Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over the chronic implantation period. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period.
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This content will become publicly available on November 1, 2024
Cell-specific alterations in autophagy-lysosomal activity near the chronically implanted microelectrodes
Intracortical microelectrodes that can record and stimulate brain activity have become a valuable technique for
basic science research and clinical applications. However, long-term implantation of these microelectrodes can
lead to progressive neurodegeneration in the surrounding microenvironment, characterized by elevation in
disease-associated markers. Dysregulation of autophagy-lysosomal degradation, a major intracellular waste
removal process, is considered a key factor in the onset and progression of neurodegenerative diseases. It is
plausible that similar dysfunctions in autophagy-lysosomal degradation contribute to tissue degeneration
following implantation-induced focal brain injury, ultimately impacting recording performance. To understand
how the focal, persistent brain injury caused by long-term microelectrode implantation impairs autophagylysosomal
pathway, we employed two-photon microscopy and immunohistology. This investigation focused
on the spatiotemporal characterization of autophagy-lysosomal activity near the chronically implanted microelectrode.
We observed an aberrant accumulation of immature autophagy vesicles near the microelectrode over
the chronic implantation period. Additionally, we found deficits in autophagy-lysosomal clearance proximal to
the chronic implant, which was associated with an accumulation of autophagy cargo and a reduction in lysosomal
protease level during the chronic period. Furthermore, our evidence demonstrates reactive astrocytes have
myelin-containing lysosomes near the microelectrode, suggesting its role of myelin engulfment during acute
implantation period. Together, this study sheds light on the process of brain tissue degeneration caused by longterm
microelectrode implantation, with a specific focus on impaired intracellular waste degradation.
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- Award ID(s):
- 1943906
- NSF-PAR ID:
- 10503023
- Publisher / Repository:
- Elsevier
- Date Published:
- Journal Name:
- Biomaterials
- Volume:
- 302
- Issue:
- C
- ISSN:
- 0142-9612
- Page Range / eLocation ID:
- 122316
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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