Structural and Functional Plasticity in the Aging Brain.

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There are a number of structural and functional changes in neurons that occur in the aging brain, however many of these changes are not well understood. In part, this is because the brain is a dynamic structure whose structure and function can be regulated by both external (i.e. exercise, social interactions) and internal (i.e. oxidative state, calcium regulation) forces. The main objective of my NSERC Discovery Grant program will be to better elucidate how these forces alter the function of n-methyl-D-aspartate receptors (NMDAr) in the aging brain. The NMDAr is a receptor protein involved in many forms of synaptic plasticity, and is known to be critical for certain types of learning and memory. Several studies have shown that the role of the NMDAr in synaptic events diminishes with age, while the role of L-type voltage gated calcium channels (VGCCs) increases. This shift in the way calcium enters the cell results in a rise in intracellular calcium that more potently activates potassium channels, resulting in an efflux of potassium that hyperpolarizes the cell membrane. This decreases synaptic plasticity and may make it harder to learn information. We have two recent findings supporting this hypothesis. First, we have shown that NMDAr dependent plasticity can be restored in aged brains by regulating the redox state of NMDArs. Second we have determined a relationship between structural plasticity and learning performance. Our new data shows that the rate of neurogenesis in the aging brain is tightly coupled to the types of strategies used to learn new information, but not to performance per se. We hope to determine if enhancing the capacity of the brain to handle oxidative stress will increase neurogenesis, as well as the role of NMDA receptors, and result in a shift to learning strategies to those that are more commonly employed by younger animals. This work will be extremely novel because it will determine if age-associated changes in brain function can be reversed by modulating the state of oxidation in the brain in both male and female animals. The work will employ state-of-the-art behavioural, electrophysiological, immunohistochemical and molecular techniques to study the aging brain.