The Role of Puberty in Corticostriatal Circuitry Development and Avoidance in Adolescents with Anxiety

Summary Nearly one in three youth are diagnosed with an anxiety disorder during childhood or adolescence, which often persists into adulthood and increases the risk of depression and suicide. Early adolescence, with the onset of puberty, coincides with sex differences in the rise of anxiety symptoms, particularly social and generalized anx- iety disorder. During this time, corticostriatal circuitry implicated in reward processing and learning (ventral teg- mental area [VTA], nucleus accumbens [NAcc], ventromedial prefrontal cortex [vmPFC]), undergo significant maturation and are altered in individuals with anxiety disorders. Yet, how puberty impacts development of this circuitry in anxious youth remains unclear. Avoidance of perceived threat is a core symptom of anxiety. Rein- forcement learning (RL)—learning from expectation and outcome—is supported by corticostriatal circuitry and provides a compelling framework to understand avoidance. Computational modeling of fMRI data with RL tasks indicates that individuals with anxiety disorders exhibit reduced reward prediction error—dopaminergic striatal signal to unexpected reward. Similar PE signaling patterns are present in women but the neurobiological mech- anisms underlying the emergence of these sex differences are unknown. Animal studies show that gonadal hormones sculpt and modulate corticostriatal circuitry implicated in reward learning. Thus, it is plausible that rise in pubertal hormones could impact corticostriatal function but how blunted reward PE signals translate into daily- life approach-avoidance behavior in anxious teens is unclear. We will test the overarching hypothesis that blunted reward PE signaling within the striatum/vmPFC will be associated with more frequent avoidance/less approach behavior and anxiety symptoms and that the rise in pubertal hormones will amplify this relationship, especially in girls. We test this hypothesis in 140 unmedicated adolescents (50% female), varying in levels of anxiety, with 2/3 oversampled for clinical levels anxiety symptoms. We will repeatedly assess participants at five timepoints. At baseline and approximately 18 months later, we will assess anxiety (clinical interviews, question- naires), pubertal status (Tanner, self-report), pubertal hormones (DHEA, testosterone, and estradiol), approach- avoidance behavior in the lab and daily life (i.e., Ecological Momentary Assessment), and indices of corticostri- atal circuitry function (passive avoidance fMRI task, resting state fMRI, dopamine function, measures of gluta- mate and GABA). We use multimodal neuroimaging with ultra high-field MRI at 7 Tesla, which will yield unprec- edented characterization of corticostriatal neurodevelopment during puberty in anxious youth. Change in symp- toms will be assessed bi-annually via online questionnaires over 18 months post-baseline visit. We aim to: 1) Characterize corticostriatal circuitry implicated in RL in anxious adolescents; 2) Determine how pubertal hor- mones are associated with corticostriatal function development, daily-life avoidance/approach behavior, and anxiety; 3) Explore associations between neural indices of corticostriatal function and wholebrain networks. Project Number: 1R01MH140962-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Cecile Ladouceur | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $782,547 | Activity Code: R01 | Study Section: Child Psychopathology and Developmental Disabilities Study Section[CPDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11205329