Neurogenesis and Depression: What’s really going on?

Depression is a pervasive illness that is not well understood despite being the subject of much intense research. For a long time, a lack of serotonin was thought to be the lead culprit (sometimes combined with norepinephrine and/or dopamine). The old idea was pretty much that if doctors could pop a depressed patient's head open and pour in a glass of serotonin, the problem would be solved. This assumption, known as the monoamine-deficiency hypothesis, is viewed as an antiquated oversimplification today. The reason for this is simple.

Prozac, and other selective serotonin reuptake inhibitors (SSRIs), work by blocking the nerve cells from transporting serotonin back into the cell after it's been released. In a way, this is like stuffing a rag in the drain of a kitchen sink with the water running. If you block the transporter, the level of serotonin will rise, just like water in the sink, because it has nowhere to go. So, by administering an SSRI, a doctor can "block off the drain" and raise brain serotonin levels within several hours. The problem with this, as a lot of people are aware, is that it takes one or two months of SSRI treatment to see an antidepressant effect. This lag in the effect of SSRIs makes it pretty clear that depression is not an easy-to-fix "chemical imbalance."

So why is there such a gap in time between administration of SSRIs and response? To explain, a little background is needed.

In order to model depression in animal models, researchers use stress paradigms (paradigm in this sense just applies to the technique and its theoretical justification) to induce behavioral states that are considered analogs of human depression. Chronic stress, mostly through hormones called glucocorticoids, is known to significantly limit neurogenesis in the hippocampus of animals. Neurogenesis is a term that more or less encapsulates the birth, survival, growth, and movement of new nerve cells in adults. Researchers have shown that depression decreases neurogenesis by injecting a fluorescent marker known as BrdU into 'depressed' mice. BrdU is a chemical that attaches to cells that have recently split, or been 'born.' After subjecting mice to a stress paradigm, and observing depressed behavior, the brains can be checked for neurogenesis.

Normal neurogenesis looks something like this:

In depression, these cells do not make it through the survival phase.

Over the years, experimental evidence has shown that SSRIs do promote neurogenesis in a brain region called the hippocampus. Neurogenesis, while far from the only effect of SSRIs, was certainly present when mice improved in depressive symptoms. After observing this, many people wondered whether this were the elusive mechanism through which SSRIs have their antidepressant effect.

So was the neurogenesis a necessary mechanism or just a coincidence? In a 2003 study, researchers irradiated the hippocampus of mice that received antidepressants (this is similar to cancer treatments, lead shields are used to protect the adjacent areas) and succeeded in eliminating 87% of the new cells. With the loss of neurogenesis, the behavioral recovery that normally coincides with administering these drugs to depressed mice was absent.

This was reasonably conclusive evidence that neurogenesis was necessary for SSRIs to have their effect. In addition, the time course of antidepressant effect in clinical cases, four to eight weeks, is about the same time that it takes for new cells to be born and then integrate themselves into the neural network of the hippocampus in these rodent studies.

Seems straightforward right? When an animal is stressed, it releases glucocorticoids, which stop neurogenesis, and then the animal becomes depressed. Give it antidepressants, which kick start neurogenesis, and it goes back to normal. There would seem to be a negative correlation between neurogenesis and depression. In other words, neurogenesis goes up and depression goes down, or vice versa. Well, not so much.

A recently published a paper in the journal Biological Psychiatry shows evidence that neurogenesis is causal in relieving depression, but not in starting it.

The researchers again used irradiation to suppress neurogenesis, and a paradigm known as unpredictable chronic mild stress (UCMS) to induce a depressed state. UCMS basically freaks out the mouse by repeatedly subjecting it to things like cage tilting, damp sawdust (lining the bottom of the cage), predator sounds, putting the mouse into another male's empty cage, and shifting the light/dark cycles.

They quantified the effects of this stress through assessment of the animal's coat state, weight, a splash test, the novelty-suppressed feeding (NSF) test and an actimiter. The coat state is an obvious sign that UCMS is working; a stressed mouse won't groom itself as much and it may start to fluctuate in weight. The other tests look for behavior analogous to depression in humans.

The paper actually has a nice graphic to illustrate the experimental design:

The paper contains about four experimental conditions, and I'll address them in the sequence that the authors did.

In the first set of conditions, the authors were simply looking to see if, when subjected to UCMS, there was a difference between mice who had their hippocampus irradiated and those that didn't. In other words, were mice without hippocampal neurogenesis more vulnerable to stress and would they show depressive signs quicker than normal mice?

The answer was no:

In the above graph, and the ones that follow, a higher score indicates a worse coat condition. A low score can be interpreted as a "happier" mouse.

As you can see, there is virtually no difference in the behavioral effects of stress on the two groups of mice. The authors' interpretation of these results was that neurogenesis doesn't play a causal role in the pathogenesis of depression.

This is a significant finding because in the past it's been hard to dissociate neurogenesis and depression. Hippocampal neurogenesis is increased by nearly every antidepressant drug. Also, fluoxetine, imiprimine (a potent tricyclic antidepressant), and cannibinoid antidepressant therapies have been shown to require neurogenesis to have their effect.

So the question was, if neurogenesis isn't causing depressive symptoms, is it always needed to relieve them?

The authors decided to do a larger set of three experiments, where they would split the conditions appropriately. The only difference between the graphs below is the drug used in each. Unlike above, all of the mice discussed below were subject to the UCMS paradigm.

The first two graphs are basically a replication of the earlier finding that the monoaminergic drugs fluoxetine and imiprimine fail to relieve depression when neurogenesis is suppressed:

As expected, only the groups that received the monoaminergic antidepressants with no irradiation were unaffected by the UCMS.

The next two graphs show the same thing, but with different drugs. The experimental drugs shown are SSR149415, a V_1b receptor antagonist, and SSR125543, a CRF₁
receptor antagonist (antagonists inhibit the function of a receptor). Both of these drugs work on the HPA axis, a neuroendocrine system that regulates a plethora of body functions. The HPA axis is usually overactive or somehow dysregulated in anxious or depressed humans, leading to an abnormally high level of glucocorticoids. This is not a good thing, seeing as glucocorticoids regulate neuronal survival, the size of structures like the hippocampus, the storage of new memories and the emotional appraisal of events. Too much of them, and you get things like hippocampal atrophy and a reduction in neuropil.

These two drugs inhibit processes in the HPA axis that are central to the release of glucocorticoids. To return to the kitchen sink simile, it's like turning down the faucet.

There are several novel drugs like SSR149415 and SSR125543 in clinical trials for anxiety and depression right now, and the authors wanted to see if they were also reliant on neurogenesis.

Here were the results:

Both groups responded to the treatment whether or not they were irradiated. So it seems that these drugs act on a different mechanism.

The authors suggest a model to explain their findings, whereby the hippocampal neurogenesis acts to repair the inhibition of the HPA axis.

T-shaped lines indicate a decrease, arrows an increase.

The general idea is that these new antidepressants potentially skip a step and directly influence the HPA axis.

This study is helpful in that it tells us something about the role of neurogenesis in depression. However, V_1b and CRF₁ receptor antagonists will not be game changers. It seems that they don't work any faster than current medications, and the irradiation factor is clinically irrelevant.

My personal opinion is that we won't make any real breakthroughs until we define the neural circuits involved in mood modulation and discover how the flow of information through them is affected by the disease.

All graphs and figures were adapted from Surget et al.

References:

1. Surget et al. Biol Psychiatry. 2008 Aug 15:64(4):293-301. Epub 2008 Apr 11. dx.doi.org/10.1016/j.biopsych.2008.02.022
2. Pariante CM and Lightman SL. Trends Neurosci. 2008 Jul 31. [Epub ahead of print] dx.doi.org/10.1016/j.tins.06006