Grant: Discovery Grants Program - Individual

Besides their role in immune regulation, cytokines have emerged as important messengers within the central nervous system (CNS). In particular, several pro-inflammatory cytokines have been demonstrated to cause neurochemical and hormonal changes that were accompanied by behavioral alterations. More recently, these inflammatory cytokines have also been reported to adversely affect CNS plasticity. For instance, interferon-alpha and ?gamma (IFN-a and ?g) reduced hippocampal neurogenesis and levels of the trophic factor, brain derived neurotrophic factor (BDNF). Similarly, IFN-a administration in human and non-human primates has been associated with cognitive and emotional deficits, and our own work found that IFN-g had a similar role in rodents (Litteljohn et al., in press). Conversely, cytokines with trophic and anti-inflammatory functions may positively influence neuroplastic processes. Indeed, granulocyte macrophage-colony stimulating factor (GM-CSF) and erythropoietin (EPO) have been linked to enhanced regulation of dendritic arborization and spine density, spatial learning, cognitive flexibility and social memory. All of these cytokines can act through the janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways, and our recent evidence also implicates the mammalian target of rapamyacin (mTOR) pathway in the CNS effects of EPO and GM-CSF. Given the paucity of data concerning the role of the IFNs, GM-CSF and EPO and their associated signaling pathways in cognition and the underlying neuroplastic processes, the present proposal sought to address the following primary hypothesis: The trophic cytokines, GM-CSF and EPO, will act through the JAK-STAT5 and mTOR pathways to enhance neuroplastic and cognitive processes, whereas the pro-inflammatory cytokines IFN-a and IFN-g act through JAK-STAT1 to exert inflammatory and deleterious consequences on neuroplastic and cognitive outcomes. Our hypothesis will be tested by assessing (1) changes in central functioning of elements of these signaling pathways (as well as neuroplastic and cognitive outcomes) following cytokine challenge, and (2) the impact of inhibition of these pathways on cytokine-induced changes in elements of neuroplasticity (neurogenesis, dendritic arborization, growth factor levels) and cognitive behaviour. Data derived from this proposal will also be used to plan future studies assessing whether repeated activation of these pathways might engender long-term or possibly permanent changes in CNS sensitivity to stressor or cytokine exposure. In effect, our long-term objectives are to determine the signaling factors that underlie the specific effects of each of these cytokines and evaluate whether the inflammatory or trophic milieu provided by the specific cytokines, might result in either augmented or diminished behavioral performance to subsequent challenges. The level of analyses will range from a cellular/molecular level to assessment of behavioural outcomes. The primary methodologies will involve our multiplex system, Western blot and qPCR analyses for quantification of JAK-STAT and mTOR signaling pathway elements. Immunohistochemistry will be used to determine the cellular source and spatial distribution of inflammatory and trophic factors. Behavioural analyses will involve assessment of cognition, including spatial memory (e.g. Barnes maze), exploration and novel objection recognition.