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Chapter 7: Why do some parts of the brain atrophy during major depression? 
    Cell shrinkage, and fewer new cells

Summary
In Chapter 6 we saw that severe mood symptoms are associated with hippocampal shrinkage (atrophy).  In this chapter, we look at what is happening inside the hippocampus (and probably also in the frontal lobes) that leads to this shrinkage.  The answer includes both a reduction in cell size, and also in cell number.  The reduction in number is associated with the slowing or stopping of a process called neurogenesis, the birth of brand new brain cells (yes, this really does occur, even though for years we thought otherwise).  There are some amazing photographs of neurogenesis in this chapter, as well as evidence that it is inhibited by mood symptoms.  

Acknowledgement
This chapter describes work of many different researchers over a long period of time.  Some of the most spectacular work, full of implications for this entire story, was published recently by Dr. Luca Santarelli and colleagues.  Dr. Ronald Duman of Yale University was one of the principal researchers leading off this line of investigation.  

Link to Chapter 8


As discussed in Chapter 6, there is large-scale shrinkage of important brain areas when a person (or in the images you'll see here, a rat) is stressed.  In this chapter, we'll look at how that shrinkage is occurring. 

There are two main ways that the brain is losing volume under stress:  existing cells shrink, and the total number of cells decreases.  The same brain chemistry seems to be involved in both of these processes.  We'll look at the full story of those chemicals in Chapter 10.  Here, however, you'll see evidence for each of these two brain-changing processes:  shrinkage and cell number reductions.   

Cellular Shrinkage
Brain cells need to stay active to maintain their connections with other neurons.  These connections, the cell-cell junctions called synapses (more on synapses, if you need a review, can be found in Chapter 9), actually disintegrate and disappear if a cell does not use them to communicate.  You can see this shift from active and connected, to inactive and much less connected, in the following pair of pictures (taken through a microscope, obviously): 

The cell in the foreground on the left has many more branches off the main arms projecting upward, compared to the cell on the left.  Although we cannot see synapses at this magnification, the branches shown here would each likely have many hundreds of synaptic connections to other neurons.  So the dramatic reduction in the total number of branches that you can see here can mean the loss of hundreds or even thousands of synapses.  

Cell Number Reductions

There is another process that may be as or more important brain volume changes during mood disorders.  If you're over age 15 or so, you can probably remember being told that your brain doesn't grow any new neurons; that you are born with all you'll ever have; and that therefore you'd better not drink alcohol in excess because each time you do, you're losing brain cells forever; etc. etc.  Heard that one?

When I went to medical school one of our professors inspired great confidence in us all by announcing -- I think it was the very first day of classes, actually -- something like this:   "half of everything you are going to learn in the next four years is wrong.  We just don't know which half."  Well, this business about not growing any new brain cells turns out to have been in the half that was indeed wrong.  Your brain does grow new neurons, it does so all the time, and when that rate of "neurogenesis" goes down, your brain can shrink.  This is because there is also a constant process of cell death going on as well. New cells growing up here, old cells dying off there:  this is how the brain reshapes itself with new life experiences.  You may know that the word "plastic" has several definitions, including able to be molded; and adapting easily and readily to change.  Thus the label for this brain-changing balance between neurogenesis and atrophic processes:  "neuroplasticity".

So now we have two things to examine, in relationship to this loss of cells: first, you must see the evidence for neurogenesis, because this is just beautiful science.  But then you'll see evidence which suggests that neurogenesis may actually be crucial to the way antidepressants of all kinds, including perhaps even exercise, actually work.  Since most of this research has been done on rats, first we'll need to learn some rat brain anatomy.  Pardon me?  You're thinking about giving up on this story at this point?  Oh, don't do that now.  Scroll down and have a look at some of the pictures first.  When you know what they mean, you're going to have a new appreciation for your brain, I daresay. 

Neurogenesis
Learning that our brains really do make new neurons was a stunning change in view.  If you're here to learn about depression, you may not want to hear the longer story of the discovery of human neurogenesis.  I'll just take you through a few photos about it. 

The next set of pictures all show mouse hippocampi.  You don't need to know the precise anatomy to follow the story, but if you really want to know just what you're looking at, here's a brief explanation of mouse hippocampal anatomy as it relates to these photos.

First, let's see what neurogenesis looks like.  In the following pictures, you can see neurons which have just been "born".  The arrow tips each point at a little tiny black dot.  That's the nucleus of a brand new cell (see the long version to understand how we know that).

In the photo on the left, the rat was allowed to live a normal rat life.  In the photo on the right, the rat was "restrained", which rats don't like.  The result of this rat stress is obvious in the photo:  there are far fewer new cells growing here, right?  Poof, almost no new neurons, just from having been stressed. 

This is one of the most important points in this chapter, perhaps in the entire set of chapters, so I'll restate it.  Stressing a rat by restraining it, if done long enough, will cause the rat to become "depressed" (with obvious behavior changes such as failing to explore new environments, or interact with other rats).  In the pictures above we see that stressing a rat also causes hippocampal neurogenesis to decrease, almost to a halt. 

Adding these results together (two plus two equals...) led some researchers to wonder if this slowing, almost stopping, of neurogenesis might actually be the cause of the depression.  One such investigation is now quite widely known, having been published in the prestigious journal Science in late 2003.  In the process of their research, Dr. Luca Santarelli and colleagues produced the following beautiful image, in which you see green "stem cells", which divide and then develop into new neurons, stained here in blue. 

Dr. Santarelli's team conducted a series of experiments.Santarelli  They subjected mice to a daily stress (restraint).  From previous research, it is well known that if mice are injected with the antidepressant fluoxetine (Prozac), they do not show the mouse equivalent of depression when subjected to stress.  But in this work, Santarelli's group took that result one step further:  they showed that Prozac also protected the mice from a decrease in hippocampal neurogenesis. 

So far, then, we have the following results:

Experiment Behavior Hippocampal Neurogenesis
Stress Alone Depressed Decreased
Stress Plus Prozac Normal Normal

Then they took the work yet one more step:  they gave another set of mice a dose of x-rays to the brain, as well as fluoxetine, before they were stressed.  The x-rays were strong enough to kill the new neurons in the hippocampus.  The result:  these mice became depressed.  Fluoxetine did not protect them, as it did the mice who had not received the x-ray treatment. 

So now we have:

Experiment Behavior Hippocampal Neurogenesis
Stress Alone Depressed Decreased
Stress Plus Prozac Normal Normal
Stress + x-ray + Prozac Depressed (decreased by the x-rays)

Here then is the key result:  without neurogenesis in the hippocampus, there was no protective effect from the antidepressant.  The implication is that antidepressants work by promoting neurogenesis.  When that mechanism in the brain was blocked (in this case by x-ray treatment, before the animal went through the stress), the antidepressant--which had been very effective in other mice not receiving x-rays -- was not effective. 

Although this research has has not yet been fully confirmed, nor shown in humans, it is completely consistent with another very large set of research results, produced by an entirely different research approach.  This is very encouraging, substantially raising the likelihood that other research will confirm the results of Santarelli and colleagues.   That other line of research will be presented in Chapters 9 and 10.  But to understand the "big picture", coming in Chapter 10, we need to look first at the molecules involved in the "stress" process, which now appear to be directly involved in causing depression.  Please take the...

Link to Chapter 8.