Early Life Stress Predicts Future Conduct Disorder in Adolescents

Early Life Stress (ELS) and adversity increase people’s risk for developing mental, social, or emotional dysregulation and disorders later in life. The objective of this study was to test whether ELS in adolescents could prospectively predict future conduct disorder. The study additionally tested potential neural mediators of the effect of ELS on future conduct disorder, and specifically targeted the structural connections from the anterior insula and medial prefrontal cortex to the Nucleus Accumbens (NAcc). Data for the project came from the Adolescent Brain Cognitive Development Study (ABCD study), which is a longitudinal multi-site consortium funded by the National Institutes of Health that is collecting the full gamut of biomedical assessments in over 11,000 adolescents. Our findings suggest ELS predicts greater likelihood of conduct disorder two years later, and further, ELS correlates with abnormalities in structural connection between the anterior insula and NAcc. This research identifies early environmental and neural factors that might lead adolescents to develop conduct disorder

Early Life Stress Predicts Future Conduct Disorder in Adolescents

Early Life Stress (ELS) and adversity increase people’s risk for developing mental, social, or emotional dysregulation and disorders later in life. The objective of this study was to test whether ELS in adolescents could prospectively predict future conduct disorder. The study additionally tested potential neural mediators of the effect of ELS on future conduct disorder, and specifically targeted the structural connections from the anterior insula and medial prefrontal cortex to the Nucleus Accumbens (NAcc). Data for the project came from the Adolescent Brain Cognitive Development Study (ABCD study), which is a longitudinal multi-site consortium funded by the National Institutes of Health that is collecting the full gamut of biomedical assessments in over 11,000 adolescents. Our findings suggest ELS predicts greater likelihood of conduct disorder two years later, and further, ELS correlates with abnormalities in structural connection between the anterior insula and NAcc. This research identifies early environmental and neural factors that might lead adolescents to develop conduct disorder

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

Distinct neural circuits support incentivized inhibition

The ability to inhibit responses under high stakes, or "incentivized inhibition," is critical for adaptive impulse control. While previous research indicates that right ventrolateral prefrontal cortical (VLPFC) activity plays a key role in response inhibition, less research has addressed how incentives might influence this circuit. By combining a novel behavioral task, functional magnetic resonance imaging (FMRI), and diffusion-weighted imaging (DWI), we targeted and characterized specific neural circuits that support incentivized inhibition. Behaviorally, large incentives enhanced responses to obtain money, but also reduced response inhibition. Functionally, activity in both right VLPFC and right anterior insula (AIns) predicted successful inhibition for high incentives. Structurally, characterization of a novel white-matter tract connecting the right AIns and VLPFC revealed an association of tract coherence with incentivized inhibition performance. Finally, individual differences in right VLPFC activity statistically mediated the association of right AIns-VLPFC tract coherence with incentivized inhibition performance. These multimodal findings bridge brain structure, brain function, and behavior to clarify how individuals can inhibit impulses, even in the face of high stakes