Behavioral and Neural Mechanisms of Serotonin Modulation of Impulsivity and Reward

Despite its prevalence in many psychiatric disorders, such as attention deficit hyperactivity disorder, suicidal depression, schizophrenia, and aggression and motivational disorders, impulsivity and its biological bases remain poorly understood. Subdivisions of impulsivity, including impulsive action (reduced response inhibition) and impulsive choice (reduced delay of gratification), sometimes present in an uncorrelated manner. This complexity renders pathological impulsivity difficult to treat, as different underlying causes likely result in different phenotypic presentations, despite being placed under one umbrella term. In order to study the behavior and biology of one particular facet of impulsivity, this dissertation utilizes the serotonin 1B receptor (5-HT1BR; an inhibitory G-protein coupled receptor) knockout mouse model, which presents with a specific elevation in impulsive action but not impulsive choice. In Chapter 1, I show that mice lacking the 5-HT1BR have increased impulsive action accompanied by enhanced motivation and responsiveness to palatable rewards, indicating that they may have dysregulation of subjective reward valuation. In Chapter 2, I then explore the 5- HT1BR knockout model from the perspective of behavioral inhibition, demonstrating that knockout mice have intact inhibitory learning despite having difficulty withhold responding for reward. Of particular interest to this particular presentation of impulsive action, therefore, is serotonin neuromodulation of reward circuitry in the brain. In Chapter 3, I first show behaviorally that normalizing reward value in 5-HT1BR knockout mice reduces impulsive action to the level of controls. Neurally, I then complete a series of experiments with targeted knockouts in reward-related brain regions, specifically projections to and from the nucleus accumbens shell, in addition to combined 5-HT1BR genetic heteroreceptor and viral autoreceptor knockout. Only combined Emx1+ heteroreceptor and autoreceptor knockout results in increased motivation and impulsivity similar to the whole brain knockout. On the other hand, combined VGAT+ heteroreceptor and autoreceptor knockout increases hedonic taste reactvity. This suggests that modified serotonin release in addition to multiple 5-HT1B heteroreceptor population losses synergistically modulate neural signaling to increase reward valuation and impulsive action. Together, these studies provide insight into the behavioral and biological bases of impulsive action and propose a framework for better understanding specific presentations of impulsivity