Impact of ClockΔ19 mutation on neural recording performance and neural inflammatory responses

Chronically implanted neural electrodes for neural recording, stimulation, and chemical sensing are essential tools in studying and treating neurological disorders. However, their performances are limited by implant-induced inflammation, causing a loss in signal quality over time. Because disease states can alter inflammatory processes, it is critical to characterize the tissue response to neural implants within relevant disease models. Circadian rhythm disruption is a hallmark of many psychiatric and neurodegenerative disorders, yet its influence on neural implant performance remains poorly understood. The Circadian Locomotor Output Cycles Kaput (Clock) gene is a core regulator of circadian rhythms and a key modulator of inflammatory pathways, including NF-κB signaling. The ClockΔ19 mutant mouse is a well-established model of circadian disruption with documented immunological abnormalities. Here, we evaluated striatal electrophysiological recording performance and quantified the host tissue response to microelectrode implants in ClockΔ19 (MU) and wild-type (WT) mice over four weeks. Silicon microelectrode arrays (MEAs) were implanted into the striatum, followed by weekly electrochemical impedance spectroscopy and neuronal recording measurements. Electrodes implanted in MU mice exhibited significantly lower impedance, noise, and peak-to-peak amplitude compared to WT mice, while signal-to-noise ratio and channel yield were comparable between groups. Endpoint immunohistological analyses revealed significantly reduced microglia and astrocyte activity, as indicated by lower Iba-1 and GFAP intensities around the implant site in MU mice. Additionally, ClockΔ19 tissue showed elevated 4- hydroxynonenal (HNE) levels and reduced nuclear NF-κB expression following implantation. Morphological analysis further identified baseline and injury-induced differences in microglia phenotypes between MU and WT animals. Notably, decreased neurofilament expression, together with a non-significant trend toward reduced neuronal density, suggests compromised neuronal health surrounding the implant in MU animals. Together, these findings demonstrate that circadian disruption alters both neural and immune responses to chronic neural implants, resulting in heightened oxidative stress and an impaired reparative inflammatory response. This work highlights the importance of circadian regulation in neuroimmune responses, providing insights into how circadian dysfunction may impact long-term neural interface performance with implications for both basic research and clinical neurotechnology development.