Effects of parvalbumin downregulation in the medial prefrontal cortex of rats in the prepubertal period on behavior and dopamine neuron activity in the ventral tegmental area during adolescence and adulthood

• Grant number: 24/21588-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Gabriel Henrique Caceres da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The excitatory-inhibitory (E/I) balance refers to the equilibrium between excitatory and inhibitory neuronal interactions in the central nervous system. This regulated state is crucial for the temporal control and synchronization of neural activity. Among the neurons involved in maintaining this balance, parvalbumin (PV)-expressing GABAergic interneurons play an important role. These interneurons are enveloped by specialized extracellular matrix structures called perineuronal nets (PNNs), which provide structural support, synaptic stability, and protection against oxidative stress and neurotoxins. The maturation and development of PV interneurons mark critical periods of brain plasticity, characterized by heightened sensitivity to changes and adaptation. The development of PNNs coincides with the closure of these critical periods by the end of adolescence. External stimuli, such as stress, can disrupt the maturation of these structures, leading to dysregulation of the E/I balance. Adolescence, a phase closely associated with the onset of psychiatric disorders, represents an important window during which stress acts as a major risk factor for the development and severity of these conditions. Preclinical studies from our group have demonstrated that rats exposed to multiple stressors during adolescence presented behavioral alterations associated with schizophrenia in adulthood. These behavioral changes were accompanied by a functional loss of PV+ interneurons in the medial prefrontal cortex and ventral hippocampus. However, the link between the impairment of these interneurons and the observed behavioral alterations remains poorly understood. This project aims to investigate whether reducing PV expression in the medial prefrontal cortex of prepubertal rats through local infusion of a viral vector containing shRNA targeting the Pvalb gene induces behavioral changes related to anxiety, sociability, and cognitive function during adolescence and adulthood. Furthermore, the study will examine how this reduction affects the electrophysiological activity of dopaminergic neuronal populations in the ventral tegmental area and assess the impact of PV reduction on PNN formation using immunofluorescence techniques.