Grant: Discovery Grants Program - Individual

Background: It has become clear that the brain and immune system regularly engage in a bi-directional dialogue. It has been my longstanding goal to understand this dialogue and especially, to uncover the most basic mechanisms through which the inflammatory immune system influence motor, emotional and cognitive behaviors. In this grant, I propose studies that continue along this line of investigation. To this end, we will assess the mechanisms through which the trophic cytokines, BDNF and EPO, have positive consequences, whereas the pro-inflammatory cytokine, interferon-gamma (IFN-g), exerts negative effects upon neuroplasticity and cognitive outcomes. We are particularly interested in how these cytokines influence the phenotype of the brain's own specialized immune cell, the microglia, which in turn, affects neuronal plasticity. Conversely, we are also interested in how neuronal derived trophic factors influence microglial inflammatory state. This bi-directional communication will be investigated using in vivo and in vitro approaches. Indeed, this work has implications for many different research areas as involves an integrative approach in dealing with how the brain and immune processes are interlinked. Research focus: My previous NSERC supported findings have indicated that pro-inflammatory cytokines modulate neurotransmission and infleunce hippocampal neurogenesis and cognitive performance. Conversely, the trophic cytokines, brain derived neurotrophic factor (BDNF) and erythropoietin (EPO) are known to promote neuroplasticity and facilitate cognition. Our recent work also indicates the importance of the mammalian target of rapamyacin (mTOR) pathway, along with the "full length" mature receptor, TrkB.FL, and truncated receptor, TrkB.T1 in many neuroimmune processes. We will assess whether the trophic cytokines, BDNF and EPO, act through the tropomyosin receptor kinase B (TrkB).FL/TrkB.T1 and mTOR pathways to promote anti-inflammatory consequences and enhance neuroplastic and cognitive processes, and whether the pro-inflammatory cytokine IFN-g exerts pro-inflammatory consequences, which impair neuroplastic and cognitive outcomes. We will also utilize: (a) a novel TrkB.FL knockdown mouse, (b) a TrkB.T1 knockout mouse and (c) mTOR acting agents. Data derived from this proposal will be used to plan future studies assessing whether repeated activation of these pathways might engender long-term or possibly permanent changes in brain sensitivity to immune challenges.