Microglia are the primary immunocompetent cells that protect the brain from environmental stressors, but can also be driven to release pro-inflammatory cytokines and induce a cytotoxic environment. Brain-derived neurotrophic factor (BDNF) is important for the regulation of plasticity, synapse formation, and general neuronal health. Yet, little is known about how BDNF impacts microglial activity. We hypothesized that BDNF would have a direct modulatory effect on primary cortical (Postnatal Day 1-3: P1-3) microglia and (Embryonic Day 16: E16) neuronal cultures in the context of a bacterial endotoxin. To this end, we found that a BDNF treatment following LPS-induced inflammation had a marked anti-inflammatory effect, reversing the release of both IL-6 and TNF-α in cortical primary microglia. This modulatory effect was transferrable to cortical primary neurons, such that LPS-activated microglial media was able produce an inflammatory effect when added to a separate neuronal culture, and again, BDNF priming attenuated this effect. BDNF also reversed the overall cytotoxic impact of LPS exposure in microglia. We speculate that BDNF can directly play a role in regulating microglia state and hence, influence microglia-neuron interactions.

Microglia are the primary immunocompetent cells that protect the brain from environmental stressors; however, their activation can also have deleterious effects on brain functioning. Indeed, environmental toxins and microbial agents can induce microglial driven inflammatory processes that increase levels of pro-inflammatory cytokines and induce a cytotoxic environment. Recent therapeutic strategies have sought to determine how to modulate microglia, so as to favour their neuroprotective effects, while minimizing toxic outcomes. BDNF is one of the most commonly expressed neurotrophins in the brain and is important for the regulation of plasticity, synapse formation, and general neuron health. Yet, little is known about how exogenous BDNF directly effects microglial activity.We hypothesized that BDNF would have a modulatory effect on inflammation in isolated microglia cultures in the context of a bacterial endotoxin. To this end, we indeed found that a BDNF treatment following LPS-induced inflammation attenuated the release of both IL-6 and TNF-α in primary microglia. In neurons, LPS-activated microglial media was able produce a minor inflammatory response, while secondary treatment of BDNF reduced this effect. Interestingly, LPS activated microglial media alone was found to increase production of anti-inflammatory IL-4 in neurons. We speculate that BDNF plays a role in regulating microglia activation and localized microglia-neuron crosstalk may be crucial in preventing damaging effects of inflammatory mechanisms.iii Acknowledgements I would like to thank several people who have helped support me and made this thesis possible:Firstly, I would like to thank my supervisor, Dr. Shawn Hayley, for his continued encouragement and feedback in a field that I had previously unexplored. Shawn's support was essential for me to complete my degree during COVID.I would also like to sincerely thank the members of the Hayley labs for their aid and collaboration. A special thank you to Teresa Fortin and Natalie Prowse for their guidance, knowledge, and experience that was integral in the success of my research. I would also like to thank everyone working in cell culture for their hard work and collaboration.Together we were able to ensure that everyone was able to succeed in cell culture and it felt like a truly collaborative team.Most of all, I would like to thank my partner, Erin MacKenzie, for her unconditional support throughout this degree. She was always there for me and knew when I needed to be pushed or take a break and gave me the confidence to keep going. A special thanks to my friends and family for their support in pursing my dream of neuroscience and research.