Stress effects on microglia activation: Sex matters

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Microglia activation is a process that has been identified throughout the brain in many human psychiatric illnesses including depression, schizophrenia, autism spectrum disorder, Parkinson’s and Alzheimer’s disease. All of these disorders include symptoms such as decreased experience of pleasure or social activity and increased threat appraisal. Additionally, all of these disorders have different rates of occurrence in men and women. We have little information on why microglia are aberrantly activated and the consequences of this activation on an individual. When activated, microglia can produce pro-inflammatory signals to protect the brain from pathogens but that also can damage host tissue. Other microglia when activated produce anti-inflammatory signals. Microglia directly interact with neurons but we don’t know which forms of activation change how the neurons and their circuit’s function. We currently lack research tools that will allow us to drive microglia activation in a region-specific manner without directly affecting other cell types. The proposed studies will develop and test a new tool set of immune directed nanoparticles. These nanoparticles are designed to only be taken up by microglia and shift them to a pro-inflammatory or anti-inflammatory state. We will test the ability of these nanoparticles to shift the cytokines released from microglia and the transcriptional state of the activated microglia within the nucleus accumbens. Once dose and immune endpoints are fully validated, we will test the ability of nanoparticles to modulate the impact of variable stress on behavior in tests that measure threat appraisal, hedonic experience and social interaction. The experiments outlined in this proposal will provide us with a new method to produce and track specific forms of microglia activation. The particles used in this proposal are, by design, exemplary cases that can be made from a diverse range of polymers commonly utilized in FDA-approved nanomedicine formulations. Completion of this project will provide us with robust and accurate design criteria for producing particles that can effectively deliver cytokines and other drugs specifically to microglia in vivo and will be made available to the greater scientific community. Once developed these studies will inform us on how to harness the immune system to identify and treat psychiatric illness.