Microelectrode technology holds enormous potential in both basic neuroscience and functional rehabilitation applications. For example, recorded signals can be used to develop our understanding of neuronal circuits or as control signals for various rehabilitation applications. Unfortunately, widespread implementation of intracortical microelectrodes is limited in both research and clinical settings due to loss in signal quality over time. Several mechanical, material and biological factors have been suggested to impact recording quality, and it is likely that multiple factors simultaneously affect recording performance. Increasing evidence suggests a dominant role of microglia/macrophages and infiltrating myeloid cells in mediating neurodegeneration and impacting microelectrode performance. To overcome challenges associated with microelectrode failure, the field has actively sought to investigate neuroprotective strategies to improve recording quality. However, the immune-privileged cortical tissue introduces an added level of complexity that has yet to be fully elucidated. The overall goal of this dissertation was to identify a key mechanistic pathway that facilitates neurodegeneration following microelectrode implantation. Here, we investigated the temporal contribution of resident microglia versus infiltrating myeloid cells in mediating neurodegeneration over time. Our results suggested a dominant role of infiltrating myeloid cells in mediating neurodegeneration. Further, using transgenic knock-out mice, we examined the role of cluster of differentiation 14 (CD14) pathways in mediating neuroinflammatory events to intracortical microelectrodes. Our results demonstrated that inhibition of CD14 from myeloid cells was sufficient to achieve neuroprotection, suggesting that systemic administration of therapeutic targets may be adequate to attenuate neurodegeneration. Hence, in a pilot study, we demonstrated the efficacy of using a CD14-antagonist to attenuate neuroinflammation following microelectrode implantation. The results of this work support the hypothesis that CD14 receptor-mediated pathways facilitate neuroinflammatory events and may aid in the development of treatment regimens to enable long-term intracortical recordings.