Development and repair of the nonhuman primate brain : role of the Eph and ephrins
Creators: name: Teo, Leon
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: In primates, including humans, the capacity for the adult brain to recover following injury is extremely rare and there are currently no effective therapeutic interventions. However, studies have demonstrated that the infant brain retains a greater capacity for recovery, which is likely related to the diverse molecular and cellular events still at play in the immature brain. It is now widely accepted that the on going developmental processes and the higher level of plasticity manifested in the infant brain is predominantly responsible for the level of regenerative/ collateral sprouting and rewiring required for the functional recovery of damaged neural networks. The gradual loss of developmental plasticity occurs as the individual approaches adulthood due to the refinement, myelination and stabilisation of neural connections across postnatal maturation. Therefore, the key to unlocking the regenerative capacity in the injured adult CNS will most likely lie in the recapitulation of developmental plasticity through novel pharmacotherapeutic strategies. To achieve this, it is imperative that the exact cellular and molecular events that occur in response to CNS injury sustained during infancy and adulthood is elucidated using clinically representable models. Nonhuman primate (NHP) models in particular remain the most suitable due to the highly representable pathophysiological responses they share with the injured human CNS. To that end, NHP models represent the most valid tool in which to investigate the consequences of injury as well as the development and subsequent testing of novel therapeutics with the greatest potential for translational clinical applications. Through a multidisciplinary approach, this thesis aims to add to the current understanding by addressing the expression and functional roles of Eph receptors (first derived from erythropoietin-producing hepatocellular carcinoma cells) and their ephrin ligands in the primate visual system throughout postnatal maturation and after infant and adulthood injuries. To achieve this, Chapter 2 addresses the spatiotemporal changes in expression profiles of a specific ephrin ligand throughout postnatal maturation through to adulthood to provide evidence that the Eph and ephrins play life-long roles in the primate visual system. Next, this thesis examines how Eph and ephrins influence the differential cellular response after infant and adulthood brain injuries: First, a comprehensive review of the existing literature regarding current models and consequences of CNS injury in NHP, and the recent trends in therapeutic strategies is presented in Chapter 3. Second, Chapter 4 addresses the development of a novel, highly reproducible model of focal ischemia in the NHP visual cortex, which can be recapitulated in infancy. Last, using this model Chapter 5 investigates the role the Eph receptors and ephrin ligands play in the differential reactive astrogliotic response observed in the infant and adult NHP following a stroke. The outcomes of this thesis are fourfold: (1) evidence of life-long expression of ephrins throughout the postnatal maturation of the NHP visual system through to adulthood; (2) a comprehensive review of models of CNS injuries employed in the NHP and current trends in therapeutic strategies; (3) development of a highly reproducible model of focal ischemia in the infant and adult NHP primary visual cortex (V1), in which the sequelae closely represents those observed in the clinic; and, (4) evidence that different Eph and ephrin signalling differentially influences astrocyte reactivity in infancy compared to adulthood, which ultimately has an effect on the subsequent formation of the glial scar. This is the first demonstration of the different astrocytic responses in infant and adulthood brain injury in NHPs after ischemic stroke. The importance of these findings has led to the proposal of a new therapeutic target for the treatment of brain injuries through the modulation of glial scar formation.