Creativity and mental illness

The association between creativity and mental illness is sort of a cliché – but that doesn't mean there's nothing to it. Standard examples given include Vincent van Gogh, Robert Lowell, and John Nash.

There has been a rather large amount of research into the connection, and a large number of biographical accounts of famous creative people who also suffered from mental illness. But the neurobiological details are emerging only slowly. After all, our understanding of the biological roots of either creativity or mental illness remains fairly rudimentary.

However, one recent study does add some tantalizing clues.

Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals

Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [¹¹C]raclopride and [¹¹C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity.

Executive summary: There is a correlation between performance on a part of a common psychological test for creativity and a certain property of neurons in a brain structure called the thalamus. The association with mental illness, specifically schizophrenia, is that the same neural abnormality in the same part of the brain has also been found to correlate with various symptoms of schizophrenia.

Let's look at creativity first. It's often defined, to quote from the research paper, as "the ability to produce work that is at the same time novel and meaningful, as opposed to trivial or bizarre". A creative work should be original and unexpected, but it should also be more than just randomly different from the ordinary. It should also impress us as insightful or solve a difficult problem.

So there are several abilities a creative person should possess. They don't necessarily correlate with each other, but all or most should be present for "true" creativity. A creative artist, for instance, should be inventive and original, but also have good artistic skills. As far as the present research is concerned, we're dealing just with the aspect of creativity that comprises novelty and originality.

The psychological test used in this research is called the "Berliner Intelligenz Struktur Test". It's a general intelligence test, and it consists of several parts. One part is the "Inventiveness battery", and the specific ability that measures is called "divergent thinking".

Even within the divergent thinking component, several characteristics can be distinguished. The test may ask, for example, to think of as many reasonable uses as possible for an object like a brick. The characteristics that might be observed include:

Fluency–the number of valid responses; Originality–how frequent the participant's responses were among the responses of the rest of the sample; Flexibility–the number of semantic categories produced; Switching–the number of shifts between semantic categories; and Elaboration–how extensive each response is (if the task involves producing more than single words).

To do well on this test, a subject must be able to quickly produce valid responses that are unobvious and diverse in nature, not just variations on a few themes.

Previous research had established that divergent thinking is influenced by the "dopaminergic" neural system, i. e., neurons whose primary neurotransmitter is dopamine. Specifically, there is a correlation between divergent thinking (as measured by the test just described) and certain variants of the dopamine D2 receptor. The present research further narrows down the relationship.

We've discussed dopamine before (list). It is involved in quite an impressive number and diversity of psychological phenomena, including appetite, addiction, risk-taking, memory, and trust. Some abnormalities of the dopaminergic system are also implicated in pathologies such as ADHD, Parkinson's disease, depression, and schizophrenia (dum-da-dum-dum).

Indeed, because dopamine is involved in so many functions, therapies for certain dopamine-related disorders can cause side effects in seemingly unrelated areas. For example, Parkinson's disease results from insufficient dopamine activity, but treatments that raise dopamine levels can cause other problems, such as pathological gambling, compulsive shopping, binge eating and other impulse control disorders. (Ref.: here.)

The reason that dopaminergic neuron abnormalities have such diverse effects is that dopaminergic neurons are common in a number of specialized areas of the brain. A dopamine abnormality will therefore affect whatever function such an area is involved in.

As far as divergent thinking is concerned, there are two brain areas of particular interest: the striatum and thalamus. Many neurons in both regions have D2 receptors. And interestingly enough, these regions are also linked with schizophrenia. As the research paper notes,

[N]etworks relevant to divergent thinking, i.e. structures and processes in associative corticostriatal-thalamocortical loops overlap to a great extent with regions and networks affected in schizophrenia and bipolar disorder. Furthermore, dopamine is known to influence processing in these networks and alterations in dopaminergic function and activity of D2 receptors have been linked to both positive and negative psychotic symptoms. Two regions appear to be of particular interest in this context: the thalamus and the striatum. Several studies have shown thalamic D2BP to be reduced in drug-naïve schizophrenia patients. Moreover, D2BP in subregions of the thalamus was found to be negatively related to total symptoms, general symptoms, positive symptoms, hostility and suspiciousness as well as grandiosity.

(D2BP refers to D2 "binding potential", which depends on the number density of D2 receptors and their ability to bind dopamine.)

Based on the known facts, the researchers decided to look for correlations between a measure of divergent thinking and D2BP in the thalamus and the striatum. What they found was that, indeed, there was a significant (p=.013) negative correlation, in a relatively small sample of healthy (non-schizophrenic) individuals, between a measure of divergent thinking and D2BP in the thalamus. There was not a similar correlation in the striatum.

In other words, non-schizophrenic people who had lower dopamine activity in the thalamus tended to have higher divergent thinking scores. This is pretty interesting in itself, especially since other studies have shown lower D2BP in the thalamus to be correlated with higher scores for pathological symptoms in schizophrenics.

What, then, is known about the function of the thalamus? It's a left-right midplane symmetric structure, situated between the cerebral cortex and the midbrain. It has a number of functions, especially as a relay station between the cortex and various subcortical areas. In particular, all sensory signals (except smell) pass through substructures of the thalamus on their way to the part of the cortex that processes them. The thalamus is also thought to be important for regulation of sleep, wakefulness, and consciousness – which makes sense, as it's in a position to control what sensory signals get through.

But why do the dopaminergic neurons of the thalamus have something to do with divergent thinking? The present research doesn't explicitly say anything about that. But the researchers suggest some hypotheses:

Based on the current findings, we suggest that a lower D2BP in the thalamus may be one factor that facilitates performance on divergent thinking tasks. The thalamus contains the highest levels of dopamine D2 receptors out of all extrastriatal brain regions. Decreased D2BP in the thalamus has been suggested, firstly, to lower thalamic gating thresholds, resulting in decreased filtering and autoregulation of information flow, and, secondly, to increase excitation of cortical regions through decreased inhibition of prefrontal pyramidal neurons. The decreased prefrontal signal-to-noise ratio may place networks of cortical neurons in a more labile state, allowing them to more easily switch between representations and process multiple stimuli across a wider association range.

Stated more clearly, perhaps, though less precisely, it seems that lower dopamine activity in the thalamus may allow a freer flow of associations to reach the cortex, which is where higher-level cognition takes place. At the same time, however, if this effect is too strong, the result could be cortical activity that is, pathologically, too chaotic.

de Manzano, �., Cervenka, S., Karabanov, A., Farde, L., & Ullén, F. (2010). Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals PLoS ONE, 5 (5) DOI: 10.1371/journal.pone.0010670

Further reading:

Creativity linked to mental health (5/18/10)

Link Between Creativity and Mental Illness Revealed (5/19/10)

More brains and bonkers connection: thinking out of a broken box (5/24/10)

Dopamine receptor binding potential in the thalamus and creativity (6/1/10)

Creative madness (8/1/10)

Related articles:

Sugar can be addictive (1/11/09)

Dopamine and obesity (11/17/08)

Sugar can be addictive

And you may well have noticed this addictive characteristic if you overindulged in sugar over the recent holidays. Turns out, the neurotransmitter dopamine plays a big role here. There's a lot of research on dopamine coming out these days. The research discussed here is just one example.

We last dealt with dopamine back in November: here. One could paraphrase the conclusions of that research as suggesting that genetic problems with a dopamine receptor lead to reduced sensitivity to dopamine, which leads to stronger than normal craving for food, leading to overeating and obesity.

The research in question here looks at a special case of this in an animal model, involving rats and sugar. In this case, reduced sensitivity to dopamine isn't a consequence of a variant allele for a dopamine receptor. Instead, it seems to result from excessive intake of the addictive substance (sugar), resulting in fewer brain receptors for dopamine.

Sugar Can Be Addictive: Animal Studies Show Sugar Dependence (12/10/08)

"We have the first set of comprehensive studies showing the strong suggestion of sugar addiction in rats and a mechanism that might underlie it," [principal investigator Bart] Hoebel said. The findings eventually could have implications for the treatment of humans with eating disorders, he said.

Lab animals, in Hoebel's experiments, that were denied sugar for a prolonged period after learning to binge worked harder to get it when it was reintroduced to them. They consumed more sugar than they ever had before, suggesting craving and relapse behavior. Their motivation for sugar had grown. "In this case, abstinence makes the heart grow fonder," Hoebel said.

The rats drank more alcohol than normal after their sugar supply was cut off, showing that the bingeing behavior had forged changes in brain function. These functions served as "gateways" to other paths of destructive behavior, such as increased alcohol intake. And, after receiving a dose of amphetamine normally so minimal it has no effect, they became significantly hyperactive. The increased sensitivity to the psychostimulant is a long-lasting brain effect that can be a component of addiction, Hoebel said.

The research investigated the physiological changes responsible for this addictive behavior:

Hoebel has shown that rats eating large amounts of sugar when hungry, a phenomenon he describes as sugar-bingeing, undergo neurochemical changes in the brain that appear to mimic those produced by substances of abuse, including cocaine, morphine and nicotine. Sugar induces behavioral changes, too. "In certain models, sugar-bingeing causes long-lasting effects in the brain and increases the inclination to take other drugs of abuse, such as alcohol," Hoebel said.

Hoebel and his team also have found that a chemical known as dopamine is released in a region of the brain known as the nucleus accumbens when hungry rats drink a sugar solution. This chemical signal is thought to trigger motivation and, eventually with repetition, addiction. ...

Hungry rats that binge on sugar provoke a surge of dopamine in their brains. After a month, the structure of the brains of these rats adapts to increased dopamine levels, showing fewer of a certain type of dopamine receptor than they used to have and more opioid receptors. These dopamine and opioid systems are involved in motivation and reward, systems that control wanting and liking something. Similar changes also are seen in the brains of rats on cocaine and heroin.

It's interesting that overstimulating with an addictive substance (sugar) not only reduces the number of dopamine receptors but also increases the number of opioid receptors. What's not so clear is the relationship between the dopamine and opioid systems. Having more opioid receptors would appear to increase cravings for substances that stimulate them, which is the opposite of what happens with dopamine receptors. Hypothetically, perhaps, opioid stimulation is able to substitute for reduced dopamine sensitivity.

Research in this area may have even wider implications than behavior linked to overconsumption, as there is other recent research that suggests addictive behavior related to other kinds of stimulation, such as gambling and risk-taking.

Watch for a lot more discussion of this line of inquiry.

Tags: dopamine, addiction

Chinese food, umami, autism, schizophrenia, and cancer

There's a fascinating interrelationship among the things mentioned in the title – and it takes us through equally fascinating topics in molecular cell biology and neurobiology.

No, Chinese food has not been found to cause the listed maladies – although with the additives that the People's Republic of China seems to be allowing in many of its food products these days (e. g. melamine), who knows for sure?

So what's the connection? Try monosodium glutamate (MSG). That, of course, is the sodium salt of glutamic acid (which itself is often referred to as "glutamate"). MSG is a rather well known food additive which at one time was very commonly used in Chinese food for its ability to "enhance" flavor. Technically, the form of glutamate responsible for flavor is the ionic form rather than the sodium salt – the former being what is found in aqueous solution rather than the latter dry crystalline form.

MSG became notorious some time ago when Chinese food became popular in western countries, because it was at first unfamiliar and also tended to cause headaches or at least a peculiar lightheaded sensation after eating food to which it had been added. Consequently, most Chinese restaurants, at least in the U. S., now carefully inform customers that their food "contains no MSG".

Nevertheless, it's impossible to escape glutamate, because glutamic acid is one of the 20 amino acids that make up all proteins. It's essential to life as we know it, and so in fact it can't be avoided.

It also happens to be one of the most important neurotransmitters, and in that role is absolutely essential to the function of animal nervous systems. This role of glutamate is the key part of the story here.

As a flavor, glutamate is responsible for the much hyped "fifth taste" known in Japanese as umami. The first four basic tastes are sweetness, bitterness, sourness, and saltiness. Each of these is detected by specialized receptors on human tongues. Like the others, umami is also detected by its own receptor, but what's actually being detected is the amino acid glutamate present in all protein-containing foods, especially meats, cheese, and soy products.

Although the flavor is enjoyable, it's as a neurotransmitter that glutamate is important for the present story. As a neurotransmitter, glutamate is excitatory. In fact, it's the most abundant excitatory neurotransmmitter in mammalian nervous system. An electrical impulse traveling down a neuron's axon triggers the release of glutamate at the presynaptic side of glutamate synapses. When this glutamate is picked up by receptors at the other side (the postsynaptic side) of the synapse it contributes to possible excitation of the postsynaptic neuron. This is the basic mechanism by which signals are transmitted through an animal's nerves. (But there are other neurotransmitters besides glutamate that may be involved.)

However, this excitatory behavior can get out of hand, and when it does glutamate can have a toxic effect, called excitotoxicity. This can kill neurons and cause disease conditions such as autism, schizophrenia, and epilepsy.

Since glutamate is both essential but also (in excessive amounts) potentially toxic, an elaborate negative feedback system has evolved to keep glutamate production and release under careful control. It is when this feedback system fails somehow that neurological diseases develop. A typical cause of failure is mutation of genes that produce proteins essential to the feedback system.

So what are some of these genes/proteins? The first of these is the metabatropic glutamate receptor, mGluR for short. This is a receptor found on the surface of an axon, close to a glutamate synapse. When glutamate outside the neuron binds to such a receptor, it acts to tamp down the exited state of the neuron that led to release of glutamate in the first place. This process is called autocrine signaling, meaning that it involves a cell releasing a signaling molecule that can trigger a receptor on the same cell to modify cell behavior. This is the start of the negative feedback loop.

One source of failure is in mutation of mGluR itself, if this mutation causes further steps in the feedback loop to fail. What are some of these further steps? The first and possibly most important involves a protein enzyme with the charming name of PI3K. That's short for "Phosphoinositide 3-kinase", and we should be grateful for not having to write it out in full every time.

PI3K is a kinase, which means its enzymatic action is to cause phosphorylation of other proteins. A sequence of phosphorylating kinsaes constitutes a signal cascade or "pathway".

PI3K is the start of a pathway that plays a huge role in cell survival and proliferation – among other things. Clearly, it's an important protein.

The next step in the pathway is another kinsase called AKT. It's actually, in humans, a small family of proteins, Akt1, Akt2, and Akt3. Akt1 is the main player. One of its main jobs is cell survival, as an inhibitor of apoptosis. There are many reasons, both good and bad, for a cell to die by apoptosis. Akt1 is there to prevent the bad reasons for being responsible for too much cell death.

However, in cells that have become cancerous, one or another member of the AKT family typically functions only too well, resulting in the uncontrolled proliferation of cells that is the hallmark of cancer. In fact, an AKT kinase is hyperactive in the majority of human cancers. These molecules have been called perhaps the most frequently activated type of oncoprotein. (Reference: here.) Not only is AKT, in one form or another, involved in a majority of cancers, in many types of cancer, some form of AKT is a key factor. For instance, in melanoma, the interaction of Akt3 and another important cancer-related protein, c-Raf, is involved in 60-70% of melanoma-related tumors. (Reference: here.)

Not too long ago we discussed several other kinases (mTOR and MAP kinases), as well as PI3K and AKT, that play a role in cancer.

Its significant involvement in cancer is far from the only reason AKT is interesting, though. It is a versatile kinase involved in multiple pathways. In particular, it also participates in the negative feedback loop for glutamate because it deactivates a FoxO transcription factor. (For many details on that topic, see here.)

Now we're really getting into the heart of the story on the negative glutamate feedback loop. Recent research on fruit fly motor neurons, which we're about to refer to, suggests (among other things) that an AKT kinase inhibits a FoxO transcription factor that otherwise would stimulate glutamate release.

In a nutshell, the autocrine stimulation of the mGluR glutamate receptor activates PI3K, which activates an AKT kinase, which then inhibits a transcription factor, thereby inhibiting further glutamate release. This negative feedback loop keeps motor neurons from becoming overactive.

Here's a picture of what's going on:



Any mutation of the signaling kinases involved in this feedback loop would, of course, destabilize the control mechanism, but would likely cause other pathology as well, because of the involvment of PI3K, AKT, and FoxO in many other important cellular processes. However, if it was the mGluR glutamate receptor that was affected by a mutation, the main consequence would be some neurological pathology such as epilepsy.

A further reasonable speculation would be that mutations affecting mGluR in other types of neurons could cause other neurological problems, such as autism or schizophrenia. The present research does not actually deal with this more general case. However, other research has implicated PI3K and mGluRs in epilepsy, neurofibromatosis (a type of non-cancerous tumor), autism, schizophrenia, and other neurological disorders in humans.

Here's the research and its abstract:

A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability

Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

Further reading:

Possible Clues To Root Of Epilepsy, Autism, Schizophrenia (12/9/08) – press release

Eric Howlett, Curtis Chun-Jen Lin, William Lavery, Michael Stern (2008). A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability PLoS Genetics, 4 (11) DOI: 10.1371/journal.pgen.1000277

Tags: autism, schizophrenia, epilepsy

Dopamine and obesity

Dopamine is a neurotransmitter that's well-known for its involvement in several notable medical and behavioral problems, such as Parkinson's disease and drug addiction. But it is connected with many other issues of medical and psychological importance.

Perhaps the main reason that dopamine is so interesting is that it plays a big role in the brain's pleasure and reward systems. And therefore it is inevitably involved in reward-motivated behaviors of all kinds, from gambling, investing, substance abuse, and sex, to – eating. After all, isn't a high percentage of behavior motivated by rewards? There are other motivations for particular behaviors – fear and physiological needs, for example – but reward covers an awful lot of it.

Consequently, problems in the reward system can lead to excesses in some behaviors (e. g., gambling, eating), and perhaps also deficiencies in other behaviors (e. g. loss of interest in normal pleasures, as might accompany depression).

And because of the importance of dopamine in the reward system, problems with dopamine signaling can lead to problems in the reward system, with predictable consequences.

In the research we're going to look at, dopamine signaling is impaired in the presence of a particular allele associated with the D2 receptor for dopamine (known as DRD2). The conclusion is reached via the observation of decreased activity, as mesured by fMRI, in a brain region called the dorsal striatum. It is known that the variant allele causes a lower density of D2 receptors in this region.

The bottom line of the research is that individuals with this variant allele tend to have impaired ability to enjoy rewards from foods that most people like, such as chocolate. As a result, such individuals are disposed to consume more food in order to achieve an acceptable level of satiation of reward.

It might be thought, instead, that since the desirable foods produce less reward in individuals with the variant allele, they might consume less, due to reduced interest. However, that's not how the reward system seems to work. It seems to require achievement of a certain signal level in order to reach satiation and thus decrease the motivated behavior.

This is similar to the way signaling works with another hormone connected with eating, namely leptin. Normally, leptin levels rise when food is consumed. There are receptors for leptin in the ventromedial nucleus of the hypothalamus, a region that is responsible for appetite. There leptin inhibits the activity of neurons that contain neuropeptide Y (NPY).

A connection has been found between obesity and insensitivity to leptin, much as diabetes results from decreased sensitivity to the hormone insulin. Preseumably, individuals with reduced sensitivity to leptin don't know when to stop eating. Much the same state of affairs seems to exist in individuals with the allele (which is a DNA restriction enzyme called TaqIA) that affects DRD2 receptor density in the dorsal striatum.

Obesity, Abnormal 'Reward Circuitry' In Brain Linked: Gene Tied To Dopamine Signaling Also Implicated In Overeating (10/16/08)

Using brain imaging and chocolate milkshakes, scientists have found that women with weakened "reward circuitry" in their brains are at increased risk of weight gain over time and potential obesity. The risk increases even more for women who also have a gene associated with compromised dopamine signaling in the brain.

The results, drawn from two studies using functional magnetic resonance imaging (fMRI) at the University of Oregon's Lewis Center for Neuroimaging, appear in the Oct. 17 issue of the journal Science. The first-of-its-kind approach unveiled blunted activation in the brain's dorsal stratium when subjects were given milkshakes, which may reflect less-than-normal dopamine output.

Here's the research paper, with abstract:

Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele

The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.

The idea that problems with dopamine signaling might be related to overeating and obesity isn't new. The following research announced in July involved rats rather than humans and considered other dopamine insufficiency mechanisms, but the basic conclusions are the same:

Obesity Predisposition Traced To The Brain's Reward System (7/29/08)

The tendency toward obesity is directly related to the brain system that is involved in food reward and addictive behaviors, according to a new study. Researchers at Tufts University School of Medicine (TUSM) and colleagues have demonstrated a link between a predisposition to obesity and defective dopamine signaling in the mesolimbic system in rats.

The mesolimbic system is a system of neurons in the brain that secretes dopamine, a neurotransmitter or chemical messenger, which mediates emotion and pleasure. The release of the neurotransmitter dopamine in the mesolimbic system is traditionally associated with euphoria and considered to be the major neurochemical signature of drug addiction. ...

Pothos says, "These findings have important implications in our understanding of the obesity epidemic. The notion that decreased dopamine signaling leads to increased feeding is compatible with the finding from human studies that obese individuals have reduced central dopamine receptors." He speculates that an attenuated dopamine signal may interfere with satiation, leading to overeating.

Paper abstract:

Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats

In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP [obesity-prone] rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

News reports of the human dopamine results:

• Researchers tie genes, lower reward response to weight gain (10/16/08) – Yale University press release
  
• Gene mutation predicts future weight gain (10/16/08) – New Scientist
  
• Milkshake study reveals brain's role in obesity (10/16/08) – Reuters
  
• Brain's reaction to yummy food may predict weight (10/16/08) — Associated Press
  
• Brain signals predict weight gain (10/16/08) – BBC
  
• Brain's pleasure signals linked to obesity (10/17/08) – ABC
  

E. Stice, S. Spoor, C. Bohon, D. M. Small (2008). Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele Science, 322 (5900), 449-452 DOI: 10.1126/science.1161550

Tags: obesity, dopamine

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