fail them. 

Sorry, did I make that a little too graphic?  You probably know such stresses all too well also.  This is the so-called "chronic" stress (as opposed to the near-accident, or near attack -- an "acute" stress). 

Our bodies are built to handle the acute stress.  It's the chronic ones that get us.  Those are the ones which are associated with depression, particularly when you repeatedly face a bad situation with little ability to control it (the so-called "inescapable" stresses, which can lead to a sense of being helpless).  This is oversimplified, to be sure.  We must not forget that how we perceive a stress can have as much or more impact on us than the situation itself.  This was emphasized in Buddhist and Greek philosophy long before "cognitive therapy", which relies heavily on this principle, came along.  Which has more impact, the stressful event, or the way the person looks at that event?  I hope by now you're beginning to think that perhaps the answer to this question might depend, in part, on which genes the person inherited... If you've already figured out that it's the way a stress is perceived that matters, then you understand one of the most important principles of psychotherapy -- although using that principle to your advantage is a lot harder than understanding it, as you probably have also discovered.  

All right then, back to the subject of stress, so we can get on to looking at the stress hormones. For now, let's just say (simplifying the life work of numerous researchers and clinicians in a single sentence, a minor criminal act) that chronic stress, the kind that goes on and on, and which is difficult to escape -- is directly tied to the origin of depression.  How?  At least part of the answer lies in the action of stress hormones on the brain.  Let's see which ones. 

Stress Hormone Control
There are several hormones involved in responding to stress.  First, there's epinephrine, also known as adrenalin.  You knew once, but may have forgotten, that adrenalin comes from the adrenal glands.  Right? you've forgotten your Latin? Ad -- next to; and renal -- kidney; here they are:

However, the adrenal glands also make another stress hormone, which comes from the outside, or cortex of the gland -- thus the name "cortisol".   Where adrenalin (epinephrine) is the hormone released when you face acute stress, like a near accident, cortisol is released in the face of more prolonged stress.  It mobilizes your fuel stores and adjusts your immune system, as well as some more subtle effects on how your brain is operating.  

But the adrenal glands are mere privates in the armed forces of stress.  They do what they are told.   Who is in charge here? 

Stress Hormone Anatomy

To find the sergeants and generals involved, we're going to look upstairs in the brain. No worries, this is pretty simple, even if you've never been here before.  On the left below, there's a look at the middle of the brain.  If you don't have the slightest idea of what you're looking at but would like to know, try the Brain Tour on Mood.  It will walk you through this same view. 

On the right, you see a diagram, from the same viewpoint, showing two structures involved in stress hormone control: the pituitary gland, and the hypothalamus.  These are colored in, on the photograph of the real thing, in the next picture. 


With me so far?  I just wanted you to see that these structures are right in the center of things in the brain.  (For a closer look at details of hormone control anatomy, try the Brain Tour of the Hypothalamus.  Then next image shows a diagram from that Tour.  

 Look closely  and you'll see the pituitary hanging on its stalk below the hypothalamus, now shown with all its subunits, in an image we'll use below (you're still with me now, aren't you?) Anatomy lesson over: you've seen all the major players in the stress system: the adrenal gland, the pituitary gland, and the hypothalamus.  Now let's look at the molecules they use to communicate. 

Stress Hormone Control
(Updated 12/2005)

From here we'll focus on cortisol, as that is the stress hormone many people have heard of, and stress hormones are clearly involved in depression. However, please understand: this whole system is vastly more complicated than just "too much cortisol is bad". As you'll see here, cortisol is controlled by a brain system regulating stress responses, including a very important compound called corticotropin releasing factor (CRF). Current research suggests that CRF is extremely important in depression, and probably merits at least as much attention as cortisol in the role of good-guy-turned-bad-guy when stress is constant instead of short-lived. Here's how CRF and cortisol are related. 

Cortisol release by the adrenal glands is controlled by two other hormones. Notice that this whole stress hormone business originates in the hypothalamus, in the center of the brain, not in the adrenal gland.  

Like soldiers in an army, organized by rank, the commander -- the hypothalamus -- tells the pituitary what to do via CRF (corticotropin releasing factor).  The sergeant -- the pituitary -- responds, via ACTH (adrenocorticotropic hormone), by telling someone else what to do, namely the adrenal gland.  As in any well organized system of command, the actions of the private are monitored by both levels of command above:  while exerting its actions in many parts of the body, cortisol also acts as a signal back up to the brain, as shown below.

When everything is working correctly, this "feedback" signal is supposed to help the system keep cortisol regulated.  Through as yet unknown events, however, in severe stress states this feedback signal does not seem to effectively regulate the system anymore.  This is a very active area of research, trying to determine what is going wrong there.   

Cortisol and CRF lead directly to the cellular atrophy we have been looking at in the last two chapters.  These are the "atrophic factors", the bad guys -- at least when they are acting in excess somehow.  In smaller or less constant amounts, they are very important regulatory hormones, which are not "bad" all the time.  We'll see them again in Chapter 10, when we try to put together a picture of all the factors involved in regulating cell atrophy and growth.  

As of 12/2005:  For now, this story of the underlying chemical basis connecting stress and depression ends here. If you're following this story closely, I hope that you're frustrated: stop now? We're just getting to the most important part, right? If depression has a chemical basis, and it starts way back here (not at the level of serotonin, for example, which is some distance downstream from here), then this is where we should be looking for "root cause" prevention and treatment. And we're going to stop here?  Sorry, this is the end of the line for now. Beyond this, the research teams are working very hard but the implications are murky. 

For example, there are two different kinds of CRF receptors in the old part of the brain where CRF and serotonin probably connect in this depression story (the brainstem; specifically, a location that is sort of "serotonin central" called the dorsal raphe). CRF1, when it receives a CRF molecule, seems associated with the immediate responses to stress (fight or flight responses). CRF2, however, binding the very same CRF molecules, is the one that may be associated with the "passive response strategies" characteristic of depression. In some ways, these two different receptors for the same hormone/transmitter cause opposite responses.  To oversimplify, CRF can thus be a good guy and a bad guy; the difference between the two effects appears to occur at the level of these receptors, and the factors which modify how much each is affecting behavior. (This is the work of the Center for Behavioral Neuroscience at Emory University, which at present is one of the world's most important centers for this kind of research. The CRF2 story here comes in part from the work of Jom Hammack and colleagues, for example). 

But finally, let's turn to the good news, the molecules with the opposite actions -- the "trophic factors".

On to Chapter 9