Microglia and Perineuronal Net Interactions in the Limbic Regions of Male and Female Juvenile Rats
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Date
2022-05
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The Ohio State University
Abstract
Early life stress (ELS) in humans is associated with vulnerability to mood and anxiety
disorders, but the mechanisms that lead to stress-induced vulnerability are not fully understood. ELS- may activate microglia, the primary immune cells of the brain, in limbic brain regions that contribute to the manifestation of psychiatric disorders. Microglia are important for brain development, and in response to stress show increased inflammatory signaling as well as engulfment and digestion of neuronal material and debris, known as phagocytosis. Stress- induced microglia activation in adulthood has been linked to anxiety and depression, and our lab investigates novel mechanisms through which microglia could program lifelong shifts in brain development after early life perturbations. My project focuses on answering a novel question: Whether microglia alter brain development in limbic brain regions after early life stress in a rat model, by promoting the loss of perineuronal nets (PNN). PNNs are a component of the extracellular matrix that are established as brain development finishes, effectively closing the critical period of development, restricting synaptic plasticity, and providing neuroprotection to mature synapses and cells ensheathed by PNNs. Microglial immune factors can induce a direct or indirect cleavage of PNN components, which can facilitate the loss of PNNs in response to immune activation. When PNNs are degraded, synapses become exposed and are in a more plastic state, making modulation of the synapses in response to environmental stimuli/stress more likely. Abnormal changes to plasticity of synapses during development may contribute to the programming of adult behavior and cognitive function characteristic of anxiety and mood disorders. In my project, I examined stressed and non-stressed male and female Sprague Dawley rats at postnatal day (PD) 21 to determine if ELS influences microglia targeted interactions with PNNs and resultant PNN degradation. High resolution microscopy and immunofluorescence were used to quantify PNN coverage and microglia engulfment of PNNs across experimental groups. Three main limbic regions of the brain (amygdala, hypothalamus, and hippocampus) were be examined, as these regions are implicated in the stress response, sociality, and mood- related behavior. I found that ELS increases microglia percent area staining in dentate gyrus of the brain preadolescence, with a baseline increase in phagocytic activity (CD68 positive microglia) in males compared to females. In contrast, ELS decreases microglia percent area staining in the amygdala, and decreases microglia number in the hypothalamus. ELS also resulted in a sex-specific effect of stress in males only within the CA3 of the hippocampus, wherein stress decreased the total volume of PNNs stained. This is the first study (to our knowledge) that examines the relationship between PNNs and microglia in the juvenile rat brain after ELS. Overall, my data supports the idea that early life stress has effects on microglia function and morphology, that could have long term sex-specific effects on not only the brain regions in which they reside, but also in the regions that project to and from these regions. Continuing to investigate how microglia interact with PNNs throughout both normal development and in early life stress conditions will provide researchers with a better understanding of how ELS can influence synaptic plasticity and consequently modulate the limbic circuit function and mood-related behavior. Examining these non-neuronal effects and including both sexes in all studies will guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of anxiety and mood-related disorders.
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Keywords
early life stress, microglia, perineuronal nets, sex differences, plasticity