Microelectrode arrays designed to map and modulate neuronal circuitry have enabled greater understanding and treatment of neurological injury and disease. However, poor biological integration remains a significant barrier to the longevity and stability of electrodes implanted in the brain, where gliosis and neuronal loss are commonly attributed to instability and loss of signal over time. However, these metrics do not reliably predict signal loss, and device failure modes remain elusive. Here, this work provides fundamental insight into biological mechanisms that contribute to these failure modes, as well as develops genetic engineering strategies to improve the biointegration of brain implants.While signal-generating neurons have traditionally been considered the important target cells for implanted electrodes, it has become increasingly appreciated that glia remodel the structure and function of neuronal networks following injury, where recent work has uncovered mechanisms relevant to the injuries and ensuing gliosis caused by the implantation of chronic devices. Chapter 2 disseminates important considerations for glial reactivity on device performance and provides a framework for topics explored in subsequent Chapters. Although decades of work has demonstrated that cortical injury generates long-term remodeling of excitatory/inhibitory synapses (the connections which facilitate the propagation of information between neurons) and ion channels (the transmembrane proteins responsible for generating neuronal signals), these mechanisms have not been investigated around implanted arrays; however, the consequences of these events hold significant implications for the long-term recording stability of implanted devices. Chapter 3 reveals novel changes in both excitatory and inhibitory synaptic circuitry surrounding implanted microelectrodes, where early elevations in excitatory synapses are followed by a shift to inhibitory tone in the chronic setting. A novel subtype of glia is also identified local to the device interface. Chapter 4 reveals a novel relationship between electrophysiological recordings and ion channel expression surrounding implanted arrays over time, where a loss of sodium channel expression and gain in potassium channel expression corresponds with a loss of recorded signals over time. Together, this work supports a trend from hyper- to hypo-excitability, which temporally coincides with signal variability and loss observed with chronic devices.The previous chapters provide fundamental insight into major circuit changes at the interface that inform both basic-science knowledge and new strategies for improving the biointegration of brain implants. We are developing new approaches to reveal the mechanistic role of these factors in affecting recorded signals over time. Chapter 5 covers ongoing work that includes the development and validation of innovative strategies to deliver genetic material at the interface in vivo to yield entirely new avenues of research with opportunities to regulate gene expression and/or introduce new genetic material to rewire the interfacial network. Future directions are discussed with opportunities to unmask key circuit-remodeling effects that impair device performance as well as inform the seamless integration of brain implants.
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