BDNF and depression

Back in March I wrote a little bit about the convoluted relationships among stress, learning, and memory (here). About the same time, I wrote about the relationship between memory and an important neural growth factor, BDNF (here).

It seems that BDNF is an important bridge connecting the topics of memory, stress, and depression. Back in March I also started to write more about how BDNF is linked to depression, but I got sidetracked. So the rest of this message is what I started to write about that connection, which is why the research covered is from March or earlier.

But before turning to that, it should be noted that there is more to say about the relationship between BDNF and stress, which I'll put off a little longer. There's also more to say about the relationship between BDNF and antidepressant drugs, some of which is more recent than March. I'll put that off too.

So let's just get into the older stuff about BDNF and depression, to start the ball rolling again.

Research has shown that one way in which BDNF is linked to depression is through the neurotransmitter serotonin – whose connection to mood, depression, anxiety, etc. is pretty well known (think Prozac).

In particular, BDNF seems to affect expression of the gene for the serotonin transporter (SERT). (The gene itself is called SLC6A4, which stands for "solute carrier family 6, member 4".) SERT is a cell membrane protein that transports serotonin from the synapse between neurons back into the neuron from whence it came – enabling "serotonin reuptake". Some forms of the gene for SERT seem to predispose individuals who carry it to mood disorder.

Here are some reports of recent research on BDNF, which give an idea of the variety of effects it has within the nervous system. (The summaries included here are mine.)

The yin and yang of genes for mood disorders (3/12/08)

This research studied conditions under which a variant of the gene for SERT (i. e. SLC6A4) predisposes the carrier to mood disorders. Apparently there are also at least two variants of the gene for BDNF. An individual with one form of BDNF is particularly susceptible to the deleterious form of the SERT gene, but with the other form of BDNF, an individual is completely protected against it.

Brain Chemistry Ties Anxiety And Alcoholism (3/4/08)

Production of BDNF is known to be stimulated by exposure to alcohol. The researchers in this study, whose leader author is Subhash Pandey, also knew from previous experiments that reduced levels of BDNF in the amygdalas of normal laboratory rats led to increased anxiety in the rats, followed by increased consumption of alcohol. The question was what happened due to deficiency of BDNF that increased anxiety, and how did consumption of alcohol reverse this effect by restoring BDNF.

It is also known that BDNF stimulate the production of another protein, Arc. If Arc could be suppressed in the amygdala even in the presence of normal levels of BDNF, and the rats experienced increased anxiety anyhow, this would show that it is probably a deficiency of Arc rather than of BDNF that is responsible for the anxiety. And indeed, when Arc was suppressed in spite or normal BDNF, the rats had higher anxiety. They also consumed more alcohol. But when Arc levels returned to normal, the anxiety returned to normal, and alcohol consumption did too.

The question then came down to how a deficiency of Arc increased anxiety. It was found that temporarily reduced levels of Arc resulted in reduced numbers of dendritic spines of neurons in the amygdala. Since axons of other neurons form synapses with dendritic spines, there will be fewer synapses when there are fewer spines. At the same time, anxiety also increased. Conversely, when levels of Arc returned to normal, either naturally or as a result of higher levels of BDNF due to alcohol consumption, the number of spines increased, and anxiety decreased. Once Arc had increased normally, alcohol consumption decreased too.

Earlier results: Brain Chemical Plays Critical Role In Drinking And Anxiety (8/8/06) – when expression of BDNF (which is regulated by CREB) is blocked, anxiety and alcohol consumption in rats increases.

Tags: BDNF, depression, serotonin

Serotonin

It's always interesting to find out that important hormones and proteins play multiple disparate roles in an organism. Such a finding suggests that problems in one area may be related to problems in very different areas.

I suppose everyone knows that serotonin is "that brain chemical" which is messed up somehow when you're depressed and need some Prozac. But it turns out there's more to it than just that.

Here are some recent examples.

The first may seem somewhat surprising, since it relates to metabolism, and it isn't obviously connected with mood, with which serotonin is commonly linked.

Actually, a link between mood and hunger via serotonin shouldn't be so surprising. The chemical name for serotonin is 5-hydroxytryptamine (or 5-HT for short). This hints at its chemical relationship to the amino acid trytophan. Although the connection between tryptophan and post-prandial drowsiness is more complicated than generally supposed, there is a connection, and synthesis of serotonin (and melatonin) from tryptophan is involved. (Have you ever felt grumpy or depressed, or had trouble sleeping, while dieting? The relative lack of tryptophan is what's responsible.)

But that's not what the recent research is about:

Eating And Weight Gain Not Necessarily Linked, Study Shows (6/3/08)

You may not be what you eat after all. A new study shows that increased eating does not necessarily lead to increased fat. The finding in the much-studied roundworm opens the possibility of identifying new targets for drugs to control weight, the researchers say.

The discovery reveals that the neurotransmitter serotonin, already known to control appetite and fat build-up, actually does so through two separate signaling channels. One set of signals regulates feeding, and a separate set of signals regulates fat metabolism. The worm, known scientifically as Caenorhabdtis elegans, shares half of its genes with humans and is often a predictor of human traits.

Serotonin affects how hungry an organism feels. But there's more to it than that. Apparently, serotonin also affects how cells metabolize fat.

An abstract of the original research summarizes this latter effect:

Serotonin Regulates C. elegans Fat and Feeding through Independent Molecular Mechanisms

Serotonergic fat regulation is dependent on a neurally expressed channel and a G protein-coupled receptor that initiate signaling cascades that ultimately promote lipid breakdown at peripheral sites of fat storage. In turn, intermediates of lipid metabolism generated in the periphery modulate feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability.

This news report explains it even better:

Mood hormone may affect fat, U.S. study finds (6/3/08)

Serotonin may help the body decide whether to burn off excess calories, or store them as fat, Ashrafi said. ...

"It has been known for a long time that increasing serotonin causes fat reduction," Ashrafi said.

"At the molecular level we are trying to understand what is the mechanism that allows that to happen. What we discovered in the worm is that those mechanisms can be separated from the mechanisms that mediate the effects of serotonin on appetite."

The research found serotonin levels affected the worms' appetite, but they also affected how much fat the worms accumulated, and this was via a separate process.

If the worms detect a food shortage, their metabolisms shift and they store more fat.

More: The Skinny on Fat: You're Not Always What You Eat (6/4/08)

The second recent research report on serotonin concerns its effects on mood, but in rather more complex ways than simply in terms of "depression". Serotonin also seems to affect feelings of fairness, anger, and aggression in social decision-making. Significantly, with respect to the research just discussed, these feelings are modulated by recent feeding experience. And there are ramifications for impulsivity and obsessive tendencies.

Serotonin Link To Impulsivity, Decision-making, Confirmed (6/5/08)

New research by scientists at the University of Cambridge suggests that the neurotransmitter serotonin, which acts as a chemical messenger between nerve cells, plays a critical role in regulating emotions such as aggression during social decision-making.

Serotonin has long been associated with social behaviour, but its precise involvement in impulsive aggression has been controversial. Though many have hypothesised the link between serotonin and impulsivity, this is one of the first studies to show a causal link between the two.

Their findings highlight why some of us may become combative or aggressive when we haven't eaten. The essential amino acid [i.e. tryptophan] necessary for the body to create serotonin can only be obtained through diet. Therefore, our serotonin levels naturally decline when we don't eat, an effect the researchers took advantage of in their experimental technique.

So the researchers reduced serotonin levels in volunteer subject by manipulating their diet. In order to probe the social effects of this, the researchers used a laboratory game called the "ultimatum game", which is something that social psychologists now like to use in order to study social variables of trust and sense of fairness. (There's much that's interesting to say about this game, as far as instinctive ideas of morality and ethics are concerned, but that must wait for another time.)

The researchers were able reduce brain serotonin levels in healthy volunteers for a short time by manipulating their diet. They used a situation known as the 'Ultimatum Game' to investigate how individuals with low serotonin react to what they perceive as unfair behaviour. In this game one player proposes a way to split a sum of money with a partner. If the partner accepts, both players are paid accordingly. But if he rejects the offer, neither player is paid.

Normally, people tend to reject about half of all offers less than 20-30% of the total stake, despite the fact that this means they receive nothing - but rejection rates increased to more than 80% after serotonin reductions. Other measures showed that the volunteers with serotonin depletion were not simply depressed or hypersensitive to lost rewards.

Contrary to how some news reports have described the results of this experiment, the increased rate of rejecting unfair was not found to be related to overall mood or perception of fairness, as this account notes:

Deal or No Deal? (6/5/08)

The lack of tryptophan did not affect the subjects' general moods or their perceptions of the fairness of an offer, the team reports online today in Science. It did, however, appear to make people more likely to reject unfair offers.

Indeed, according to the published abstract of the research:

Serotonin Modulates Behavioral Reactions to Unfairness

Participants with depleted 5-HT levels rejected a greater proportion of unfair, but not fair offers, without showing changes in mood, fairness judgments, basic reward processing, or response inhibition.

Additional reports: here, here, here

Further reading:

Low Serotonin Increases Desire To Punish Unfairness (6/5/08) – blog post

Tags: serotonin, ultimatum game, fairness