A growing number of implantable neural electrode devices are being developed to map brain circuit or restore function and treat diseases. The performance of these devices hinges on the quality and stability of the electrode-neural tissue interface. Undesirable brain tissue responses, including persistent microglia activation and blood brain barrier breach, glial scarring, neuronal loss and degeneration, have been consistently reported in animal studies. For electrode devices that require intimate contact with host neurons, their performance functionality may be compromised by these responses. As an example, single unit neural recording via microelectrode arrays experiences deterioration in yield and quality over time, which is a major barrier to applications of this technology in long-term neuroscience research and clinical translation. There are many
molecules and pathways involved in inflammation and neuronal death. We began
our study by focusing on caspase-1, as caspase-1 is a key mediator of both
inflammation and programmed cell death. Activation of caspase-1 is the earliest
detectable event in neuronal apoptosis in
vitro and in brains with ischemic, injury and neurodegenerative conditions.
Furthermore, caspase-1 activates interleukin-1β (IL-1β), a pro-inflammatory
cytokine highly expressed in the tissue surrounding implanted electrodes,
especially those that showed poor electrophysiological outcome. IL-1β triggers
inflammatory gliosis and exacerbates BBB breach; both are hypothesized causes
of chronic recording failure. Therefore, we hypothesize that caspase-1 mediates
the neuronal death and inflammation around neural implants and inhibiting
caspase-1 may improve neuronal survival, reduce inflammation and lead to
improved electrode performance. We have performed a preliminary study comparing
the neural recording performance of microelectrode arrays implanted in
caspase-1 knockout (KO) vs. wild-type (WT) mice. The single unit yield and
signal quality are significantly greater in the knockout animals over the 6
month time period, strongly supporting the critical role for caspase-1 in maintaining
the quality of the electrode-tissue interface. However, closer examination of
the recording over time revealed dynamic changes that cannot be interpreted
with end-point histology. To better understand the mechanism(s) by which
caspase-1-mediated pathways affect recording, this project will use 2-photon
live animal imaging to characterize the cellular and vascular responses to
implanted neural probes in conjunction with neural recording and comprehensive
tissue and biochemical analyses. Therapeutics targeting caspase-1 or the
inflammation/cell death in general will be evaluated in an effort to improve
the chronic neural interface. Pharmaceutical
treatments will also be used to attenuate caspase-1 activity without transgenetic
intervention. This proposal uses a multidisciplinary approach to uncover the molecular
and cellular mechanism contributing to neural recording performance. Kozai TDY, Li X, Bodily LM, Caparosa EM, Zenonos GA, Carlisle DL, Friedlander RM, Cui XT. Effects of caspase-1 knockout on chronic neural recording quality and longevity: Insight into cellular and molecular mechanisms of the reactive tissue response. Biomaterials. 2014. 35(36). 9620-9634 The findings will increase our scientific understanding of neural implant pathology, and guide the development of therapeutic and/or biomaterial strategy for stable and reliable neural interface. Data and technology developed in this project may also contribute to the study of neuronal degeneration and inflammation in traumatic brain injury, stroke and neural degenerative diseases. |
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