Friday, May 9, 2025
5/9/2025
Structural and Functional Plasticity Surrounding Implanted Neuroprostheses - PROJECT SUMMARY The development of implantable devices capable of recording or stimulating electrical activity in the brain has created unprecedented opportunities to treat and study neurological diseases and injuries. However, a reactive tissue response typically occurs following implantation which is widely believed to interfere with long-term device performance. Inflammatory microglia and astrocytes encapsulate and isolate devices from neurons, while neuronal signal sources are lost within the recordable radius of the electrode surface. While these observations may contribute to signal instability and recording loss over time, the mechanistic link between specific inflammatory events and changes in signal quality remains unclear. Our group is expanding upon the current basic science understanding of device-tissue integration and recently published a study which showed shifts in subtype-specific markers of synaptic transmission surrounding implanted electrode arrays. Our data indicated an early elevation of markers of excitatory transmission (vesicular glutamate transporter-1, VGLUT1) three days post-implantation that was followed by a subsequent shift to increased expression of labeling for inhibitory neurotransmission (vesicular GABA transporter, VGAT). We hypothesize that structural and functional plasticity of synaptic inputs surrounding devices could contribute to loss of recorded signals. We further hypothesize that the timed elevation of glutamate and GABA release may act as “go” and “stop” cues which mediate the reactive tissue response. In this proposal, we will build upon our initial observations, further investigating the underlying mechanisms and functional consequences of synaptic plasticity on device performance. In Specific Aim 1, we will define the functional impacts of glutamatergic synaptic remodeling at the electrode interface on recorded signal quality and reactive gliosis. We will correlate transporter expression with signal quality and assess the effects of VGLUT1 knockdown on signal quality and tissue response. In Specific Aim 2, we similarly will define the functional impacts of GABAergic synaptic remodeling at the electrode interface on recorded signal quality and reactive gliosis. We hypothesize that while early glutamate release may incite neurotoxicity and reactive gliosis, subsequent GABA release acts in an anti-inflammatory capacity to preserve neuronal viability and mitigate further glial reactivity. In Specific Aim 3, we will reveal structural plasticity in the dendritic arbors of neurons at the electrode interface. For this aim, we will use two photon imaging to assess changes in dendritic spine density and morphology surrounding devices captured in ex vivo brain tissue slices. For all aims, we will test both silicon and polyimide-based arrays to compare results between device designs commonly used in the field. We will inspect impedance measurements and post-mortem scanning electron microscopy images for signs of device failure to strengthen the interpretation of our results. By exploring novel mechanisms of synaptic plasticity surrounding implanted electrode arrays, we expect to open new opportunities to both understand, and improve upon, long-term device function and biocompatibility.
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