Effects of prenatal valproic acid exposure on DCC receptor expression and mesocorticolimbic dopamine circuitry during early adolescence and adulthood

• Grant number: 25/17824-3
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: February 01, 2026
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Mariana Grigório de Sant'Ana
• Supervisor: Ana Cecilia Flores
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: McGill University, Canada
• Associated to the scholarship: 24/12687-5 - Evaluating the activity of dopamine neurons in the Ventral Tegmental Area and Substantia Nigra in an animal model for autism, BP.MS

Abstract

Autism spectrum disorder (ASD) comprises neurodevelopmental conditions characterized by social impairments and repetitive and stereotype behaviors. The etiology of ASD is thought to involve both genetic and environmental factors. Prenatal exposure to valproic acid (VPA) is a known environmental risk factor for ASD, which can lead to disrupted axon growth. Although the pathophysiology of ASD remains unclear, alterations in the midbrain dopamine system have been proposed to underlie core symptoms of ASD. Recently, our group reported increased population activity of dopamine neurons in the ventral tegmental area (VTA) in both male and female adult rats exposed to VPA in utero. In addition, findings from my Master's studies indicated an increased number of spontaneously active dopamine neurons in the Substantia Nigra (SN). However, the organization of dopamine circuitry in this model is not fully elucidated. Seminal studies from Dr. Cecilia Flores (the host of this proposal) have shown that the Deleted in Colorectal Cancer (DCC) guidance cue receptor is critical for dopamine axonal targeting. Amphetamine-induced DCC downregulation in the VTA in adolescence is associated with adult aberrant dopamine innervation and dysfunction in the medial prefrontal cortex (mPFC) in mice. Notably, mPFC dysfunction is also observed in VPA-exposed animals. Given that the relationship between VPA exposure and DCC expression remains unexplored, this study aims to investigate the effects of prenatal VPA exposure on DCC expression in the midbrain dopamine system and its consequences for mesocorticolimbic circuitry organization. To test this, pregnant Sprague-Dawley rats will receive intraperitoneal injection of VPA (600 mg/kg) or saline on gestational day 12. On postnatal day 31 the brains of male offspring will be assessed for RT-qPCR analysis of Dcc mRNA in the VTA and SN. On postnatal day 75 brains from a separate cohort of male offspring will be processed for immunofluorescence assessment of DCC/TH-positive axon innervation in the mPFC.