Biology subjects

Smith, W. C.

Publications and source records attributed to Smith, W. C..

4 recordsLinked to original sources

bioRxiv2026

A modified Arrestin1 Slows Retinal Degeneration Across Genetically Distinct Mouse Models of Inherited Retinal Disease

Inherited retinal diseases (IRDs) are a genetically heterogeneous group of disorders caused by mutations in more than 340 genes, limiting the applicability of gene-targeted therapies and creating the need for broader treatment strategies. Photoreceptor dysfunction is a hallmark of IRDs and often results in disrupted retinal metabolic homeostasis, as photoreceptors have exceptionally high metabolic demands and provide metabolic resources to surrounding retinal cells. Consequently, enhancing retinal metabolism has emerged as a promising gene-agnostic strategy for treating IRDs. We previously developed a modified arrestin1 (ArrGG) that relieves arrestin1-mediated inhibition of the glycolytic enzyme enolase1, thereby increasing glycolytic output and slowing retinal degeneration in the RhoP23H/+ mouse model. Here, we investigated the therapeutic potential of ArrGG as a gene-agnostic approach targeting endogenous metabolic enzyme activity across genetically distinct models of IRD. Using two complementary photoreceptor-enriched transcriptomic analyses, we found no widespread, reproducible transcriptional changes following ArrGG treatment. These findings support our hypothesis that ArrGG modulates photoreceptor metabolism without inducing substantial transcriptional remodeling. The therapeutic efficacy of ArrGG was evaluated in three IRD mouse models representing rapid rod degeneration (rd10), cone degeneration (GC1KO), and RPE-associated retinal degeneration (rd6). ArrGG treatment was associated with preserved retinal function and slowed structural degeneration across all three models. Together, these findings support the potential of modulating endogenous metabolic enzyme activity to preserve photoreceptors across genetically distinct IRD models. This work suggests that ArrGG could be a promising gene-agnostic metabolic therapy for slowing retinal degeneration and preserving visual function in inherited retinal diseases.

neuroscience↗

bioRxiv2024

Investigation of neural functional connectivity in thick acute mouse brain slices with novel multi-region 3D neural probe arrays

There are significant limitations in investigating complex neural circuits in vivo, including drawbacks to midline-adjacent surgeries, limited accessibility to deep brain regions and number of feasible regional targets for simultaneous recordings, and analytical or experimental biases from recording one columnar plane. On the other hand, recording extracellular neural signals ex vivo or in vitro using planar microelectrode arrays (MEAs) only permits slice surface recordings, and since conventional slices under 400 m-thick or dissociated cultures are used, no experiments contain a physiological multi-region circuit, drastically limiting conclusions about connectivity and pharmacology. Using thick, tract-preserving acute brain slices to record otherwise unassailable neural circuits ex vivo combines the strengths of both types of experiments, but is assumed to precipitate ischemic injury due to oxygen scarcity within the slice. Here, we report the first application of custom, multi-region silicon neural probe arrays to record spontaneous activity & optogenetically-induced functional connectivity acrosshe mesocorticolimbic pathway within tract-preserving 800 m sagittal mouse brain slices, compared with 400 m slices, among three brain regions: the ventral tegmental area (VTA), ventral striatum (VS), & medial prefrontal cortex (mPFC). We show that most single-unit signals are an order of magnitude below the noise floor seen using silicon probes in vivo, providing unit yields far higher than previously assumed, allowing for a deep functional understanding of acute slice condition compared to the assumed deterioration due to ischemia. Overall, our method allows for acute circuit manipulations beyond what is available in vivo, with far more information than conventional slice preparations.

neuroscience↗

bioRxiv2022

In vivo Quantification of Neural Criticality and Complexity in Mouse Cortex and Striatum in a Model of Cocaine Abstinence

Self-organized criticality is a hallmark of complex dynamic systems at phase transitions. Systems that operate at or near criticality have large-scale fluctuations or "avalanches", the frequency and duration power of which are best fit with a power law revealing them to be scale-free and fractal, and such power laws are ubiquitous. It is an attractive concept in neuroscience since spiking avalanches are exhibited by neural tissue, and may underpin how minuscule events could scale up to circuits and provide adaptive psychobiological function. Much is yet to be understood about criticality in vivo in the healthy brain and in disorders such as addiction, as drugs may alter the critical states "tuning" to generate drug seeking and dysphoria. Thus, here a novel toolset was developed to use neural avalanches and their self-similarity, rather than power law fit slope exponents as is canonically done, to quantify criticality in a previously collected high-density electrophysiological in vivo corticostriatal dataset from a mouse model of early cocaine abstinence. During behavioral quiescence, in the prefrontal cortex but not ventral striatum of cocaine-dosed mice, it was found that critical tuning is enhanced compared to drug-free controls. Additionally, an empirical biological demonstration of complexitys theoretical correlation to criticality was shown in drug-free mice, was exponentially enhanced in drug-treated cortex, but was absent in the drug-treated striatum. As shown, quantifying criticality grants experimental support for the "critical brain hypothesis" and allows for statistical interpretation of inter-subject variability and development of further testable hypotheses in systems neuroscience. Significance StatementThe "critical brain hypothesis" asserts neural networks are comparable to material in phase transitions at a critical point, their "avalanches" of system-wide spike bursts best seen in log-log plots of probability vs. avalanche size or duration, with slope following a scale-free or fractal power law. In discussing criticality, "critical tuning" is mentioned but quantification thereof left for later experimentation, despite being necessary for a scientific hypothesis. Presented are methods to quantify critical tuning through assessing similarity or fractalness among corticostriatal avalanches collected using high-density electrophysiology in cocaine-conditioned mice, along with an empirical in vivo confirmation of the mathematical concept that data complexity correlates with criticality. Interestingly, cocaine enhances critical tuning in cortex and aberrantly modifies complexity in a region-specific manner.

neuroscience↗

bioRxiv2020

Deep origins for the tectal visual processing centers in chordates

Visual processing transforms the complex visual world into useful information. Ciona, a close relative of vertebrates, has one of the simplest nervous systems known, yet has a range of visuomotor behaviors. Among them are negative phototaxis and a looming-shadow response. These two behaviors are mediated by separate photoreceptor groups acting via distinct, but overlapping, neural circuits. We show here that processing circuits underlying both behaviors transform visual inputs to generate fold-change detection (FCD) outputs. In FCD, the response scales with the relative fold changes in input, but is invariant to the overall magnitude of the stimulus. Several different circuit architectures can generate FCD responses. Both the behavioral outputs and the putative circuitry for the two visuomotor behaviors point to them using different FCD circuits. Pharmacological treatment points to circuits in the posterior brain vesicle of Ciona, a region we speculate shares homology with the vertebrate midbrain, as important for FCD.

neuroscience↗