Grant: Discovery Grants Program - Individual

An emerging concept in neuroscience is that brain plasticity is dependent not only on neurons and glia, but also on structures present outside of these cells. The extracellular matrixwhich comprises about 20% of the brain's volume (1) and contributes to neuronal and glial communication (2)is a prime candidate for this role. Indeed, recent evidence from my lab suggests that one extracellular matrix component called a perineuronal net (PNN) may go beyond it's established role in neurodevelopment and contribute to fundamental learning and memory processes in the adult brain. The overarching goal of this research program is to develop a comprehensive understanding of mechanisms by which PNNs are involved in adult cognition. PNNs are a component of the extracellular matrix that are primarily found wrapped around inhibitory, parvalbumin positive cortical neurons. PNNs form during development, and are central in the closure of critical periods of heightened synaptic plasticity during development to lower levels during adulthood(3). Enzymatic degradation of chondroitin sulphate proteoglycans (CSPGs), major components of PNNs, can re-open the juvenile critical period for ocular dominance plasticity in adult rats (3) and can facilitate recovery from spinal cord injury and other forms of damage to the nervous system(4,5). Synaptic plasticity is also essential for learning and memory across the lifespan(6-8), however, almost no work has investigated whether PNNs contribute to fundamental learning and memory processes in the adult brain. Recent work from my lab has shown that depletion of PNNs can enhance recognition memory in adult mice (9-11), suggesting that PNNs comprise a critical regulatory component in normal learning and memory. Moreover, recent evidence suggests that PNNs may also have an important role in neuroprotection(12). PV neurons without a surrounding PNN are more vulnerable to oxidative stress(13) which has a knock-on effect on learning and memory(14). My hypothesis is that PNNs contribute substantially to adult learning and memory processes via two primary mechanisms (i) regulation of neuroplasticity and (ii) neuroprotection. My short-term objective is to test this hypothesis by degrading PNNs in cortical regions critical for learning, memory and behavioural control, and/or manipulating levels of oxidative stress via diet, exercise, or environmental enrichment, and then assessing the mice on cognitive tests dependent on those brain regions. We predict that performance on the tests will reflect a trade-off between increased synaptic plasticity and reduced neuroprotection, so may be improved or impaired depending on how the two types of manipulation are combined. In the long term, this research program will provide valuable insight into the mechanistic underpinnings of adult learning and memory processes, and how lifestyle factors including diet, exercise, and environmental enrichment can fundamentally alter both brain and behaviour.