DESCRIPTION (provided by applicant): The initial onset of mania, and by definition bipolar I disorder, typically occurs during adolescence, a developmental period associated with the maturation of orbitofrontal cortex (OFC) structural and functional connectivity with the amygdala (AMY). Adolescent manic patients exhibit accelerated and excessive OFC gray matter loss, frontal white matter integrity deficits, and OFC-AMY functional connectivity deficits compared with healthy developing youth. While OFC-AMY functional connectivity deficits represent a new neuroanatomical `endophenotype' for bipolar disorder, there exists a significant knowledge gap regarding associated modifiable risk and resilience mechanisms, identification of which could have significant implications for informing early intervention and prevention strategies. Adolescents with bipolar disorder often initially present with externalizing symptoms of inattention, agitation, aggression, and hyperactivity and are therefore frequently initially treate with psychostimulants (e.g., amphetamine, AMPH). However, a growing body of evidence suggests that early psychostimulant exposure may precipitate mood and behavioral symptoms including irritability and aggression, and accelerate the onset of mania in high-risk individuals. n rodents, repeated AMPH administration is uniquely associated with enduring neuronal excitability and dendritic spine atrophy in the OFC. Translational evidence therefore suggests that early psychostimulant exposure may represent a risk factor for OFC-AMY functional connectivity deficits in bipolar disorder. Additionally, clinical evidence indicates that adolescens with or at risk for developing bipolar disorder exhibit significant deficits in the long-chain omeg-3 (LCn-3) fatty acid docosahexaenoic acid (DHA), and preclinical evidence suggests that low DHA status during brain development impairs cortical maturation and reduces synaptic and white matter resilience. We believe that these and other translational data support our overarching HYPOTHESIS that the combination of low synaptic DHA status and chronic AMPH exposure (i.e., a `two-hit' model) during adolescence produces long-standing OFC-AMY functional connectivity deficits by promoting excessive synaptic pruning. As an initial evaluation of this pathogenic model, we propose to combine established dietary n-3 fatty acid interventions, quantitative histological techniques, multimodal in vivo neuroimaging, and behavior to investigate the effects of chronic AMPH exposure and/or LCn-3 fatty acid status on adolescent rat OFC-AMY circuit maturation and function. To integrate each study component, we will determine postmortem OFC and AMY dendritic spine density (Golgi) to investigate hypothesized interrelationships with neuroimaging (e.g., gray matter volume), histology (i.e., tract-tracing), and behavioral (i.e., aggression) outcome measures. It is anticipated that the results of this proposal will provide proof-of-concept evidence regarding modifiable risk and resilience mechanisms for OFC-AMY circuit maturation deficits associated with adolescent bipolar disorder, and could have significant implications for informing early intervention and prevention strategies for at risk youth.

PUBLIC HEALTH RELEVANCE: Although extant evidence suggests that adolescents with bipolar disorder exhibit deficits in orbitofrontal cortical (OFC) structural and functional connectivity with the amygdala (AMY), there exists a significant knowledge gap regarding associated risk and resilience mechanisms. Adolescents with bipolar disorder are frequently initially treated with psychostimulants, which may accelerate the onset of mood symptoms in vulnerable individuals, and exhibit deficits in long-chain omega-3 (LCn-3) fatty acids which have neurotrophic and neuroprotective properties. This preclinical proposal will investigate whether adolescent psychostimulant exposure is a risk factor for OFC-AMY circuit maturation deficits, and whether LCn-3 fatty acid status is a risk moderator using multimodal imaging, quantitative histology, and behavioral techniques.