Biology subjects

Kozai, T. D. Y.

Publications and source records attributed to Kozai, T. D. Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Astrocyte modulation of neural activity during intracortical microstimulation

Electrical manipulation of neural circuits has advanced our understanding of brain function, but the mechanisms that shape neural activity during stimulation remain incompletely understood. This gap reflects a persistent neuron-centric view of stimulation that overlooks the regulatory influence of glial cells, especially for long duration stimuli. Here we investigated whether astrocytes actively shape the brains response to different patterns of stimulation. Using two-photon and mesoscale calcium imaging of the visual cortex in awake mice, we bidirectionally manipulated astrocyte calcium signaling during intracortical microstimulation (ICMS) via chemogenetic (hM3Dq) and optogenetic (melanopsin) tools. We show that astrocytes respond to stimulation in a pattern-dependent way and shape ongoing neural activity rather than simply following it. Near the electrode, neurons responded to astrocyte modulation in mixed directions, some increasing and some decreasing. Instead of uniformly raising or lowering activity, changing astrocyte calcium pulled neuronal responses toward an intermediate state, with the direction determined by each neurons starting response and its distance from the electrode. Our results identify astrocyte calcium as a source of this shaping during electrical stimulation, and highlight the need to incorporate neuron-glia dynamics into the design of therapeutic neurostimulation.

bioengineering↗

bioRxiv2025

Fus depleted oligodendrocytes reduce neuronal damage and attenuate AD progression in the AppNL-G-F mouse

AbstractOligodendrocytes (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of Alzheimers Disease (AD). OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. To gain insight on how OL and myelin may improve neuronal deficits associated with AD, we have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse which carries three human AD mutations in the mouse App gene with the FusOLcKO, which has thicker myelin associated with greater cholesterol biosynthesis. The spatial working memory deficits manifested by the aged AD mouse were fully rescued by the FusOLcKO. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the plaque niches and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Single cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in protecting neurons and affecting microglia state in AD pathology.

neuroscience↗

bioRxiv2025

Chronic alteration of Ca2+ and hemodynamic signals induced by intracortical microstimulation in the visual cortex of awake mice

Understanding the chronic effects of intracortical microstimulation (ICMS) and device implantation on cortical function is essential for the development of stable neuroprosthetics. We chronically implanted microelectrode into Thy1-GCaMP6s mice and conducted longitudinal mesoscopic widefield and two-photon Ca2#x002B; imaging alongside intrinsic optical signal recordings over 12 weeks. Six ICMS frequencies (10-500 Hz) and contralateral visual LED stimuli were delivered in repeated sessions. Oxygen extraction fraction (OEF) was estimated from dual-wavelength reflectance, and hemodynamic response functions (HRF) were derived via regularized deconvolution. Over the chronic period, 25-Hz ICMS evoked progressively larger Ca2+ responses whose duration was extending, while spatial spread remained stable around 500 {micro}m. Concurrently, OEF reductions deepened, reflecting increased relative blood supply, and the spatial extent of OEF signals contracted in the first week before expanding by day 21. After discharge-like Ca2+ events emerged in nearly half of mice, predominantly under 25-Hz ICMS. HRF peak amplitude increased between day 0 and days 7-21, with latency decreasing. Chronic ICMS induces progressive potentiation of neuronal and vascular responses alongside local neurovascular uncoupling on day 0 and sustained silencing of spontaneous activity near the implant. These dynamics exhibiting a stabilization 6-7 weeks after the implantation, coupled with frequency-dependent after discharges, underscore the need for adaptive stimulation strategies prior to the stabilization and to prevent the after discharge and implant designs that mitigate local suppression and ensure long-term stability of cortical neuroprostheses.

bioengineering↗

bioRxiv2025

Aging diminishes interlaminar functional connectivity in the mouse cortical V1 and CA1 hippocampal regions

Aging disrupts brain network integration and is a significant risk factor for cognitive decline and neurological diseases, yet the circuit-level mechanisms underlying these changes remain unclear. Most previous studies have utilized cross-sectional or acute approaches, limiting insights into the longitudinal dynamics of the neural network. In this study, we chronically recorded laminar electrophysiological activity in both the primary visual cortex (V1) and hippocampal CA1 region of young (2-month-old) and aged (13-month-old) mice over 16 weeks. This approach allowed us to directly assess how aging modulates functional connectivity within hierarchically connected cortical and hippocampal circuits. We found that single-unit spiking activity and the signal-to-noise ratio were largely preserved in aged versus young mice, suggesting intact neuronal firing properties. However, aged mice showed global reductions in local field potential (LFP) power and a selective decrease in coherence across delta, alpha-beta, and gamma frequency bands within and between cortical layers and V1-CA1 pathways, while phase amplitude coupling remained unaffected. Interestingly, population level excitatory activity in CA1 was increased in aged animals. These findings indicate that aging selectively impairs network-level synchrony and temporal coordination in specific frequency bands and regions, with minimal loss of single-neuron function. Our results highlight the necessity of longitudinal, multi-region measurements to uncover the multi-scale vulnerabilities of the aging brain. Understanding the depth- and region-dependent circuit changes will guide strategies to preserve cortical-hippocampal communication and cognitive function in aging, as well as enhance neural interface technologies for older populations. NEW & NOTEWORTHYAging non-uniformly degrades cortico-hippocampal networks, leading to region- and frequency-specific breakdowns in coordinated activity. While single-neuron activity remains preserved, disruptions in frequency-selective synchrony (delta and alpha-beta) were observed in aged mice, indicating impaired V1-CA1 communication as a marker of aging rather than neuronal degeneration. By separating single-neuron activity and large-scale dynamics, we reveal that aging alters communication between sensory and memory systems, underscoring the need for longitudinal approaches to capture age-related impairments in laminar connectivity.

neuroscience↗

bioRxiv2025

Hypermyelination Improves Strength and Detection of Neuronal Activity in the CA1 Hippocampus and Facilitates Neuroprotection in FusOLcKO Mice

1.0.Loss of oligodendrocytes (OLs) and myelin impairs cortical neuronal firing and network stability, whereas enhancement of oligodendrogenesis improves electrophysiological stability in cortex and, to a lesser extent, hippocampus. OLs exhibit regional heterogeneity, especially in their ability to synthesize cholesterol, a critical driver of myelin wrapping and ensheathment of axons. Conditional depletion of the Fused in sarcoma (Fus) gene in OLs, referred to as FusOLcKO, increases cholesterol biosynthesis, myelin thickness, and tissue cholesterol content. We examine whether this hypermyelination alters extracellular recordings across the layers of visual cortex and the underlying hippocampal CA1 over 16 weeks. In FusOLcKO mice, visually-evoked single-unit detectability and firing rate in CA1 increased relative to wild-type littermates, whereas cortical recordings showed no improvement. At the population level, FusOLcKO cortex exhibited reduced firing rates and lower functional connectivity, indicating altered network dynamics. Post-mortem histology revealed higher neuron density in recorded cortex and greater excitatory synapse density in CA1 of FusOLcKO mice suggesting region-specific neuroprotection and synaptic strengthening. These results demonstrate that cholesterol-driven hypermyelination enhances chronic hippocampal recordings while disrupting cortical network communication. Our study highlights myelins region-dependent roles in supporting single-cell reliability, tuning population dynamics, and maintaining circuit integrity under chronic perturbation. 2.0. SIGNIFICANCE STATEMENTMyelin critically regulates neural circuit function via conduction and metabolic support. Here, we show that cholesterol-driven hypermyelination in FusOLcKO mice augments single-unit detection and firing in hippocampal CA1 but reduces population firing and interlaminar connectivity within the cortex. These findings reveal a dual role for myelin: it can both safeguard specific circuit activity and perturb large-scale cortical communication. Understanding these dynamics is essential for designing myelin-targeted therapies in neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Microglia surveillance is directed toward neuron activation during sustained intracortical microstimulation

Intracortical microstimulation (ICMS) is a widely used tool for neuroprostheses, but its long-term efficacy is often limited by biofouling and neuroinflammatory responses at the electrode-tissue interface. Microglia orchestrate neuroinflammation and regulate synaptic plasticity, and low-frequency stimulation has been shown to promote anti-inflammatory microglial phenotypes. We therefore examined, over the first three days post-implantation, how 10-Hz ICMS influences microglial-neuronal interactions in vivo using two-photon imaging in Cx3cr1-GFP/jRGECO1a mice. A one-hour session of 10-Hz ICMS did not induce overt morphological activation of microglia but increased their process motility, directing extensions toward both the electrode and neurons exhibiting elevated calcium activity. By post-implantation Day 2, microglial extensions were significantly biased toward neurons whose {Delta}F/F surpassed a 3 standard deviation threshold after stimulation onset (74.26{degrees} {+/-} 11.83{degrees}) but shifted away from those same neurons after 40 min of continuous stimulation (116.99{degrees} {+/-} 9.19{degrees}) (p = 0.001732), suggesting a dynamic, homeostatic response to sustained neuronal calcium elevations. Although multi-day electrode insertion accelerated microglial motility and polarization toward the device, 10-Hz ICMS alone did not alter microglial branching or soma shape. Microglial contact frequency scaled with neuronal adaptation profiles: depressed neurons received the most contacts immediately post-implant (1.15 {+/-} 0.3 contacts; p = .0460). These findings reveal stimulus-associated, neuron-dependent surveillance behaviors of microglia during early post-implantation ICMS and implicate them as active participants in short-term modulation of cortical circuits.

bioengineering↗

bioRxiv2025

Finite element model predicts micromotion-induced strain profiles that correlate with the functional performance of Utah arrays in humans and non-human primates

ObjectiveUtah arrays are widely used in both humans and non-human primates (NHPs) for intracortical brain-computer interfaces (BCIs), primarily for detecting electrical signals from cortical tissue to decode motor commands. Recently, these arrays have also been applied to deliver electrical stimulation aimed at restoring sensory functions. A key challenge limiting their longevity is the micromotion between the array and cortical tissue, which may induce mechanical strain in surrounding tissue and contribute to performance decline. This strain, due to mechanical mismatch, can exacerbate glial scarring around the implant, reducing the efficacy of Utah arrays in recording neuronal activity and delivering electrical stimulation. ApproachTo investigate this, we employed a finite element model (FEM) to predict tissue strains resulting from micromotion. Main ResultsOur findings indicated that strain profiles around edge and corner electrodes were greater than those around interior shanks, affecting both maximum and average strains within 50 {micro}m of the electrode tip. We then correlated these predicted tissue strains with in-vivo electrode performance metrics. We found negative correlations between 1 kHz impedance and tissue strains in human motor arrays and NHP area V4 arrays at 1-mo, 1-yr, and 2-yrs post-implantation. In human motor arrays, the peak-to-peak waveform voltage (PTPV) and signal-to-noise ratio (SNR) of spontaneous activity were also negatively correlated with strain. Conversely, we observed a positive correlation between the evoked SNR of multi-unit activity and strain in NHP area V4 arrays. SignificanceThis study establishes a spatial dependence of electrode performance in Utah arrays that correlates with tissue strain.

neuroscience↗

bioRxiv2024

Spatiotemporal properties of cortical excitatory and inhibitory neuron activation by sustained and bursting electrical microstimulation

Intracortical microstimulation (ICMS) of sensory cortices produces artificial sensation yet the neural mechanisms underlying evoked responses, particularly among inhibitory subpopulations, remain unclear. We investigated how long durations (30 s) of ICMS shape spatiotemporal patterns in excitatory and inhibitory network activation using two-photon imaging of visual cortex in transgenic mice. Inhibitory neurons were more likely to facilitate (increase in activation) across 30 s of ICMS, whereas excitatory neurons were more likely to adapt (decrease in activation) and exhibit post-ICMS depression. Different temporal profiles led to preferential activation of excitatory or inhibitory neurons, with theta-burst stimulation driving the strongest inhibitory response and 10-Hz burst patterns driving the strongest peak excitatory response. Neurons located farther from the electrode exhibited more diverse responses to ICMS, highlighting synaptic recruitment dynamics such as inhibition and disinhibition. This study reveals how ICMS differentially influences excitatory and inhibitory neuron activity across long durations of ICMS and suggests temporal patterning can be used to potentially target neuronal subpopulations and drive desirable activity patterns.

bioengineering↗

bioRxiv2024

Dynamic changes in structure and function of brain mural cells around chronically implanted microelectrodes

1.0Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

bioengineering↗

bioRxiv2024

Potential of Photoelectric Stimulation with Ultrasmall Carbon Electrode on Neural Tissue: New Directions in Neuromodulation Technology Development

ObjectiveNeuromodulation technologies have gained considerable attention for its clinical potential in treating neurological disorders and their capacity to advance cognition research. Nevertheless, traditional neuromodulation methods such as electrical stimulation and optogenetics manipulation currently experience technical and biological challenges that hinge their therapeutic potential and chronic research applications. Recently, a promising alternative neuromodulation approach based on the photoelectric effect has emerged. This approach is capable of generating electrical pulses when exposed to near-infrared (NIR) light and allows modulation of neuronal activity without the need for genetic alterations. In this study, we investigate a variety of design strategies aimed at enhancing photoelectric stimulation using minimally invasive, ultrasmall, untethered carbon electrodes. ApproachA multiphoton laser was employed as the NIR light source. Benchtop investigations were conducted using a three-electrode setup, and chronopotentiometry was used to record photo-stimulated voltage. For in vivo evaluation, we used Thy1-GCaMP6s mice with acute implantation of ultrasmall carbon electrodes. Main resultsWe revealed the beneficial effects of high duty-cycle laser scanning and photovoltaic polymer interfaces on the photo-stimulated voltages of ultrasmall carbon electrodes. Additionally, we demonstrated the promising potential of carbon-based diamond electrodes for photoelectric stimulation and examined the application of photoelectric stimulation in precise chemical delivery by loading mesoporous silica nanoparticles (SNPs) co-deposited with polyethylenedioxythiophene (PEDOT). SignificanceThese findings on photoelectric stimulation utilizing ultrasmall carbon electrodes underscore its immense potential for advancing the next generation of neuromodulation technology. This approach offers the opportunity to effectively modulate neural tissue while minimizing invasive implantation-related injuries in freely moving subjects, which hold significant promise for a wide range of applications in neuroscience research and clinical settings.

bioengineering↗

bioRxiv2024

Activation and depression of neural and hemodynamic responses induced by the intracortical microstimulation and visual stimulation in the mouse visual cortex.

Objective. Intracortical microstimulation can be an effective method for restoring sensory perception in contemporary brain-machine interfaces. However, the mechanisms underlying better control of neuronal responses remain poorly understood, as well as the relationship between neuronal activity and other concomitant phenomena occurring around the stimulation site. Approach. Different microstimulation frequencies were investigated in vivo on Thy1-GCaMP6s mice using widefield and two-photon imaging to evaluate the evoked excitatory neural responses across multiple spatial scales as well as the induced hemodynamic responses. Specifically, we quantified stimulation-induced neuronal activation and depression in the mouse visual cortex and measured hemodynamic oxyhemoglobin and deoxyhemoglobin signals using mesoscopic-scale widefield imaging. Main results. Our calcium imaging findings revealed a preference for lower-frequency stimulation in driving stronger neuronal activation. A depressive response following the neural activation preferred a slightly higher frequency stimulation compared to the activation. Hemodynamic signals exhibited a comparable spatial spread to neural calcium signals. Oxyhemoglobin concentration around the stimulation site remained elevated during the post-activation (depression) period. Somatic and neuropil calcium responses measured by two-photon microscopy showed similar dependence on stimulation parameters, although the magnitudes measured in soma was greater than in neuropil. Furthermore, higher-frequency stimulation induced a more pronounced activation in soma compared to neuropil, while depression was predominantly induced in soma irrespective of stimulation frequencies. Significance. These results suggest that the mechanism underlying depression differs from activation, requiring ample oxygen supply, and affecting neurons. Our findings provide a novel understanding of evoked excitatory neuronal activity induced by intracortical microstimulation and offer insights into neuro-devices that utilize both activation and depression phenomena to achieve desired neural responses.

bioengineering↗

bioRxiv2023

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation.

Microglia are important players in surveillance and repair of the brain. Their activation mediates neuroinflammation caused by intracortical microelectrode implantation, which impedes the application of intracortical brain-computer interfaces (BCIs). While low-intensity pulsed ultrasound stimulation (LIPUS) can attenuate microglial activation, its potential to modulate the microglia-mediated neuroinflammation and enhance the bio-integration of microelectrodes remains insufficiently explored. We found that LIPUS increased microglia migration speed from 0.59{+/-}0.04 to 1.35{+/-}0.07 {micro}m/hr on day 1 and enhanced microglia expansion area from 44.50{+/-}6.86 to 93.15{+/-}8.77 {micro}m2/min on day 7, indicating improved tissue healing and surveillance. Furthermore, LIPUS reduced microglial activation by 17% on day 6, vessel-associated microglia ratio from 70.67{+/-}6.15 to 40.43{+/-}3.87% on day 7, and vessel diameter by 20% on day 28. Additionally, microglial coverage of the microelectrode was reduced by 50% in week 1, indicating better tissue-microelectrode integration. These data reveal that LIPUS helps resolve neuroinflammation around chronic intracortical microelectrodes.

bioengineering↗

bioRxiv2023

Impact of electrodes design and insertion methods to surrounding cortical tissues from high-density arrays.

ObjectiveOver the past decade, neural electrodes have played a crucial role in bridging biological tissues with electronic and robotic devices. This study focuses on evaluating the optimal tip profile and insertion speed for effectively implanting Paradromics high-density Fine Microwire Arrays (FA) prototypes into the primary visual cortex (V1) of mice and rats, addressing the challenges associated with the "bed-of-nails" effect and tissue dimpling. ApproachTissue response was assessed by investigating the impact of electrodes on the blood-brain barrier (BBB) and cellular damage, with a specific emphasis on tailored insertion strategies to minimize tissue disruption during electrode implantation. Main ResultsElectro-sharpened arrays demonstrated a marked reduction in cellular damage within 50 m of the electrode tip compared to blunt and angled arrays. Histological analysis revealed that slow insertion speeds led to greater BBB compromise than fast and pneumatic methods. Successful single-unit recordings validated the efficacy of the optimized electro-sharpened arrays in capturing neural activity. SignificanceThese findings underscore the critical role of tailored insertion strategies in minimizing tissue damage during electrode implantation, highlighting the suitability of electro-sharpened arrays for long-term implant applications. This research contributes to a deeper understanding of the complexities associated with high-channel-count microelectrode array implantation, emphasizing the importance of meticulous assessment and optimization of key parameters for effective integration and minimal tissue disruption. By elucidating the interplay between insertion parameters and tissue response, our study lays a strong foundation for the development of advanced implantable devices with a reduction in reactive gliosis and improved performance in neural recording applications.

bioengineering↗

bioRxiv2023

Neuronal functional connectivity is impaired in a layer dependent manner near the chronically implanted microelectrodes

ObjectiveThis study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near the chronically implanted microelectrode. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how does the FBR impact affect the functional stability of neural circuits near implanted Brain-Computer Interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders. ApproachThis study utilized multisite Michigan-style microelectrodes that span all cortical layers and the hippocampal CA1 region to collect spontaneous and visually-evoked electrophysiological activity. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of LFP and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation. Main ResultsThe study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations. SignificanceThis study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our studys understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

bioengineering↗

bioRxiv2023

Impairment of 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 the autophagy-lysosomal 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 suggests astrocytes contribute to the clearance of myelin debris via autophagy-lysosomal degradation near the implanted microelectrode. Together, this study sheds light on the process of brain tissue degeneration caused by long-term microelectrode implantation, with a specific focus on impaired intracellular waste degradation.

bioengineering↗

bioRxiv2023

Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimers disease

1.0.Electrical stimulation has had a profound impact on our current understanding of nervous system physiology and provided viable clinical options for addressing neurological dysfunction within the brain. Unfortunately, the brains immune suppression of indwelling microelectrodes currently presents a major roadblock in the long-term application of neural recording and stimulating devices. In some ways, brain trauma induced by penetrating microelectrodes produces similar neuropathology as debilitating brain diseases, such as Alzheimers disease (AD), while also suffering from end-stage neuron loss and tissue degeneration. To understand whether there may be any parallel mechanisms at play between brain injury from chronic microelectrode implantation and those of neurodegenerative disorder, we used two-photon microscopy to visualize the accumulation, if any, of age- and disease-associated factors around chronically implanted electrodes in both young and aged mouse models of AD. With this approach, we determined that electrode injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in wild-type and AD mice alike. Furthermore, we reveal that chronic microelectrode implantation reduces the growth of pre-existing amyloid plaques while simultaneously elevating amyloid burden at the electrode-tissue interface. Lastly, we uncover novel spatial and temporal patterns of glial reactivity, axonal and myelin pathology, and neurodegeneration related to neurodegenerative disease around chronically implanted microelectrodes. This study offers multiple novel perspectives on the possible neurodegenerative mechanisms afflicting chronic brain implants, spurring new potential avenues of neuroscience investigation and design of more targeted therapies for improving neural device biocompatibility and treatment of degenerative brain disease.

neuroscience↗

bioRxiv2023

Pro-myelinating Clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health

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 chronic implantation. 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/526463v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1a729d0org.highwire.dtl.DTLVardef@1aa3f8aorg.highwire.dtl.DTLVardef@31b231org.highwire.dtl.DTLVardef@a9dd39_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

In vivo spatiotemporal dynamics of astrocyte reactivity following neural electrode implantation

Brain computer interfaces (BCIs), including penetrating microelectrode arrays, enable both recording and stimulation of neuronal cells. However, device implantation inevitably causes injury to brain tissue and induces a foreign body response, leading to reduced recording performance and stimulation efficacy. Astrocytes in the healthy brain play multiple roles including regulating energy metabolism, homeostatic balance, transmission of neural signals, and neurovascular coupling. Following an insult to the brain, they are activated and observed to gather around the site of injury. These reactive astrocytes have been regarded as one of the main contributors to the formation of a glial scar which affects the performance of microelectrode arrays. This study investigates the dynamics of astrocytes within the first 2 weeks after implantation of an intracortical microelectrode into the mouse brain using two-photon microscopy. From our observation astrocytes are highly dynamic during this period, exhibiting patterns of process extension, soma migration, morphological activation, and device encapsulation that are spatiotemporally distinct from other glial cells, such as microglia or oligodendrocyte precursor cells. This detailed characterization of astrocyte reactivity will help to better understand the tissue response to intracortical devices and lead to the development of more effective intervention strategies to improve the functional performance neural interfacing technology.

bioengineering↗