Serotonin-dependent Modulation of Working Memory and Decision Activity in Primate Prefrontal Cortex

Abstract

The serotonergic system is one of the oldest and most widespread neuromodulator systems in the animal kingdom. In mammals, serotonin is synthesized in the raphe nuclei in the brain stem, from where serotonergic neurons project to almost all areas of the brain. Especially the prefrontal areas receive rich input from the anterior located raphe nuclei. With its many different receptor types, the serotonin system is suited to fulfill various functions throughout the brain. One of serotonins best known functions is its role in the emotional and motivational behavior in humans and its connection to the pathology of mood disorders. Treatment with serotonin reuptake inhibitors and other drugs targeting the serotonin system often show positive effects not only on the emotional state of the patients but also improve different cognitive functions in cases of accompanying cognitive impairments. There is further evidence that serotonin modulates individual aspects of cognition, such as working memory and decision-making. Most studies made use of systemic application or depletion of serotonin or its derivates, eliciting behavioral effects. This, however, leaves the question unanswered how serotonin modulates working memory and decision-related single cell activity; therefore, we recorded neurons in the dorsolateral prefrontal cortex in two awake monkeys performing a numerical same-different decision task. Simultaneously to the extracellular recordings we used Iontophoresis to apply minute amounts of serotonin and a serotonin 2A receptor antagonist in proximity of the recorded cells. We report, that serotonin decreased numerosity tuning during the first stimulus presentation by suppressing neuronal firing for the preferred stimulus whereas blockage of serotonin 2A receptor blockage increased working memory, reducing neuronal activity for not preferred stimuli. Further, we find that sensory information is reduced by blockage of serotonin 2A receptors, while information about the decision is increased by serotonin itself. The results suggest that different serotonin receptor types contribute differently to cognitive and sensory processes in prefrontal cortex and highlight the importance of further research to tackle mental illnesses with accompanying cognitive impairment.