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Enduring functional consequences of early-life insults: mechanisms, prediction and intervention

Creative Commons 'BY-ND' version 4.0 license

Early life experiences, whether positive or negative, have the potential to enduringly shape the brain. This work investigates two types of early experiences and the mechanisms by which they influence the developing brain: prenatal adversity and developmental prolonged febrile seizures. This work finds that maternal stress and placental corticotropin releasing hormone (CRH) are able to influence neuronal development by diminishing dendritic branching, a potential mechanism for the decreased cortical thickness found in children exposed to high levels of CRH in utero. The region-selective reduction in cortical thickness is associated with cognitive and emotional outcomes in childhood. Prolonged febrile seizures of childhood, also known as Febrile Status Epilepticus (FSE), can lead to the development of spontaneous epileptic seizures and cognitive problems that last into adulthood. The experiments described here examine the mechanisms of those effects on a molecular, cellular, and structural level. There are many perturbations that arise after experimental FSE (eFSE) within the brain that potentially crucial for the observed detrimental outcomes of these seizures in rodents and humans. This work focuses on two of them: the induction of inflammation in the brain and increased expression of the transcription factor Neuron Restrictive Silencer Factor (NRSF). This thesis describes experiments that acutely modulate these signaling cascades, resulting in the prevention of eFSE-induced structural and functional changes within the hippocampal formation. Importantly, this work also addresses the need for predictive markers for individuals experiencing eFSE who will go on to develop epilepsy and cognitive deficits, in order to target any intervention. Magnetic resonance imaging (MRI) allows for real time measurements of brain changes in vivo, enabling the measurement of structural alterations and prediction of epileptogenesis before the first spontaneous seizure occurs.

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