Structural and functional MRI of normal and compromised rat brain development

Abstract

Neuropsychiatric illness constitutes a major disease burden worldwide, yet its neurobiological substrates remain elusive. It is increasingly believed that early disturbances during critical and sensitive periods of brain development contribute to a delayed manifestation of psychiatric disease. This is especially evident from the age of disease onset distribution which peaks during adolescence, a transitional period that is accompanied with large-scale reorganization of neuronal function and connectivity. Advanced magnetic resonance imaging (MRI) techniques in experimental animals offer unique opportunities to address the gaps in our knowledge of neurodevelopmental processes and the disease mechanisms underlying neuropsychiatric illness. This thesis describes structural and functional MRI-based properties of normal, therapeutically targeted, and genetically altered rat brains during adolescence and adulthood. The effects of psychoactive drug treatment on the developing brains of children and adolescents are poorly studied. This has raised concerns particularly with regard to methylphenidate treatment for attention deficit hyperactivity disorder (ADHD). We first explored the dynamics of functional connectivity between brain regions as measured with resting-state fMRI in healthy rats during development from pre-adolescence into adulthood. We observed age-related declines, with distinct temporal patterns in different brain regions. Functional connectivity peaked between late-adolescence and early-adulthood, followed by stabilization into adulthood. This indicates ongoing developmental alterations beyond adolescence. Next, we studied the effects of long-term oral treatment with methylphenidate on the healthy rat brain and its dependence on age of treatment. We found that methylphenidate reduced striatal volume and myelination upon adolescent, but not adult treatment, without affecting striatal functional activity. Furthermore, our results indicate that methylphenidate may predominantly affect the ventral domain of the hippocampus and induce contrasting effects in adolescent and adult rats, with differences in hippocampus-mediated behavior that were paralleled by opposite effects on adult neurogenesis and granule cell proliferation. These small but significant age-dependent effects of psychostimulant treatment in the striatum and hippocampus of healthy rats highlight the importance of further research in children and adolescents that are exposed to methylphenidate. We also studied the effects of a lifetime genetic down-regulation of the brain's serotonin transporter, which is crucially involved in maintaining homeostasis of the serotonin neurotransmitter. We found that DTI-based fractional anisotropy was reduced in the genu of the corpus callosum of knockout rats, which could indicate that knockouts have a reduced capacity for information integration across hemispheres. It is argued that these experimental results encourage the translational application of advanced MRI and analysis techniques, as they may provide complementary information in humans and animal models. When applied in animal models, these tools can be used to study normal brain development and aid in developing appropriate psychiatric disease models. This may then increase our insight in the neurobiological substrates and aid in drug discovery. Furthermore, it is argued that brain plasticity endures beyond adolescence into young adulthood. This transition period has been coined `emerging adulthood' from a psychosocial perspective to emphasize a prolonged time period that young people experience changes in day-to-day environment and relationships, yet we argue that there is a strong contribution of intrinsic development.