Recovery of the aged brain after acquired injury

We will model acquired brain injury (stroke and traumatic injury) in aged animals and focus on key processes altered with age, i.e. energy metabolism and neuroinflammation, and their influence on the repair and plasticity of brain circuits, including axonal growth, synapse formation and neurogenesis. Aged animals have reduced brain glucose uptake, an increased basal glial activation (astrocytes and microglia) and decreased neurogenesis (Marschallinger et al., 2015). We will study the recovery after injury using models of localized cortical impact or localised ischaemia in aged rats. We will compare the response to injury in young adults vs. aged animals using behaviour (motor and cognitive performance), imaging and post-mortem analysis (lesion volume, mitochondrial markers, neurogenesis, angiogenesis, axon regeneration and sprouting, glial scar, myelin inhibitors, neuroinflammation and synapse dynamics). To elucidate the interplay between alteration in energy metabolism and neuroinflammation and response to injury, we will model injury factors in vitro. We will characterize the alterations in energy metabolism following injury-relevant stimuli (e.g. hypoxia, excitotoxicity) of neuronal cultures. Subsequently, using pharmacological and nutrient manipulation, we will assess the contribution of different energy pathways and their ability to meet altered demands after injury. We can mimic the reduced glucose metabolism seen with old age, and provide nutrients targeting the remaining pathways to compensate the energy gap. Both energy metabolism and neuroinflammation are sensitive to nutrient status, therefore the in vitro exploration will allow us to identify nutrients that support energy metabolism and also target neuroinflammation.
It has been shown that the response of young animals to brain injury can be modified by sensory-motor stimulation (environmental enrichment) (Monaco et al., 2013; de la Tremblaye et al., 2019), exercise and task-specific rehabilitation (Maldonado et al., 2008) as well as specialised nutrients including antioxidants, phospholipids and alternative energy substrates (Thau-Zuchman et al., 2019, Thau-Zuchman et al., in press). The specific nutritional intervention developed in this project will be based on our in vitro findings. We will explore the impact of these various interventions (enrichment, rehabilitation, specific nutrients), alone or in combination, on the neurological recovery of the aged animals and on injury tissue markers, in order to identify an optimum management regime which could be translated to elderly patients.