Evaluating the activity of dopamine neurons in the Ventral Tegmental Area and Substantia Nigra in an animal model for autism

• Grant number: 24/12687-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Mariana Grigório de Sant'Ana
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 25/17824-3 - Effects of prenatal valproic acid exposure on DCC receptor expression and mesocorticolimbic dopamine circuitry during early adolescence and adulthood, BE.EP.MS

Abstract

Autism Spectrum Disorder (ASD) is a set of conditions associated with neurodevelopment and is characterized by social impairment and the presence of repetitive and stereotyped behaviors. The etiology of ASD is still unknown; however, it is proposed that the interaction of genetic and environmental factors may be related to the development of the disorder, as well as exposure to medications during pregnancy, such as valproic acid (VPA). Despite ongoing efforts, the pathophysiology of ASD has not yet been fully elucidated. However, alterations in the dopamine system have been proposed as a potential source for the genesis of the core symptoms of ASD. In the meantime, recent data from our group have demonstrated an increase in the number of spontaneously active dopamine neurons in the Ventral Tegmental Area (VTA) in animals exposed to VPA in utero. Additionally, it is known that the Substantia Nigra pars compacta (SNpc) may be related to the symptoms of ASD, considering its crucial role in the development of motor behaviors. In light of this, we hypothesize that adolescent and adult animals exposed to VPA in utero will show impairments in sociability and cognitive function, along with increased activity in the dopamine systems of the VTA and SNpc. To test our hypothesis, pregnant Sprague-Dawley rats will receive intraperitoneal administration of VPA (600 mg/kg) or saline on the 12th day of gestation. The offspring will be tested during adolescence and adulthood in behavioral tests to assess sociability (social interaction test) and cognitive function (object recognition). Finally, the activity of dopamine neurons in the VTA and SNpc will be measured through in vivo electrophysiology. To evaluate potential sexual differences, both male and female animals will be tested. We hope that the results of our study will contribute to a better understanding of alterations in the dopaminergic system in the neurobiology of ASD.