Serotonin and Behavior: Deconstructing the 5-HT6 Receptor

By Caleb Winn


Serotonin and dopamine are buzzwords in modern conversation for good reason. These compounds participate in many regions of the limbic system including the basal ganglia for habit formation. Research by Eskenazi, Brodsky, and Neumaier (2015) on serotonin, dopamine, and habit offers a new perspective on how the basal ganglia is constructed and how we will study the basal ganglia going forward. Their research, “Deconstructing 5-HT6 receptor effects on the striatal circuit function”, examines the difference between the direct and indirect pathways in the basal ganglia and how these two pathways can be experimentally isolated.


Let’s first describe the basal ganglia (BG). The BG is a behavior circuit of neurons in the mammalian brain which refines our actions. A behavioral psychologist could name it the Choose-Between-a-Carrot-Stick-or-a-Cheeto-Ganglia, and a cognitive neuroscientist could name it simply The Maze. Researchers agree certain external influences (such as drugs or environmental contexts) can alter how the BG refines behavior. This influence can be seen on a molecular scale, with an example being individuals experiencing drug addiction. The BG in the individual with addiction will exhibit strengthened habitual behavior manifesting as visible markers of cellular activation in certain pathways.

Broadly, the direct pathway activates behavior output while the indirect inhibits behavior.


A metaphor for the direct and indirect pathways of the BG could be two parallel water slides that you’re designing in RollerCoaster Tycoon (remember that game, c. 2002?). The longer and squigglier you make one water slide the longer it will take water to get to the bottom, while water poured down the straight slide will reach the bottom faster. As we understand it the direct and indirect pathways are complex water slides for behavior, and certain neurotransmitters like dopamine and serotonin play integral roles in the timing and activation of these parallel circuits. To complete the metaphor, an individual experiencing addiction will likely have a waterslide for habit that consistently outcompetes their water slide for behavior inhibition.


Both the direct and indirect pathways are structurally similar although they are designed to balance one another in behavior production. Eskenazi et al. brilliantly leveraged a simple molecular difference between the direct and indirect pathways to manipulate a single pathway, allowing the researchers to attribute differences in behavior to differences in one pathway’s over-activation. Eskenazi et al. introduced a virus into the BG, a virus designed to tell a certain type of cell to express more serotonin receptors in only one of the two pathways. In this way, if behavior is different between experimental and control groups then conclusions can be drawn regarding serotonin receptor density and behavioral output.


Before this research neuroscientists have long-pondered how the direct and indirect pathways can be isolated for behavioral experiments. This research by Eskenazi et al. is the first to examine the difference between the direct and indirect pathway using an endogenous neurotransmitter receptor via viral vectors, not an exogenous pharmacotherapy, to study the influence serotonin and dopamine play on formation and flexibility of habit.


Expect future research to employ viral vectors to manipulate behavioral pathways. We’re a long shot from using these techniques to ameliorate drug addiction in humans, but understanding how our brains create behavior is an important step in improving quality of healthcare and treatment for all.

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