Category Archives: neurotransmitters

The Algorithm of The Brain

I know that the computer metaphor does not do justice to the brain, but can we conceivably come up with a universal algorithm in how the brain processes stimuli and reacts/responds to them? Further, can we then tie up those algorithmic sub-modules to actual neural subsystems/structures and neurotransmitter systems as substantiated in the physical brain?

That is what I intend to do today, but first let us list our very basic algorithm of how the brain processes stimuli and responds to it. Consider it like a flowchart with each step there being made a decision. At each step that is numbered 1, nothing further happens; at each step numbered 2, further 2 choices are available.

  1. Stimuli comes!
    1. Ignore?
    2. Attend?
      1. Unimportant?
      2. Important?
        1. Default response?
        2. Choose response?
          1. Unfeasible?
          2. Feasible?
            1. Execute response!

Now, let me unpack this a bit. The first step for the purposes of this post is an incoming stimulus. When the stimuli comes we (the brain) can be in different levels of alertness and lookout for incoming stimuli; thus the brain may miss or detect the stimuli. We may be in neuro-vegetative states like sleep and feeding and may be relaxing and miss on both threatening as well rewarding stimuli. Or we can be in a vigilant mode either on lookout for danger or say alert while ready to pounce on prey. A Vigilance system can be reliably conjectured to underlie this and indeed Locus Coerelus- Nor epinephrine (LC-NE) system may just be exactly that system that makes us alert and inhibits neuro vegetative states. Another brain structure relevant here is Amygdala which is popularly known for its role in detecting threatening stimuli, but is involved in pleasant stimuli detection too. Hypersensitiveness of this system can conceivably lead to anxiety at one end (constant lookout for trouble) and addiction (constant lookout for possible gains) at the other. One can also extend this line of reasoning and posit that differential sensitivity of this system may underlie the personality trait of Neuroticism.

Once you have noticed or attended to a stimuli what next? Not every stimuli is salient or important. The next step for the brain is to identify whether the stimuli is indeed important from a functional point of view- whether it is an indicator of, or an actual, reward or punishment. Here comes the incentive salience function of Dopamine. Dopamine neurons in say Nucleus Accumbens (NAcc) area code for whether the incoming stimuli is important or not (see work of Berridge et al) ; if its not important nothing needs to be done; however if it is important and consequential than an appropriate response needs to be executed. Activity has to ensue. Please note that though NAcc is typically thought of as part of a reward circuit, it is equally involved in determining salience of an aversive stimuli. Hypersensitiveness of this incentive salience system can conceivably lead to depression at one end (where all stimuli are important , but negatively toned or aversive) and mania at the other end (where all stimuli are important, but perceived as positively valenced). One can also extend this line of reasoning and associate differential sensitivity in this system to trait of Extraversion.

Once you have determined that the stimuli is important and needs responding, how do you determine the right response? One effortless and ‘hot’ way is to use the default response – if someone threatens you, punch them in the face! The other, more effortful, and ‘cold’ way is to choose a response from the response sets that have been activated or by overriding the default response and selecting something better. This is the selfregulation system. As a brain region, I’m sure ACC has a major role to play here- detecting conflicts between responses and also inhibiting dominant default response. In terms of neurotransmitters I see a role for Serotonin here – regulating the response, especially emotional and instinctual response. Hypersensitiveness of this system may lead to obsessions (rigid thinking) and compulsions (rigid acting) and differential sensitivity in the system may be associated with Conscientiousness.

Now, that you/ your brain has chosen the most appropriate response, one further step needs to be executed before you actually execute the action. Many readers of this blog will be familiar with the Value -Expectancy model of motivation: Value was coded by dopamine neurons using incentive salience, what about expectancy? Basically the V-E model posits that an action will be taken only if you value the outcome and are reasonably sure that you can act in such a way as to achieve the outcome. Neurons in PFC may conceivably code for outcome prediction. PFC is important to predict whether a particular course of action will lead to desired results. It is also conceivable that dopamine neurons may play an important role here. The basic idea is to predict whether you can execute the response and receive the reward or avoid the punishment and only then if the action is feasible, then execute the action. This outcome prediction module I think recruits PFC to a large extent. Hypersensitivity of this system may lead to ADHD and differential sensitivity associated with Openness to experience.

To me the above looks very neat and logical and elegant and I would love your comments regarding the same and also any contradictions you see in literature or any additional thoughts you may have.

Perosnality and Neurotransmitters

Although all introductory Psychology textbooks warn against any simplistic correlations between neurotransmitters and complex behavioral and cognitive measures like Personality traits, I am going to do exactly that in this post. In an earlier post , I had related personality traits to neurotransmitter systems and operant learning paradigm and here I present some corroborating evidence for the personality- neurotransmitter system linkage.

First to recap:

  1. Nueroticism/ Harm Avoidance: Serotonin system
  2. Conscentiousness/ novelty seeking: Dopamine system
  3. Extarversion/ Reward Dependence:  Norepinephrine system 
  4. Agreeableness/ Persistance: Epinepherine system
  5. Openesses/ Rebeliious-conformity/self-directedness: Histamine system

 First off to bat consider the following- Neuroticism is manifested as anxiety and if serotonin system is implicated , then genes affecting the serotonin system should affect the neuroticism levels of individuals . This is exactly what was found by Lesh et al.

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

Next comes a recent study finding that a gene variant related to NO (a neurotrasmitter) is related to Impulsiveness. Now One of the defining traits of NS/ C is Impulsiveness. This has been found related to NOS1 gene. Here is the original study.

Context Human personality is characterized by substantial heritability but few functional gene variants have been identified. Although rodent data suggest that the neuronal isoform of nitric oxide synthase (NOS-I) modifies diverse behaviors including aggression, this has not been translated to human studies.

Objectives To investigate the functionality of an NOS1 promoter repeat length variation (NOS1 Ex1f variable number tandem repeat [VNTR]) and to test whether it is associated with phenotypes relevant to impulsivity.

Design Molecular biological studies assessed the cellular consequences of NOS1 Ex1f VNTR; association studies were conducted to investigate the impact of this genetic variant on impulsivity; imaging genetics was applied to determine whether the polymorphism is functional on a neurobiological level.

Setting Three psychiatric university clinics in Germany.

Participants More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (ADHD), 151 with familial ADHD, 189 suicide attempters, and 182 criminal offenders.

Main Outcome Measures For the association studies, the major outcome criteria were phenotypes relevant to impulsivity, namely, the dimensional phenotype conscientiousness and the categorical phenotypes adult ADHD, aggression, and cluster B personality disorder.

Results A novel functional promoter polymorphism in NOS1 was associated with traits related to impulsivity, including hyperactive and aggressive behaviors. Specifically, the short repeat variant was more frequent in adult ADHD, cluster B personality disorder, and autoaggressive and heteroaggressive behavior. This short variant came along with decreased transcriptional activity of the NOS1 exon 1f promoter and alterations in the neuronal transcriptome including RGS4 and GRIN1. On a systems level, it was associated with hypoactivation of the anterior cingulate cortex, which is involved in the processing of emotion and reward in behavioral control.

Conclusion These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.

Now there does exist a relationship between NO and dopamine (but then which two neurotransmitter systems are not related) and that way I can still save my face by claiming that it is the dopamine that is finally mediating the impulsivity and not NO.

There is evidence suggesting that nitric oxide (NO) may play an important role in dopamine (DA) cell death. NO may act as a neuroprotector or neurotoxic agent in dopamine neurons, depending on cell redox status. Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains of Parkinson’s disease (PD) patients. However, data from animal models show that GSH depletion by itself is not sufficient to induce nigral degeneration. Low NO concentrations have neurotrophic effects on DA cells via a cGMP-independent mechanism that may implicate up-regulation of GSH. On the other hand, higher levels of NO induce cell death in both DA neurons and mature oligodendrocytes that is totally reverted by soluble factors released from glia. Alterations in GSH levels change the neurotrophic effects of NO in dopamine function into neurotoxic, under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterised by an early production of free radicals followed by late activation of the sGC/cGMP/PKG pathway. Arachidonic acid metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. Neurotrophism of NO switches into neurotoxicity after GSH depletion, due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these cell death signaling pathways in pathological conditions like Parkinson’s disease, where GSH depletion, glial dysfunction and NO overproduction have been documented, are discussed.

Next we move to the sociability factor underlying Extraversion/ Reward dependence. Here studies show that Noardrenaline is related to sociability/ dependence etc. Here is a study showing effects of NA on sociability.

Rationale: Treatment with antidepressants has been shown to affect social functioning, but drugs with actions on different neurotransmitters may have a different profile of effects. Objective: To study the effects of acute manipulation of two neurotransmitters, serotonin and noradrenaline, on social behaviour in healthy volunteers. Methods: Sixty volunteers were randomly assigned to a single dose of a selective noradrenaline reuptake inhibitor, reboxetine (4 mg), a selective serotonin reuptake inhibitor, citalopram (10 mg), or placebo. They socially interacted with a confederate behaving in a non-sociable manner in a stranger-dyadic social interaction paradigm 1.5 h postdrug. Social behaviour during the interaction was video recorded by a hidden camera and subsequently analysed. After the interaction, volunteers played the mixed-motive game with the confederate. This game has been shown to measure cooperative behaviour and communication. Volunteers read a short story and rated their mood predrug and before and after the interaction. Results: Subjects on reboxetine showed reduced hand fiddling during the interaction and gave significantly more cooperative communications during the mixed-motive game. More volunteers on reboxetine were classified as cooperative players. On the reading task, the speech of subjects on citalopram showed less reduction of energy variation after the social interaction. Conclusion: Reboxetine had clear effects on social behaviour. Noradrenaline was related to increased social engagement and cooperation and a reduction in self-focus. Citalopram had less effect on cooperative behaviour but serotonin may be associated with protection of the self from the negative consequences of social interaction.

Also, Zuckerman has clearly related NA to sociability and dependence.As per him:

Ellison studies the effects of chemical lesions of either dopamine or noradrenaline system in rats. …Norepeinepherine-lesioned rats spent more time in their burrows and less time in a behavioral arena in which spontaneous social interactions could occur….

That takes us to the fourth trait of agreeableness and the related Empathy system . Here the famous Scacter- singer experiment of administering Adrenaline and then finding that the mood became congruent with that of other people has to be reinterpreted in terms of empathy at work rather than james-lange two-step appraisal of emotion. Do read the expermine in more detail at the above link.

The Experiment in a nut shell.
Independent Variables

1. Injected Adrenaline or Saline solution
2. The subjects were given a description of side-effects, misinformed about the side-effects, or told nothing.
3. The subjects were placed in a ‘Euphoric’ (Happy) or ‘Angry’ situation.

Dependent Variables

1. Observed signs of happiness
2. Observed signs of anger
3. Self-report of happiness or anger

Euphoria: As expected, the adrenaline misinformed group, and the adrenaline ignorant group, reported being happiest
Anger:  This didn’t work. Most subjects were positive about their feelings. Schachter and Singer attribute this to the fact that they were students eager to please their tutors

It is important that those people who were placed with confederates exhibiting happy states felt happy and the same was felt by those who received adrenaline; a more valid interpretation is that adrenaline increased the empathetic feelings and lead to transmission or contagion of mood. the situational variable where one tried to induce anger by being irritable did not lead to to anger; perhaps if the confederate was irritated, they might have become irritated too due to empathy; but no anger is expected as per my interpretation that it is empathy that is primary and not the cognitive appraisal of emotional physiological state.

Finally I agree that I have not been able to find much about histamine system and how it may be affect the openness/ rebellious/conformity trait. As an exercise to reader here are some low histamine condition links.

That is it for now. would love if somebody points to some other studies that corroborate the case.
K.-P. Lesch, D. Bengel, A. Heils, S. Z. Sabol, B. D. Greenberg, S. Petri, J. Benjamin, C. R. Muller, D. H. Hamer, D. L. Murphy (1996). Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region Science, 274 (5292), 1527-1531 DOI: 10.1126/science.274.5292.1527
Wai Tse, Alyson Bond (2002). Difference in serotonergic and noradrenergic regulation of human social behaviours Psychopharmacology, 159 (2), 216-221 DOI: 10.1007/s00213-001-0926-9