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

Moral choice: fairness, utility, and the insula

We continue to learn more about the neuropsychological basis of moral thinking and moral emotions in humans:

Justice In The Brain: Equity And Efficiency Are Encoded Differently (5/8/08)

Which is better, giving more food to a few hungry people or letting some food go to waste so that everyone gets a share" A study appearing in Science finds that most people choose the latter, and that the brain responds in unique ways to inefficiency and inequity.

The study, by researchers at the University of Illinois and the California Institute of Technology, used functional magnetic resonance imaging (fMRI) to scan the brains of people making a series of tough decisions about how to allocate donations to children in a Ugandan orphanage.

There are two main issues regarding moral decision making here.

The first involves two separate principles often used in analyzing moral/ethical problems related to the distribution of goods within a group of people. (The group might be children in a family or different classes of people in a society, among many possibilities.) On one hand, it is generally regarded as "good" to maximize "equity" in moral decisions, so that some individuals are not favored over others without significant justification. (I prefer the term "fairness" for this.)

On the other hand, it is also regarded as "good" to maximize "efficiency", so that the greatest total amount of benefit accrues to a group as a whole. (I prefer the term "utility" for this.)

But these principles can come into conflict, and the research discussed here investigates a contrived, but sharp, example. Philosophers of ethics call such dilemmas the problem of "distributive justice".

The second issue concerns the style of thinking that a decision maker faced with this kind of dilemma does use, and also, perhaps, what style the decision maker "should" use. On one hand, the decider might try to systematically and logically apply some standard set of rules that are considered appropriate for the situation. But on the other hand, the decider might rely more on emotional factors that indicate what "feels right", the "gut feeling", about what seems "right" in a concrete situation.

Philosophers often describe these two alternatives as "cognitivist" vs. "sentimentalist". The former is sometimes associated with the philosopher Immanuel Kant, and the latter with David Hume.

What emerges from the research is (not surprisingly) that individual decision makers differ in the degree that they favor "equity" vs. "efficiency", and also whether they tend to rely more on logic or emotion to make their decisions.

More interestingly, most people normally process considerations of both equity and efficiency in order to reach a decision, but different parts of the brain are used for the two. Likewise, in making the decision, distinct parts of the brain which normally handle emotional or logical processing can become involved in processing the equity/efficiency trade-off.

One way to think of this is that there are separate calculations of both equity and efficiency that are made for each available choice. And then the result of those calculations are fed to separate subsystems to weigh the alternatives.

The different moral and ethical decisions that different people will arrive at can be attributed to individual differences as to how the various stages of the decision process are handled. For instance, an individual may favor equity over efficiency, and tend to use emotion rather than logic to reach the decision.

Here's what the study found:

In these trails, subjects overwhelmingly chose to preserve equity at the expense of efficiency, Hsu said. "They were all quite inequity averse." The findings support other studies that show that most people are fairly intolerant of inequity.

The animation, in conjunction with the fMRI, allowed the researchers to view activity in the brain at critical moments in the decision-making process. After analyzing the data, they found that different brain regions -- the insula, putamen and caudate -- were activated differently, and at different points in the process, Hsu said.

Activation of the insula varied from trial to trial in relation to changes in equity, while activity in the putamen corresponded to changes in efficiency, he said.

In contrast, the caudate appeared to integrate both equity and efficiency once a decision was made.

The role of the insula (or, more formally, insular cortex) is especially interesting, since this brain region has been associated with quite a few other types of social-emotional mental processing. We'll come back to that in a moment. But here are the conclusions of the researchers:

The involvement of the insula appears to support the notion that emotion plays a role in a person's attitude towards inequity, Hsu said.

The insula is known to play a key role in the awareness of bodily states and emotions. Studies have shown that it is activated in people experiencing hunger or drug-related cravings, and in those feeling intense emotions such as anger, fear, disgust or happiness. Other research has implicated the insula in mediating fairness. ...

Together, the results "show how the brain encodes two considerations central to the distributive justice calculus and shed light on the cognitivist/sentimentalist debate regarding the psychological underpinnings of distributive justice," the authors wrote.

Here's how another report about this research summed it up:

Your Brain on Ethics (5/8/08)

The fMRI scans contain hints of how these two factors might be encoded by the brain. The insula, a brain region linked to processing emotion, became more active when subjects considered more inequitable distributions of meals; it was also more active in subjects whose choices suggested a greater-than-average aversion to inequity. Activity in another region, the putamen, seemed to track the common good, rising in proportion to the total number of meals that could be donated in a given case.

Now let's have a quick overview of the insula. Turns out that it's involved in a lot more than just moral decision-making. Here's a general article from a bit over a year ago:

A Small Part of the Brain, and Its Profound Effects (2/6/07)

According to neuroscientists who study it, the insula is a long-neglected brain region that has emerged as crucial to understanding what it feels like to be human.

They say it is the wellspring of social emotions, things like lust and disgust, pride and humiliation, guilt and atonement. It helps give rise to moral intuition, empathy and the capacity to respond emotionally to music. ...

If it does everything, what exactly is it that it does?

For example, the insula “lights up” in brain scans when people crave drugs, feel pain, anticipate pain, empathize with others, listen to jokes, see disgust on someone’s face, are shunned in a social settings, listen to music, decide not to buy an item, see someone cheat and decide to punish them, and determine degrees of preference while eating chocolate.

Damage to the insula can lead to apathy, loss of libido and an inability to tell fresh food from rotten. ...

Of course, like every important brain structure, the insula — there are actually two, one on each side of the brain — does not act alone. It is part of multiple circuits.

The insula itself is a sort of receiving zone that reads the physiological state of the entire body and then generates subjective feelings that can bring about actions, like eating, that keep the body in a state of internal balance. Information from the insula is relayed to other brain structures that appear to be involved in decision making, especially the anterior cingulate and prefrontal cortices.

Stay tuned. We'll be discussing the insula quite a bit more here, I think.

Further reading:

The Right and the Good: Distributive Justice and Neural Encoding of Equity and Efficiency – Original research report published 5/8/08 at Science Express (sub. rqd. for full access)

Which Orphans Do You Want to Starve? – Blog article by Sharon Begley at Newsweek

How Fairness Is Wired In The Brain – 5/28/08 press release about the research dealing with fairness and the insula

Tags: morality, fairness, utility, neuroscience, neurobiology, insula, insular cortex