Browsing by Author "Wise, Andrew K"
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- ItemAuditory nerve responses to combined optogenetic and electrical stimulation in chronically deaf mice.(Journal of Neural Engineering, 2023-04-11) Ajay, Elise A; Trang, Ella P; Thompson, Alexander C; Wise, Andrew K; Grayden, David B; Fallon, James B; Richardson, Rachael T. Optogenetic stimulation of the auditory nerve offers the ability to overcome the limitations of cochlear implants through spatially precise stimulation, but cannot achieve the temporal precision nor temporal fidelity required for good hearing outcomes. Auditory midbrain recordings have indicated a combined (hybrid) stimulation approach may permit improvements in the temporal precision without sacrificing spatial precision by facilitating electrical activation thresholds. However, previous research has been conducted in undeafened or acutely deafened animal models, and the impact of chronic deafness remains unclear. Our study aims to compare the temporal precision of auditory nerve responses to optogenetic, electrical, and combined stimulation in acutely and chronically deafened animals.. We directly compare the temporal fidelity (measured as percentage of elicited responses) and precision (i.e. stability of response size and timing) of electrical, optogenetic, and hybrid stimulation (varying sub-threshold or supra-threshold optogenetic power levels combined with electrical stimuli) through compound action potential and single-unit recordings of the auditory nerve in transgenic mice expressing the opsin ChR2-H134R in auditory neurons. Recordings were conducted immediately or 2-3 weeks following aminoglycoside deafening when there was evidence of auditory nerve degeneration.. Results showed that responses to electrical stimulation had significantly greater temporal precision than optogenetic stimulation (< 0.001 for measures of response size and timing). This temporal precision could be maintained with hybrid stimulation, but only when the optogenetic stimulation power used was below or near activation threshold and worsened with increasing optical power. Chronically deafened mice showed poorer facilitation of electrical activation thresholds with concurrent optogenetic stimulation than acutely deafened mice. Additionally, responses in chronically deafened mice showed poorer temporal fidelity, but improved temporal precision to optogenetic and hybrid stimulation compared to acutely deafened mice.. These findings show that the improvement to temporal fidelity and temporal precision provided by a hybrid stimulation paradigm can also be achieved in chronically deafened animals, albeit at higher levels of concurrent optogenetic stimulation levels.
- ItemCombined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers.(Frontiers in Neuroscience, 2023-06-08) Matarazzo, Jerico V; Ajay, Elise A; Payne, Sophie C; Trang, Ella P; Thompson, Alex C; Marroquin, Jason B; Wise, Andrew K; Fallon, James B; Richardson, Rachael TElectrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges. In this study we employed a combined protocol of optical and electrical stimulation to the sciatic nerve in an optogenetic mouse model to allow for better selectivity, efficiency, and safety to overcome fundamental limitations of electrical-only and optical-only stimulation.
- ItemCombined-electrical optogenetic stimulation but not channelrhodopsin kinetics improves the fidelity of high rate stimulation in the auditory pathway in mice.(Scientific Reports, 2024-09-09) Ajay, Elise A; Thompson, Alex C; Azees, Ajmal A; Wise, Andrew K; Grayden, David B; Fallon, James B; Richardson, Rachael TNovel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.
- ItemGene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".(Advanced Science News, 2024-06-14) Pinyon, Jeremy L; von Jonquieres, Georg; Crawford, Edward N; Abed, Amr Al; Power, John M; Klugmann, Matthias; Browne, Cherylea J; Housley, David M; Wise, Andrew K; Fallon, James B; Shepherd, Robert K; Lin, John Y; McMahon, Catherine; McAlpine, David; Birman, Catherine S; Lai, Waikong; Enke, Ya Lang; Carter, Paul M; Patrick, James F; Gay, Robert D; Marie, Corinne; Scherman, Daniel; Lovell, Nigel H; Housley, Gary DViral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.