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Genetic Research on Serotonin

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Genetic Research on Serotonin

Spending time in the sun, experiencing or thinking about happy things or, conversely, being threatened or experiencing a fearful situation triggers the release of serotonin in our brain.

As mentioned before, serotonin is a neurotransmitter with a widespread inhibitory effect on the brain. Normal serotonin levels in the orbitofrontal cortex (OFC) correlate with greater self-control levels. Decreased levels of serotonin usually mean a person acts more impulsively.

Considering the effect the function of serotonin has on the brain and behaviour, it is essential to understand its genetic origins and the research surrounding it, especially concerning aggression (for this particular topic).

DNA Genes Serotonin Aggression DNA helix and allele serotonin gene mutation StudySmarterDNA helix and allele, Flaticon

According to Popova (2008), behaviours such as attacking, defending, and other aggressive traits apply to both animals and humans, and serotonin specifically has a role in modulating these behaviours. Namely, the functioning of a serotonin system relies on:

  • Synthesis (making) and appropriate degradation (scrubbing away) of serotonin.

  • Serotonin uptake (whilst it is in the synaptic cleft, the space between two neurones that a transporter also affects).

  • Serotonin 5-HT receptors/degradation.

Genes can be linked to serotonin and behaviour through this system and mechanism. Genes may not directly affect behaviour, but how genes act on the regulators, i.e., the neurotransmitters that affect behaviours is how serotonin becomes an essential player in genetics and aggression (Popova, 2008).

Is there a genetic predisposition to low serotonin levels? If the genetic components for serotonin production/synthesis are affected, it will cause issues that could result in low serotonin levels.

In previous articles, we have seen how serotonin is involved in aggression and the behaviours manifesting through this aggression. Now, we will assess how genes affect the above system and how that may cause this aggression.

Serotonin and aggression: genotype and its effects on the serotonergic system

The amino acid tryptophan, composed of two enzymes, makes serotonin (5-HT). We care specifically about the enzyme tryptophan hydroxylase (TPH), as this is the enzyme that focuses on serotonin metabolisation. The other enzyme has more widespread effects and therefore is not particularly influential.

Monoamine oxidase A and B (MAOA and MAOB) break down the serotonin, the process of which is known as degradation. MAOA is the most influential, as the MAOA gene mutation has been linked to aggression.

The genes associated with TPH and MAOA are considered the most influential genes associated with serotonin and how it subsequently affected a person’s or animal’s mood.

Any serotonin gene mutations can affect these aspects of an animal or person.

Evaluation of the genetic research on serotonin’s function in aggression

  • Brunner et al. (1993) assessed a Dutch family and found a genetic issue causing a mutation in the structure of the MAOA gene.

    • Fourteen affected men had complex behavioural issues and had a syndrome of borderline mental retardation.

    • The behaviours exhibited were impulsivity, especially concerning aggressive acts, including arson, attempted rape, and exhibitionism.

    • When researchers tested their urine, there were deficiencies in their enzymatic activity of MAOA, which we know is involved in the degradation of serotonin (5-HT).

    • They found that the MAOA deficiency was directly related to these behavioural issues, notably, impulsive aggression.

  • George et al. (2001) compared the concentrations of serotonin and serotonin metabolite (5-HIAA) and testosterone in the cerebral spinal fluid of alcoholic abusers, non-alcoholic abusers, and healthy controls.

    • This study was about intimate partner violence perpetration, assessing their aggression.

    • All abusers scored significantly higher on the measures used to assess aggression than the healthy controls.

    • Non-alcoholic abusers had significantly lower serotonin levels and higher physical aggression than alcoholic abusers and the controls.

    • Alcoholic abusers had higher testosterone than non-alcoholics and the controls and significantly higher physical aggression than controls.

  • New et al. (2003) found that those who acted aggressively, such as domestic violence cases, had links between their genetics (issues and dysfunctions) and their serotonergic systems.

  • Cases et al. (1995) manipulated the gene that codes for MAOA in transgenic mice (mice with genetic information inserted into their DNA to alter it), which caused it to be deleted (knockout mice, the gene is ‘knocked out’).

    • This effect caused a deficiency of MAOA.

    • Serotonin concentrations increased ninefold, as MAOA could no longer break down the serotonin in the mice’s brains.

    • A few issues ensued: baby mice (pups) had behavioural problems such as trembling and fearfulness.

    • There was an increase in aggressive behaviours in adult mice, developing the distinct behavioural syndrome.

    • This study suggests that the inability to regulate serotonin levels causes behavioural issues in mice, specifically in male adult mice.

  • Walther et al. (2003) found that the tryptophan hydroxylase (TPH) gene was not the only one in the genome that affected serotonin synthesis.

    • The human tryptophan hydroxylase gene encodes the enzyme (that catalyses a particular step) for 5-HT (remember, 5-HT is serotonin) synthesis (Veenstra-VanderWeele, 2000). Therefore, any variations of this gene can cause issues with serotonin synthesis. It will cause a dysfunction in the serotonergic system.

    • Researchers genetically altered the mice, so they were deficient for the TPH gene.

    • What they found was surprising when compared to the control mice.

    • In brain regions of both the TPH deficient mice and the controls, 5-HT levels were normal.

    • However, TPH deficient mice lacked 5-HT in the blood, periphery tissues, and the pineal gland.

    • They discovered a genome in mice, rats, and humans that codes for TPH; the tryptophan hydroxylase (TPH) gene was not the only one in the genome that affected serotonin synthesis, and it was called TPH2.

    • TPH2 is expressed in the brainstem in humans and is responsible for serotonin’s central nervous system effects. TPH affects serotonin levels in the blood, periphery tissues, and pineal gland. TPH2 is what affects serotonin levels in the brain.

    • This study has implications for the source of serotonin and how affecting these genes affects behaviours. The following study illustrates why.

  • Kulikov et al. (2005): In this study on mice, the TPH2 gene was genetically altered (knockout mice) to see its effects on serotonin and aggression.

    • They changed a particular section of the allele from C to G on the gene.

    • Mice who had the original C gene had higher levels of 5-HT.

    • These mice were more prone to attacking other mice if they intruded on their territory. These are textbook examples of aggressive behaviours. TPH activity levels were higher in the C mice.

    • Mice altered to the G variant were less prone to attack intruders and had lower TPH activity.

    • This only affected interpersonal aggression, however. Mice would defend themselves.

    • Also, the C allele seems to be more common in mice, and the G allele is associated with decreased intensity of intermale aggression. Perhaps the C form is more common because of the success of these more aggressive mice in retaining their territories, finding and fighting for food, and showing dominant behaviours to attract mates, which increases the likelihood of passing it on.

  • Holmes et al. (2002): In this study, the researchers knocked out the serotonin transporter (5-HTT, or SERT) and assessed the aggression level of these mice in their cages.

    • They isolated the male mice and tested them with control mice, using the same intruder test mentioned above.

    • The SERT deficient mice were less inclined or slower overall with attacking the intruder than the controls. They showed similar levels of investigation, however. Aggression levels were overall reduced.

    • By getting rid of the transporter gene, a reduction in aggression and home-cage activity was produced in the mice, suggesting the dysfunction in the serotonergic system caused less aggression in mice.

These studies provide ample evidence of the genes associated with serotonin synthesis, transportation, and degradation, and the effects of dysfunction within this system on mood regulation, specifically, aggression.

Aggression is a common result of serotonergic dysfunction in most cases. Whether that is an increase or overflow of serotonin or a lack thereof, it remains that serotonin is intrinsically linked to aggression in some form.

Despite this, certain factors need to be considered, namely gender, as in:

  • Williams et al. (2003): here, women with specific genotypes had higher levels of 5HIAA (a byproduct of the breakdown of serotonin) than men. The study suggests it may be due to oestrogen, as it increases tryptophan hydroxylase gene expression.

    • Sullivan et al. (2006): women with major depressive disorder and comorbid panic disorder had higher levels of 5HIAA in their urine than a control group, indicating they have a higher serotonin release, increased serotonin metabolism, and decreased 5-HIAA clearance. This finding could potentially explain why women suffer from these disorders and behaviours.

    • Moberg et al. (2011): serotonin dysfunction had been linked to impaired aggression control and suicidal behaviours. It was found that in women, but not in men, 5HIAA showed a significant negative correlation to exposure to trauma in childhood, particularly violent trauma. In those who were suicidal, those with low 5HIAA were more prone to committing violent acts than those with higher levels of 5HIAA. Low 5HIAA usually means less serotonin. Less serotonin usually means less self-control and higher levels of aggression.

  • Similarly, ethnicity may also be a factor, as in Williams et al. (2003), African Americans with a specific genotype affecting their serotonin transporter promoter had higher 5HIAA levels, too. It’s been reported that African Americans respond less to SSRI’s and suffer more so with dealing with mental illnesses such as depression, which could be linked to this.

Higher 5HIAA levels typically mean more serotonin, so both ethnicity and gender seem to affect serotonergic function. This, in turn, may have other effects on the behaviours of these individuals.

Although much of the research indicates that serotonin has a causal relationship with mood regulation, this does not entirely translate to aggression. A lack or surplus of serotonin can cause multiple issues, so it is correlational.


Genetic Research on Serotonin - Key takeaways

  • Serotonin relies on three functions as a system: serotonin synthesis, serotonin uptake/transportation, and serotonin degradation.
  • Genes may not directly affect behaviour, but how genes act on the regulators - aka, the neurotransmitters that do affect behaviours, is how serotonin becomes an essential player in the game of genetics and aggression.
  • The amino acid tryptophan, composed of two enzymes, makes serotonin (5-HT). The specific focus is on the enzyme tryptophan hydroxylase (TPH), as it focuses on serotonin metabolisation.
  • TPH2 is the factor affecting serotonin within the brain.
  • Monoamine oxidase A and B (MAOA and MAOB) break down serotonin, the process of which is known as degradation.
  • A dysfunction in this process can result in aggressive behaviours, impulse control issues, and other problems. Multiple studies show those with these genes deleted or altered affect aggression in the affected individuals.

Frequently Asked Questions about Genetic Research on Serotonin

Genes affect serotonin in multiple ways, either through causing issues with the synthesis of serotonin (lowering or increasing production), causing problems with the serotonin transportation, or reducing the uptake of serotonin after it has been produced.

Yes. If the genetic components for serotonin production/synthesis are affected, it will cause issues that could result in low serotonin levels.

There’s not a single gene that completely controls serotonin. However, genes such as the TPH gene and the MAOA gene affect the synthesis and degradation of serotonin.

The transporter gene is responsible for transporting serotonin out of the synaptic cleft. This allows more serotonin to be released into the cleft and stops the action of serotonin when needed. If anything interferes with this process, it can cause problems with all moods, including feelings of happiness. A person may feel happy for a while, but an excess of serotonin in the cleft would eventually lead to desensitisation to serotonin and a lower level of happiness.

Several activities release serotonin: going out in the sun, experiencing or thinking about happy things, or conversely, being threatened or experiencing a fearful situation.

Final Genetic Research on Serotonin Quiz

Question

What is serotonin?

Show answer

Answer

It is a neurotransmitter.

Show question

Question

If a person has normal serotonin levels, what can they usually do?

Show answer

Answer

Normal levels of serotonin in the orbitofrontal cortex (OFC) correlate with greater self-control levels. Decreased levels of serotonin usually mean a person acts more impulsively.

Show question

Question

What are the critical components of a functioning serotonin system?

Show answer

Answer

Serotonin synthesis, serotonin transportation/uptake, and serotonin receptors/degradation.

Show question

Question

Do genes have direct control over behaviours?

Show answer

Answer

No. Genes may not directly affect behaviour, but how genes act on the regulators, i.e., the neurotransmitters that influence behaviours, are how they affect behaviours.

Show question

Question

What amino acid produces serotonin?

Show answer

Answer

The amino acid tryptophan.

Show question

Question

What important enzyme is part of tryptophan?

Show answer

Answer

Tryptophan hydroxylase (TPH).

Show question

Question

What breaks down serotonin?

Show answer

Answer

Monoamine oxidase A and B (MAOA and MAOB).

Show question

Question

What did Cases et al. (1995) find in their study?

Show answer

Answer

For mice who had their MAOA gene deleted, serotonin concentrations increased ninefold, as MAOA could no longer break down the serotonin in the mice’s brains. Adult male mice showed increases in aggressive behaviours.

Show question

Question

What did Walther et al. (2003) find in their study?

Show answer

Answer

The TPH gene was not the only one in the genome that affects serotonin synthesis. TPH affects serotonin levels in the blood, periphery tissues, and pineal gland. TPH2 is what affects serotonin levels in the brain.

Show question

Question

What did Kulikov et al. (2005) find in their study?

Show answer

Answer

In this study on mice, the TPH2 gene was genetically altered (knockout mice) to see its effects on serotonin and aggression. They changed a particular section of the allele from C to G on the gene. Mice who had the original C gene had higher levels of 5-HT. These mice were more prone to attacking other mice if they intruded on their territory.

Show question

Question

What did Holmes et al. (2002) find in their study?

Show answer

Answer

In this study, the serotonin transporter (5-HTT, or SERT) was knocked out, and they assessed the aggression level of these mice in cages. The SERT deficient mice were less inclined or slower overall with attacking the intruder than the controls.

Show question

Question

What did Brunner et al. (1993) find in their study?

Show answer

Answer

Brunner et al. (1993) assessed a Dutch family and found a genetic issue causing a mutation in the structure of the MAOA gene. 14 affected men had complex behavioural issues (related explicitly to aggression) and were affected by a syndrome of borderline mental retardation.

Show question

Question

What did Williams et al. (2003) find in their study?

Show answer

Answer

Women with specific genotypes had higher levels of 5HIAA (a byproduct of the breakdown of serotonin) than men. Similarly, African Americans with particular genotypes had higher levels of 5HIAA, too, when compared to Caucasians.

Show question

Question

What do we mean when we say knockout mice?

Show answer

Answer

In this case, it means the gene in these mice has been altered/deleted or knocked out.

Show question

Question

Is the evidence for serotonin causing aggression causal?

Show answer

Answer

No. It is causal in its relation to mood regulation, but not for aggression. It is only correlational.

Show question

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