The objective of this Career Development Award is to support new mentored training in cognitive neuroscience studies of dopamine-related function in healthy adolescents and first-episode psychosis, as the candidate begins an independent research program. Psychosis is a devastating illness that afflicts ~3% of the world?s population, and has sever economic and social/emotional consequences for both patients and their caregivers. Prior research has implicated deficits in dopamine systems in both the etiology and pathology of the disorder, and thus remediation of this system has been a prominent target for intervention. Although these deficits have been well documented, open questions remains as to how and why these deficits emerge. Prominent models of psychosis have implicated aberrant development of neural systems regulating the activation of dopamine systems. However, very little research has investigated how these regulatory systems develop in normative populations; let alone how deviations from normative development may be implicated in psychosis. Thus, a full understanding of psychosis necessitates a characterization of dopamine-related networks in healthy adolescence and deviations from these trajectories in psychosis. These findings will provide insight into determinants of risk for conversion from a developmental perspective and in turn the timing of interventions. The proposed award will build upon the candidate?s prior training in cognitive neuroscience, to extend this knowledge into the domain of normative development in adolescents and aberrant development in psychosis within dopamine-related networks.
Aim 1 will investigate the normative development of neural systems regulating engagement of the ventral tegmental area and substantia nigra, the core of the mesolimbic dopamine system, using multimodal neuroimaging. These developmental neuroimaging markers will then be associated with direct and indirect measures of dopamine to assess how they relate to dopaminergic function.
Aim 2 will evaluate how individuals with first-episode psychosis deviate from the normative trajectories characterized in Aim 1, and further probe how these deviations relate to anti-psychotic medication status. Finally, Aim 3 will have first-episode patients return for a 2-year follow-up to characterize how the clinical course of psychosis relates to early markers of dopamine-related dysfunction. Mentored training will compliment the candidate?s expertise in neuroimaging of dopamine-related circuits in healthy adults. Paralleling the proposed research, training will focus on the candidate gaining expertise in conducting neuroimaging studies in adolescent (Aim 1) and psychosis populations (Aim 2,3). Further, the candidate will gain expertise in the translation of animal models of behavior in adolescent and psychosis population, with a focus on understanding the nature of homology across multiple species (Aims 1-3). Finally, the candidate will gain expertise in experimental techniques associated with studying neurodevelopment (e.g., longitudinal data analysis;
Aims 1 -3), psychosis (e.g., adjustment for antipsychotic medication, characterizing clinical phenomenology;
Aims 2 -3), and translational neuroscience (e.g., integration of direct/indirect measures of dopamine;
Aim 3). The candidate has recruited a mentoring team with expertise in all of the above domains led by mentor Dr. Bea Luna, an expert in adolescent development, and co-mentor Deanna Barch, an expert in neuroimaging in psychosis populations. Further, the candidate will take advantage of the known strengths of the schizophrenia and adolescent research communities, as well as the emphasis on cross-species translation at the University of Pittsburgh. The proposed research will offer novel insight into dopamine dysfunction in psychosis through the lens of adolescent neurodevelopment. Further, the training will lay the foundation for an independent research program assaying the neurodevelopmental of neuromodulatory systems in psychosis. !
Prominent models suggest that development of the neural systems regulating dopamine-related circuits which underlie the emergence of psychosis. While prior research has characterized dopamine-related dysfunction in psychosis, relative few have investigated the regulation of these systems and/or their developmental trajectories. This proposal examines the development of neural systems that regulate engagement of dopamine systems in healthy adolescence, and to characterize deviations from normative development in first- episode psychosis. Thus, these investigations provide a novel characterization of dopamine-related dysfunction in psychosis through the lens of adolescent neurodevelopment. !
| Murty, Vishnu P; Shah, Hemali; Montez, David et al. (2018) Age-Related Trajectories of Functional Coupling between the VTA and Nucleus Accumbens Depend on Motivational State. J Neurosci 38:7420-7427 |
| Murty, Vishnu P; McKinney, Rachel A; DuBrow, Sarah et al. (2018) Differential patterns of contextual organization of memory in first-episode psychosis. NPJ Schizophr 4:3 |
| Shermohammed, Maheen; Davidow, Juliet Y; Somerville, Leah H et al. (2018) Stress impacts the fidelity but not strength of emotional memories. Brain Cogn : |
| Jalbrzikowski, Maria; Murty, Vishnu P; Stan, Patricia L et al. (2017) Differentiating between clinical and behavioral phenotypes in first-episode psychosis during maintenance of visuospatial working memory. Schizophr Res : |
| Murty, Vishnu P; Calabro, Finnegan; Luna, Beatriz (2016) The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. Neurosci Biobehav Rev 70:46-58 |
