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Objective.Intracortical brain interfaces are an ever evolving technology with growing potential for clinical and research applications. The chronic tissue response to these devices traditionally has been characterized by glial scarring, inflammation, oxidative stress, neuronal loss, and blood-brain barrier disruptions. The full complexity of the tissue response to implanted devices is still under investigation.Approach.In this study, we have utilized RNA-sequencing to identify the spatiotemporal gene expression patterns in interfacial (within 100µm) and distal (500µm from implant) brain tissue around implanted silicon microelectrode arrays. Naïve, unimplanted tissue served as a control.Main results.The data revealed significant overall differential expression (DE) in contrasts comparing interfacial tissue vs naïve (157 DE genes), interfacial vs distal (94 DE genes), and distal vs naïve tissues (21 DE genes). Our results captured previously characterized mechanisms of the foreign body response, such as astroglial encapsulation, as well as novel mechanisms which have not yet been characterized in the context of indwelling neurotechnologies. In particular, we have observed perturbations in multiple neuron-associated genes which potentially impact the intrinsic function and structure of neurons at the device interface. In addition to neuron-associated genes, the results presented in this study identified significant DE in genes which are associated with oligodendrocyte, microglia, and astrocyte involvement in the chronic tissue response.Significance. The results of this study increase the fundamental understanding of the complexity of tissue response in the brain and provide an expanded toolkit for future investigation into the bio-integration of implanted electronics with tissues in the central nervous system.