It is increasingly recognized that the immune system can exert profound effects on the central nervous system. Past research has shown that peripheral immune activation has the capability of affecting cognition, including memory function. While there has been much research on how immune stimulation can affect neuronal function or behavioral performance in memory tasks, there is a lack of research linking molecular alterations to behavioral impairment. This dissertation examines effects of acute immune challenge on hippocampus-dependent memory with a systematic approach that links molecular mechanisms, neural circuit activity, and behavior within a consistent experimental model. For all experiments, subjects received a systemic injection of lipopolysaccharide (LPS) that served as a mild immune challenge that reliably induced a proinflammatory tone within the brain. Afterward, subjects were tested for context discrimination memory followed by analysis of circuit activity patterns and/or neural gene expression in dorsal hippocampus. Chapter 2 asks whether pharmacological attenuation of neuroimmune activation prevents impairments of contextual memory and circuit activity that had been previously observed during acute neuroinflammation. Blocking neuroimmune activation successfully prevented LPS-induced impairments in memory and circuit activity, and the extent of circuit activity disruption was associated with behavior of a given subject. In Chapter 3, gene expression was analyzed for the same subjects employed in Chapter 2. Using statistical modeling, differential gene expression was linked to circuit activity patterns and memory performance in order to build an overarching experimental model of neuroimmune modulation of memory function. Furthermore, specific genes with potential roles in neuroimmune-mediated impairment were identified. The study detailed in Chapter 4 asked whether environmental enrichment, a behavioral intervention providing enhanced physical, cognitive, and social stimulation, is able to protect memory impairment during neuroinflammation. Unlike the pharmacological intervention used in Chapter 2, this study did not find robust protective effects associated with environmental enrichment, but ways in which the experiment could be improved are discussed. Collectively, the experiments contained within Chapters 2-4 contribute knowledge on fundamental interactions between an activated immune system and memory processes. Future study is needed for translation of findings into therapeutic advances for people suffering from cognitive symptoms during proinflammatory disease.