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Abstract
Manganese (Mn) is a ubiquitous essential metal; however, overexposures lead to adverse neurological consequences. The majority of Mn rodent exposure studies utilize males, leaving females under-researched. Mn treatment strategies mainly focus on removal from exposure source, symptomatic treatment, and reduction of body Mn load. This dissertation sought to investigate sex differences in behavior, neurochemical and inflammatory alterations induced by subchronic Mn DW exposure within two rodent strains. The rodent strains utilized herein include 1) CX3CR1GFP with GFP-tagged monocytes/microglia (WT) and 2) miRNA-155 knockout (KO). After 6-weeks of Mn exposure, WT mice showed both motor and mood alterations. At 8-weeks, Mn-exposed WT males, with and without lipopolysaccharide (LPS) challenge, still exhibited decreased fear/anxiety-like behavior. Mn exposure increased inflammatory cytokines in combination with LPS in males, but not in females. These behavioral alterations were diminished in the KO mice with miRNA-155 absent. Since Mn is known to interfere with neurotransmitter homeostasis and sex-specific behavioral and inflammatory changes were observed in WT mice, major neurotransmitters systems, astrocytes, and microglia were evaluated. The striatal levels of GABA and GLU, ventral hippocampal levels of GLN and GABA, and prefrontal cortex (PFC) levels of 5-HT, NE, 5-HIAA, GLN, and GABA were all impacted differently by Mn and sex. Females had higher numbers of microglia and astrocytes present in multiple hippocampal areas and Mn exposure increased microglia activation while LPS increased astrocyte activation, more in the females. Males, but not females, exposed to Mn showed a decrease in TH+ neurons in the substantia nigra, fewer microglia in the VTA, and increased microglial activation in the ventromedial striatum. These findings suggest that the motor and mood alterations induced by Mn exposure are male-biased, partly dependent on intact miRNA-155 signaling, and associated with region-specific neurochemical and inflammatory changes; female mice are affected by Mn differentially, mostly at the neurochemical level, and more by LPS than the male.