Towards an Integrated Foreign Body Response: Multi-Modal Investigation of Glial, Vascular, and Disease-Associated Factors at the Electrode-Tissue Interface

The success of neural electrode technology to understand brain function and restore lost motor or sensory control is dependent on a reliable and robust recording of neuronal signals. However, the ability to detect extracellular potentials within the brain over long periods of time using penetrating recording electrodes is impeded by a gradually progressive and insurmountable biological reaction to a foreign body. The brain’s immune response to intracortical microelectrodes is traditionally characterized as an early onset of neuroinflammation due to activated microglia and astrocytes resulting in the formation of an encapsulating glial scar and neurotoxic microenvironment, ultimately leading to end-stage neuron loss. Attempts at correlating these biological events with electrode recording performance are complicated by a high variability in tissue response outcomes. This may be attributed to a currently incomplete representation of all the biological constituents that are impacted by electrode implantation within the brain, such as other essential glial and vascular cell populations also present near microelectrode implants. In this dissertation, we apply a multi-modal approach involving two-photon microscopy, electrophysiology, and immunohistology to discern the fate and function of historically understudied cells at the electrode-tissue interface, such as oligodendrocytes, oligodendrocyte precursor cells, and perivascular pericytes. We demonstrate that oligodendrocyte precursor cells react spatiotemporally to penetrating microelectrodes in a manner which is distinct from activated microglia cells. We also reveal that myelinating oligodendrocytes, the differentiated target of oligodendrocyte precursors, are critical for the robust detection and electrophysiological firing of neurons around chronically implanted recording electrodes. Furthermore, we reveal alterations in the structure and function of brain pericytes over the course of device implantation. Lastly, we offer new insights on the accumulation of pathological tissue factors related to aging and neurodegenerative disease around chronic brain implants. In sum, our findings provide multiple new perspectives towards a more accurate description of the integrated foreign body response at the electrode-tissue interface. A more holistic understanding of the potential adverse tissue reactions occurring within the microenvironment of chronic brain implants will better inform innovative electrode designs and give rise to more targeted clinical therapies for improving the bio-integration of neural interfacing technology in the future