Rerun - Of Mice and Neurons

Two of my recent blog pieces offered a "macro" systems view of the brain experiencing breakdown. Here's a complementary "micro" cellular view I first published in March ...

I simply love reporting on brain science. Perhaps it's because the degree of difficulty is so high that nailing the landing, so to speak, has a way of setting off my dopamine in a highly pleasurable way.

Or maybe it's simply the fact that I love dealing with smart people working on really cool stuff.

About eight or nine years ago, I came across a journal article about how a research team led by Ron Duman PhD at Yale found that antidepressants caused brain cells to grow in the hippocampus.

Brain cells can actually grow? I thought. Then I asked: What the hell's a hippocampus?

We need to go back a year or two earlier when Fred Gage PhD of the Salk Institute discovered that we are not, in fact, stuck with the brain cells we are born with, that new brain cell growth takes place in an area of the brain known as the hippocampus.

The hippocampus is a tiny region in the limbic system of the brain that is involved in learning and memory, as well as complicit in regulating the stress response and in modulating dopamine's reward and motivation systems. New brain cell growth and regeneration is called "neurogenesis."

Around the same time, Husseini Manji MD and his team at the NIMH found that lithium increased brain cell growth. At first, I thought the fact that psychiatric meds could act as brain fertilizer was the story.

No, Dr Manji told me. Sure, the fact that the brain could grow new cells was important, but the real story, he said, was in how these new and regenerated brain cells connected to other brain cells. Let's return to Dr Duman's research:

In his experiments, Dr Duman and his team exposed lab rats to repeated foot shocks to induce behavioral helplessness equating to depression. When the rats were "depressed," neurogenesis was virtually shut down. But when the animals were treated with different classes of antidepressants, the process was reversed. Neurogenesis cranked up and the little guys were happy again.

Subsequent studies found these new cells and restored older cells established connections with existing neuronal systems. In other words, weakened brain pathways became stronger. The brain functioned better.

I had the pleasure of hearing both Dr Duman and Dr Gage talk about their research in two separate lectures two years ago at the American Psychiatric Association annual meeting in San Diego.

Think of it this way: Under the old way of thinking, psychiatry assumed that all we had to do was squirt serotonin or other neurotransmitters at a neuron and - poof! - no more depression. They even had a name for this: the monoamine hypothesis.

But suppose whole brain systems are off-line, that brain cells aren't talking to one another. That vital "be happy" and "get excited" messages get lost in the mail. What then?

Well, the serotonin may work, but it's going to take time. First, the individual brain cells need to boot up. Both Drs Manji and Duman have been pioneering in figuring out which "signal transduction pathways" and their constituent proteins inside the neuron play key roles in the booting up and other processes.

I have heard Dr Manji at numerous conferences explain that if we can develop treatments that directly target the proteins in these specific pathways we may be able to, in effect, get atrophied neurons booting up much quicker, and thus expeditiously bring entire brain systems back online.

This would translate into quick and safe and effective treatments for depression and bipolar and other mental illnesses.

Today I came across an article in the March 1 Biological Psychiatry that illustrated how Dr Duman's team has been dialing in their research. Their latest study used the same foot shock techniques as their earlier ones. This time, postmortem examination (that's right, they killed the poor guys after torturing them) using electron microscopy in the brain tissue revealed loss in the hippocampal neuron spines.

These dendritic spines play a key role in neurotransmitter traffic, that is in neurons connecting to other neurons.

The study also found that six days of antidepressant treatment reversed the process. In other words, the spines grew back.

Thus, in the entire depression-recovery cycle, we are beginning to see - actually see - the structural changes taking place in the brain and understand the significance of these changes. This particular study represents but a jigsaw puzzle piece in the overall scheme of things, but a picture is forming, one that is changing how we think about mental illness.

Further reading from mcmanweb:

Inside the Neuron

Dr Manji explained how for the last three decades, neurotransmitters have been the focus of mental health research. But recently, he went on to say, we have been learning that mental illness is much more complicated than that. Nerve cells communicate with each other through neurotransmitters, but do not actually go inside the nerve cell. Rather, they are merely the keys that unlock what is going on inside the neuron, "where all the action is." ...