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“Even though it is common knowledge, it never ceases to amaze me that all the richness of our mental life - all our feelings, our emotions, our thoughts, our ambitions, our love lives, our religious sentiments and even what each of us regards as his or her own intimate private self - is simply the activity of these little specks of jelly in our heads, in our brains. There is nothing else.” -V.S. Ramachandran


 Brain cells. Source: University of Rochester

Read Part 1: [The Brain Soup: Neurotransmitters and Neuromodulators]
In the previousarticle, we analysed the most common chemical messengers of our brain. This time we will probe into how they can interact together to produce intricate behaviors. Later on, I will highlight some of the chemical processes running in the background, without which brain function would not be feasible, and conclude by discussing the role of neural receptors.


Chemical recipes: The interactions between neurotransmitters 

In the same way that a chef mixes different ingredients to create a wide range of dishes, the brain combines different neurotransmitters to fine-tune a myriad of functions. A good example of this involves dopamine and serotonin in behavior control.


These two neurotransmitters signal diametrically opposite forms of behavior: adopting quickly gratifying actions vs. withholding potentially negative impulses.Dopamine acts as a strong motivator by increasing the expectancy of reward, whereas serotonin is associated with the ability to refrain from impulsive behaviors, such as to attack someone or engage in self-harming practices.


These systems have long been studied apart, but researchers have recently put forward a model that integrates the two. In this model — based on large behavioral, anatomical and physiological research — dopamine and serotonin are thought to code for the long term history of rewards and punishments, respectively. The main idea is that the ratio of the two neurotransmitters works as a baseline or aspiration level to which outcomes and goals are evaluated.


Feedback and dopamine in the brain (comic)

 Imagine the following scenario involving an average student named Emma. Early this week, she was given surprisingly good marks on two different tests and received lots of positive feedback for her interventions in class. Each of these outcomes were probably registered in the brain by sharp releases of dopamine, whereas the absence of negative feedback means low serotonergic activity. By the end of the week, Emma’s brain is “running” on a ratio of high dopamine and low serotonin – a baseline that broadly reflects the recent positive experiences. But on the last class of the week, the teacher returns Emma’s homework with an average mark, which she interprets as a complete failure. On top of all things, the teacher acts unimpressed by her last-minute intervention, which is likely signaled by a quick release of serotonin that leaves Emma in a state of dispiritedness.


This example shows how the same “mundane achievement” can be perceived as comparatively bad if the baseline is positive (high dopamine and low serotonin), or good when the baseline is negative (low dopamine and high serotonin). In the same logic, a “mundane failure” feels more threatening in the context of a positive baseline, than in a negative one. Ultimately, these evaluations are used to decide whether to keep or change behaviors.

Obtained rewards, computed by fast dopamine signals

Obtained rewards, computed by fast dopamine signals, are compared to average rewards, which are computed by basal dopamine levels, to decide whether to maintain or switch to another strategy. The final decision would likely incorporate similar calculations of punishment, computed by serotonin. Source: Cools, Nakamura, & Daw (2011).


In a 2006 study, researchers showed that a single dose of serotonin reuptake inhibitor (a common antidepressant), which temporarily decreases basal levels of serotonin, increased the chances of people changing their behavior inappropriately in response to very unlikely punishments. In this experiment, participants had to choose the correct button out of two options (green or red). When they pressed the right button, eight of ten times they were informed of having chosen well, whereas on the remaining two trials they were misled by a message informing they had been mistaken. Compared to placebo, the patients under serotonin treatment were much more likely to change their choice after receiving wrong information, suggesting a higher sensitivity to negative feedback.


Similar results from genetic and acute tryptophan depletion (the chemical precursor to serotonin) research offerconverging evidence that changes in the levels of serotonin alter human reactivity to punishments. In parallel, changes in basal levels of dopamine due to pharmacological interventions or genetic profiles affect people’s sensitivity to rewards.When considering that most behaviors entail competing likelihoods of reward and punishment, it becomes evident why the brain needs to incorporate distinct physiological markers for each, in order to make balanced decisions and properly evaluate results. 

Model of how dopamine and serotonin regulate behavioral activity or inhibitio

Model of how dopamine and serotonin regulate behavioral activity or inhibition, according to competing rewards and punishments. Source: Boureau & Dayan (2011).


Indispensable kitchenware: Glial cells, Reuptake Molecules and Enzymes 

As important as having the right ingredients is having the right utensils for cooking and cleaning the mess afterwards. Nobody in his right mind would cook a meal over burned leftovers or inside a rusty pot. It also goes without saying that one should keep the stove and exhauster constantly clean.


When it comes to the brain, the situation is not very different. One does not want used neurotransmitters to pile up, or to have defective neurons lying around in the brain. Glial cells, which match neurons in numerical terms, perform many of these “less prestigious” tasks; from cleaning synapses, to delivering needed nutrients, insulating neurons, destroying old or defective cells, fighting infections, and some more.


Multiple sclerosis is perhaps the most drastic example of what happens when glial cells stop working. This devastating condition is caused by a reduction in the function of oligodendrocytes, a group of glial cells responsible for neural insulation. Recent research has implicated glial cells in a myriad of other brain disorders, ranging from chronic pain, to depression, autism, epilepsy, and schizophrenia; each one further reinforcing the importance of these cells.


Types and functions of glial cells in the brain

Types and functions of glial cells in the brain [Source]


Crammed between neurons and glial cells, an important group of transporter molecules is also working diligently to gather the neurotransmitters still floating around the synapses and send them back into the host neurons. Once there, enzymes destroy or recycle the neurotransmitters, completing their life cycle. As we will discuss later on in this series, it is by targeting these two kinds of molecules that most modern psychiatric medicines act.


Finally, do not forget the cutlery: neurotransmitter receptors


What good is a perfectly made pancake if we do not have a fork and knife to eat it? Similarly, neurotransmitters are of no use if there are not enough functioning receptors in neighboring neurons to detect and translate their presence into useful electrical signals.


If you have experienced sleep deprivation at some point in your life, you already know what a lack of enough receptors feels like. A human study from 2012 showed that sleep deprivation leads to a decrease in a subset of dopamine receptors in a certain region of the brain, the striatum, where dopamine usually acts to increase arousal and process reward. This change in the quantity of receptors was directly associated with feelings of sleepiness and fatigue, as well as with decreased alertness. The authors confirmed that sleep deprivation was not altering the release of dopamine, concluding that the effects were probably due to receptor changes alone.


Brain regions where dopamine receptors decrease due to sleep deprivation

Brain regions where dopamine receptors decrease due to sleep deprivation (blue). Source: Volkow et al. (2012).


We have discussed how neurotransmitters interact to modulate complex behaviors and mental processes, focusing on the opponent roles of serotonin and dopamine. Then, we briefly covered some of the cells and molecules that support the complex communication networks of our brains, and concluded by examining the importance of neural receptors.


In thenext article of this series we will delve into the effects that diets and drugs have on brain function, starting with the most common of them all: coffee!



Ricardo Oliveira is a neuroscientist passionate about research and science divulgation, based in Portugal.



Azevedo, F. A., Carvalho, L. R., Grinberg, L. T., Farfel, J. M., Ferretti, R. E., Leite, R. E., ... & Herculano‐Houzel, S. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain.Journal of Comparative Neurology,513(5), 532-541.

Bear, M.F., Connors, B.W., Paradiso, M., Bear, M.F., Connors, B.W. and Neuroscience, M.A., 1996. Exploring the brain.Neuroscience: Williams & Wilkins.

Boureau, Y. L., & Dayan, P. (2011). Opponency revisited: competition and cooperation between dopamine and serotonin.Neuropsychopharmacology, 36(1), 74-97.

Chamberlain, S. R., Müller, U., Blackwell, A. D., Clark, L., Robbins, T. W., & Sahakian, B. J. (2006). Neurochemical modulation of response inhibition and probabilistic learning in humans.Science,311(5762), 861-863.

Cools, R., Nakamura, K., & Daw, N. D. (2011). Serotonin and dopamine: unifying affective, activational, and decision functions.Neuropsychopharmacology,36(1), 98-113.

Kandel, E.R., Schwartz, J.H. and Jessell, T.M. (eds., 2000).Principles of neural science. New York: McGraw-hill.

Perry, S. (2010). Glia: the other brain cells.Society for Neuroscience.Retrieved from: http://www.brainfacts.org/brain-basics/neuroanatomy/articles/2010/glia-the-other-brain-cells/

Ramachandran, V. S. (2004). A brief tour of human consciousness: from impostor poodles to purple numbers.

Volkow, N. D., Tomasi, D., Wang, G. J., Telang, F., Fowler, J. S., Logan, J., ... & Ferré, S. (2012). Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain.The Journal of Neuroscience,32(19), 6711-6717.

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