Study of brain circuits involved in the dysregulation of dopaminergic system induced by stress exposure in adolescence and adulthood

• Grant number: 23/14677-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2024
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Flávia Alves Verza
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets, AP.JP

Abstract

Depression and schizophrenia share stress as a risk factor, but the age of diagnosis specifically sets them apart. While schizophrenia is typically diagnosed in late adolescence, depression is more prevalent in adults. Stress plays a pivotal role in the development of psychiatric disorders, but the neurobiological mechanisms underlying stress susceptibility remain not fully understood. Key brain structures such as the prefrontal cortex, the hippocampus, and the amygdala are central in regulating stress responses. Altered activity of these regions contributes to the dysregulation in other brain areas, including dopaminergic neurons in the ventral tegmental area (VTA), which are impacted by stress-induced changes in the activity of the medial prefrontal cortex (mPFC), ventral hippocampus (vHip), and basolateral amygdala (BLA). Dopaminergic system dysregulation is implicated in various psychiatric disorders., such as schizophrenia, where there is a hyperdopaminergic state associated with psychotic symptoms, and depression, where dopaminergic hypo-responsiveness is linked to anhedonia and lack of motivation. Findings from our group indicate that rats subjected to stressors during the adolescent period experience functional loss of parvalbumin (PV)-positive interneurons in the ventral hippocampus, resulting in dysregulation of the dopaminergic system with an increase in the number of spontaneously active dopamine neurons in the VTA, similar to what is suggested to occur in schizophrenia. On the other hand, the same stressors applied to adult animals result in decreased activity of the VTA dopamine system, similar to what is observed in animal models of depression. Given the significant challenges in diagnosing and treating schizophrenia and depression, understanding the mechanisms underlying the impact of stress on the development of these disorders is crucial. Our study aims to investigate the behavioral changes and abnormalities in the VTA dopamine neuron activity induced by stress at different life stages (adolescence and adulthood) and the neural circuits involved in these alterations. Specifically, we will assess the involvement of changes in the ventral hippocampus-nucleus accumbens-ventral pallidum pathway in the increased VTA dopamine system activity caused by stress during adolescence and the medial prefrontal cortex-basolateral amygdala-ventral pallidum pathway in the decreased activity of the VTA dopamine system activity observed after stress in adulthood. We hope that the results of this project will enhance our understanding of how stress at different ages can act as a risk factor for psychiatric disorders such as schizophrenia and depression and suggest strategies for their prevention and treatment. (AU)