Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Brain-wide arousal signals are segregated from movement planning in the superior colliculus.

The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions including spatial attention. When it comes to oculomotor areas such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with the subjects' arousal levels. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.

Transcranial Focused Ultrasound Remotely Modulates Extrastriate Visual Cortex with Subregion Specificity.

Low-intensity transcranial focused ultrasound (tFUS) has emerged as a powerful neuromodulation tool characterized by its deep penetration and precise spatial targeting to influence neural activity. Our study directed low-intensity tFUS stimulation onto a region of prefrontal cortex (the frontal eye field, or FEF) of a rhesus macaque to examine its impact on a remote site, the extrastriate visual cortex (area V4). This pair of cortical regions form a top-down modulatory circuit that has been studied extensively with electrical microstimulation. To measure the impact of tFUS stimulation, we recorded local field potentials (LFPs) and multi-unit spiking activities from a multi-electrode array implanted in the visual cortex. To deliver tFUS stimulation, we leveraged a customized 128-element random array ultrasound transducer with improved spatial targeting. We observed that tFUS stimulation in FEF produced modulation of V4 neuronal activity, either through enhancement or suppression, dependent on the pulse repetition frequency of the tFUS stimulation. Electronically steering the transcranial ultrasound focus through the targeted FEF cortical region produced changes in the level of modulation, indicating that the tFUS stimulation was spatially targeted within FEF. Modulation of V4 activity was confined to specific frequency bands, and this modulation was dependent on the presence or absence of a visual stimulus during tFUS stimulation. A control study targeting the insula produced no effect, emphasizing the region-specific nature of tFUS neuromodulation. Our findings shed light on the capacity of tFUS to modulate specific neural pathways and provide a comprehensive understanding of its potential applications for neuromodulation within brain networks.

Reduced Concussion Symptom Burden in Early Adolescent Athletes Using a Head-Neck Cooling Device.

OBJECTIVE: To determine whether an investigational head-neck cooling device, Pro2cool, can better reduce symptom severity compared with standard postconcussion care in early adolescent athletes after a sports-related concussion. DESIGN: Prospective, longitudinal, randomized trial design conducted over a 28-day period. SETTING: Six pediatric medical centers in Ohio and Michigan. PARTICIPANTS: The study enrolled 167 male and female 12- to 19-year-old athletes who experienced a sports-related concussion within 8 days of study enrollment and registering a Sports Concussion Assessment Tool 5 (SCAT5) composite score >7. INTERVENTIONS: Pro2cool, an investigational head-neck cooling therapy device, was applied at 2 postinjury time points compared with postconcussion standard of care only. MAIN OUTCOME MEASURES: Baseline SCAT5 composite symptom severity scores were determined for all subjects. Sports Concussion Assessment Tool 5 scores for concussed athletes receiving cooling treatment were analyzed across 6 independent postenrollment time points compared with subjects who did not receive cooling therapy and only standard care. Adverse reactions and participate demographics were also compared. RESULTS: Athletes who received Pro2cool cooling therapy (n = 79) experienced a 14.4% greater reduction in SCAT5 symptom severity scores at the initial visit posttreatment, a 25.5% greater reduction at the 72-hour visit posttreatment, and a 3.4% greater reduction at the 10-day visit compared with subjects receiving only standard care (n = 88). Overall, 36 adverse events (increased blood pressure, decreased pulse, and dizziness) were reported, with 13 events associated with the device, of which 3 were classified as moderate in severity. CONCLUSIONS: This study demonstrates the efficacy and safety of head and neck cooling for the management of concussion symptoms in adolescent athletes of an age group for which little to no prior data are available.

Computed Tomography Topographical Analysis of Incomplete Humeral Intracondylar Fissures in English Springer Spaniel Dogs.

OBJECTIVE: The aim of this study was to use computed tomography (CT) images obtained from English springer spaniels (ESS) with different sizes of humeral intracondylar fissure (HIF) to describe the typical shape, origin and a possible propagation pattern of HIF in this breed. STUDY DESIGN: It is a retrospective analysis of 32 elbow CT from 27 ESS with incomplete HIF. Measurements included HIF articular surface length, centre of HIF at articular surface relative to the caudal edge of the supratrochlear foramen (CHIF), HIF depth and sagittal area of fissure. Measurement of isthmus area and diameter was obtained for each elbow. Humeral intracondylar fissure measurements were analysed as proportions of the isthmus. For parts of analysis, elbows were grouped by HIF area as a percentage of isthmus area (%HIF) into less than 20% (n = 10), 20 to less than 40% (n = 8), 40 to less than 60% (n = 9) and 60 to less than 90% (n = 5). RESULTS: The mean isthmus diameter was 12.31 mm (range: 10.96-13.69 mm). Mean CHIF for %HIF groups less than 20%, 20 to less than 40%, 40 to less than 60% and 60 to less than 90% were 57, 74, 86 and 96 degrees, respectively. The less than 20% group was significantly lower than 20 to less than 40% group (p = 0.035) and 40 to less than 60% and 60 to less than 90% groups (p < 0.001); the 20 to less than 40% group was significantly lower than the 60 to less than 90% group (p = 0.015). Humeral intracondylar fissure articular surface length increased in a sigmoidal fashion relative to %HIF, corresponding to segmental enlargement of the fissure as %HIF increases. CONCLUSION: In ESS, HIF typically originates approximately 57 degrees caudal to the supratrochlear foramen in the sagittal plane and may propagate in a segmental fashion with lesser propagation through the proximal intracondylar region.

Compact deep neural network models of visual cortex.

A powerful approach to understanding the computations carried out in visual cortex is to develop models that predict neural responses to arbitrary images. Deep neural network (DNN) models have worked remarkably well at predicting neural responses [1, 2, 3], yet their underlying computations remain buried in millions of parameters. Have we simply replaced one complicated system in vivo with another in silico? Here, we train a data-driven deep ensemble model that predicts macaque V4 responses ~50% more accurately than currently-used task-driven DNN models. We then compress this deep ensemble to identify compact models that have 5,000x fewer parameters yet equivalent accuracy as the deep ensemble. We verified that the stimulus preferences of the compact models matched those of the real V4 neurons by measuring V4 responses to both 'maximizing' and adversarial images generated using compact models. We then analyzed the inner workings of the compact models and discovered a common circuit motif: Compact models share a similar set of filters in early stages of processing but then specialize by heavily consolidating this shared representation with a precise readout. This suggests that a V4 neuron's stimulus preference is determined entirely by its consolidation step. To demonstrate this, we investigated the compression step of a dot-detecting compact model and found a set of simple computations that may be carried out by dot-selective V4 neurons. Overall, our work demonstrates that the DNN models currently used in computational neuroscience are needlessly large; our approach provides a new way forward for obtaining explainable, high-accuracy models of visual cortical neurons.

Taxifolin as a Metallo-ß-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing Pseudomonas aeruginosa.

Among the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of ß-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy-in which a ß-lactamase inhibitor is administered together with a ß-lactam antibiotic-has proven effective against serine-ß-lactamases, there are no currently approved metallo-ß-lactamase inhibitors. Herein, we demonstrate that quercetin and its analogs are promising starting points for the further development of safe and effective metallo-ß-lactamase inhibitors. Through a combined computational and in vitro approach, taxifolin was found to inhibit VIM-2 expressing P. aeruginosa cell proliferation at <4 µg/mL as part of a triple combination with amoxicillin and clavulanate. Furthermore, we tested this combination in mice with abrasive skin infections. Together, these results demonstrate that flavonol compounds, such as taxifolin, may be developed into effective metallo-ß-lactamase inhibitors.

Expectation reshapes V4 neuronal activity and improves perceptual performance.

Recent visual experience creates expectations that heavily influence our visual perception. How does expectation shape the activity of cortical neurons to allow for improved perceptual discrimination of visual inputs? We recorded from populations of neurons in visual cortical area V4 while monkeys performed a natural image change detection task under different expectation conditions. We found that higher expectation led to an improvement in the ability to detect a change in an image. This improvement was associated with decreased neural responses to the image, providing evidence that a reduction in activity can improve stimulus encoding. The decrease in response could not be fully explained by short-timescale adaptation, suggesting partially separate mechanisms of adaptation and expectation. Additionally, higher expectation was associated with decreased trial-to-trial shared variability, indicating that a reduction in variability is a key means by which expectation influences perception. Taken together, the results of our study contribute to an understanding of how visual experience and expectation can shape our perception and behavior through modulating activity patterns across the visual cortex.

Colony size buffers interactions between neonicotinoid exposure and cold stress in bumblebees.

Social bees are critical for supporting biodiversity, ecosystem function and crop yields globally. Colony size is a key ecological trait predicted to drive sensitivity to environmental stressors and may be especially important for species with annual cycles of sociality, such as bumblebees. However, there is limited empirical evidence assessing the effect of colony size on sensitivity to environmental stressors or the mechanisms underlying these effects. Here, we examine the relationship between colony size and sensitivity to environmental stressors in bumblebees. We exposed colonies at different developmental stages briefly (2 days) to a common neonicotinoid (imidacloprid) and cold stress, while quantifying behaviour of individuals. Combined imidacloprid and cold exposure had stronger effects on both thermoregulatory behaviour and long-term colony growth in small colonies. We find that imidacloprid's effects on behaviour are mediated by body temperature and spatial location within the nest, suggesting that social thermoregulation provides a buffering effect in large colonies. Finally, we demonstrate qualitatively similar effects in size-manipulated microcolonies, suggesting that group size per se, rather than colony age, drives these patterns. Our results provide evidence that colony size is critical in driving sensitivity to stressors and may help elucidate mechanisms underlying the complex and context-specific impacts of pesticide exposure.

Cerebrovascular Impedance as a Function of Cerebral Perfusion Pressure.

Goal: Cerebrovascular impedance is modulated by a vasoactive autoregulative mechanism in response to changes in cerebral perfusion pressure. Characterization of impedance and the limits of autoregulation are important biomarkers of cerebral health. We developed a method to quantify impedance based on the spectral content of cerebral blood flow and volume at the cardiac frequency, measured with diffuse optical methods. Methods: In three non-human primates, we modulated cerebral perfusion pressure beyond the limits of autoregulation. Cerebral blood flow and volume were measured with diffuse correlation spectroscopy and near-infrared spectroscopy, respectively. Results: We show that impedance can be used to identify the lower and upper limits of autoregulation. Conclusions: This impedance method may be an alternative method to measure autoregulation and a way of assessing cerebral health non-invasively at the clinical bedside.

A digitally driven manufacturing process for high resolution patterning of cell formations.

This paper presents the engineering and validation of an enabling technology that facilitates new capabilities in in vitro cell models for high-throughput screening and tissue engineering applications. This is conducted through a computerized system that allows the design and deposition of high-fidelity microscale patterned coatings that selectively alter the chemical and topographical properties of cell culturing surfaces. Significantly, compared to alternative methods for microscale surface patterning, this is a digitally controlled and automated process thereby allowing scientists to rapidly create and explore an almost infinite range of cell culture patterns. This new capability is experimentally validated across six different cell lines demonstrating how the precise microscale deposition of these patterned coatings can influence spatiotemporal growth and movement of endothelial, fibroblast, neuronal and macrophage cells. To further demonstrate this platform, more complex patterns are then created and shown to guide the behavioral response of colorectal carcinoma cells.

In vivo Modulation of Intraocular and Intracranial Pressures Causes Nonlinear and Non-monotonic Deformations of the Lamina Cribrosa and Scleral Canal.

Purpose: To evaluate changes in monkey optic nerve head (ONH) morphology under acutely controlled intraocular pressure (IOP) and intracranial pressure (ICP). Methods: Seven ONHs from six monkeys were imaged via optical coherence tomography while IOP and ICP were maintained at one of 16 conditions. These conditions were defined by 4 levels for each pressure: low, baseline, high and very high. Images were processed to determine scleral canal area, aspect ratio, and planarity and anterior lamina cribrosa (ALC) shape index and curvature. Linear mixed effect models were utilized to investigate the effects of IOP, ICP and their interactions on ONH morphological features. The IOP-ICP interaction model was compared with one based on translaminar pressure difference (TLPD). Results: We observed complex, eye-specific, non-linear patterns of ONH morphological changes with changes in IOP and ICP. For all ONH morphological features, linear mixed effects models demonstrated significant interactions between IOP and ICP that were unaccounted for by TLPD. Interactions indicate that the effects of IOP and ICP depend on the other pressure. The IOP-ICP interaction model was a higher quality predictor of ONH features than a TLPD model. Conclusions: In vivo modulation of IOP and ICP causes nonlinear and non-monotonic changes in monkey ONH morphology that depend on both pressures and is not accounted for by a simplistic TLPD. These results support and extend prior findings. Translational Relevance: A better understanding of ICP's influence on the effects of IOP can help inform the highly variable presentations of glaucoma and effective treatment strategies.

Comparing Acute IOP-Induced Lamina Cribrosa Deformations Premortem and Postmortem.

Purpose: Lamina cribrosa (LC) deformations caused by elevated intraocular pressure (IOP) are believed to contribute to glaucomatous neuropathy and have therefore been extensively studied, in many conditions, from in vivo to ex vivo. We compare acute IOP-induced global and local LC deformations immediately before (premortem) and after (postmortem) sacrifice by exsanguination. Methods: The optic nerve heads of three healthy monkeys 12 to 15 years old were imaged with spectral-domain optical coherence tomography under controlled IOP premortem and postmortem. Volume scans were acquired at baseline IOP (8-10 mm Hg) and at 15, 30, and 40 mm Hg IOP. A digital volume correlation technique was used to determine the IOP-induced three-dimensional LC deformations (strains) in regions visible premortem and postmortem. Results: Both conditions exhibited similar nonlinear relationships between IOP increases and LC deformations. Median effective and shear strains were, on average, over all eyes and pressures, smaller postmortem than premortem, by 14% and 11%, respectively (P's < 0.001). Locally, however, the differences in LC deformation between conditions were variable. Some regions were subjected premortem to triple the strains observed postmortem, and others suffered smaller deformations premortem than postmortem. Conclusions: Increasing IOP acutely caused nonlinear LC deformations with an overall smaller effect postmortem than premortem. Locally, deformations premortem and postmortem were sometimes substantially different. We suggest that the differences may be due to weakened mechanical support from the unpressurized central retinal vessels postmortem. Translational Relevance: Additional to the important premortem information, comparison with postmortem provides a unique context essential to understand the translational relevance of all postmortem biomechanics literature.

Using near-infrared spectroscopy and a random forest regressor to estimate intracranial pressure.

Significance: Intracranial pressure (ICP) measurements are important for patient treatment but are invasive and prone to complications. Noninvasive ICP monitoring methods exist, but they suffer from poor accuracy, lack of generalizability, or high cost. Aim: We previously showed that cerebral blood flow (CBF) cardiac waveforms measured with diffuse correlation spectroscopy can be used for noninvasive ICP monitoring. Here we extend the approach to cardiac waveforms measured with near-infrared spectroscopy (NIRS). Approach: Changes in hemoglobin concentrations were measured in eight nonhuman primates, in addition to invasive ICP, arterial blood pressure, and CBF changes. Features of average cardiac waveforms in hemoglobin and CBF signals were used to train a random forest (RF) regressor. Results: The RF regressor achieves a cross-validated ICP estimation of 0.937 r 2 , 2.703 - mm Hg 2 mean squared error (MSE), and 95% confidence interval (CI) of [ - 3.064 3.160 ] mmHg on oxyhemoglobin concentration changes; 0.946 r 2 , 2.301 - mmHg 2 MSE, and 95% CI of [ - 2.841 2.866 ] mmHg on total hemoglobin concentration changes; and 0.963 r 2 , 1.688 mmHg 2 MSE, and 95% CI of [ - 2.450 2.397 ] mmHg on CBF changes. Conclusions: This study provides a proof of concept for the use of NIRS in noninvasive ICP estimation.

Effects of Different Feeding Regimes on Growth Rates and Fatty Acid Composition of Largemouth Bass Micropterus nigricans at High Water Temperatures.

As the northern Largemouth bass (LMB) (Micropterus nigricans) industry shifts toward fingerling production, implementing practical feeding strategies to ensure efficient growth during high water temperatures is paramount. Twenty (12.7 ± 0.2 g) (Trial 1) and fifteen (7.2 ± 0.1 g) (Trial 2) LMB fingerlings were stocked in two recirculating systems (each containing nine tanks), acclimated to 30 °C, with one system fed daily rations of 3, 5 and 7% body weight (Trial 1), and the second system fed to satiation daily, every second day, or every third day (Trial 2), for 28 days each. All treatments were triplicated. Multiple growth metrics and lipid composition were analyzed. The 3% treatment yielded the lowest final average weight (36.05 g) and FCR (0.83), with no difference in final biomass in Trial 1 treatments. Fish fed to satiation daily and every second day produced FCRs and biomasses of 0.83 and 356.78 g, and 0.93 and 272.26 g, respectively. There were no differences in total lipid concentration, however, fatty acid profiles differed significantly between all treatments within their respective trials. Feeding LMB fingerlings 3% of total body weight or feeding daily to satiation allows for efficient growth at 30 °C and implements cost-effective feeding strategies.

Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO2) and cerebral autoregulation (CA). However, current mathematical models for CMRO2 estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO2/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies.

Precise Quantification of Behavioral Individuality From 80 Million Decisions Across 183,000 Flies.

Individual animals behave differently from each other. This variability is a component of personality and arises even when genetics and environment are held constant. Discovering the biological mechanisms underlying behavioral variability depends on efficiently measuring individual behavioral bias, a requirement that is facilitated by automated, high-throughput experiments. We compiled a large data set of individual locomotor behavior measures, acquired from over 183,000 fruit flies walking in Y-shaped mazes. With this data set we first conducted a "computational ethology natural history" study to quantify the distribution of individual behavioral biases with unprecedented precision and examine correlations between behavioral measures with high power. We discovered a slight, but highly significant, left-bias in spontaneous locomotor decision-making. We then used the data to evaluate standing hypotheses about biological mechanisms affecting behavioral variability, specifically: the neuromodulator serotonin and its precursor transporter, heterogametic sex, and temperature. We found a variety of significant effects associated with each of these mechanisms that were behavior-dependent. This indicates that the relationship between biological mechanisms and behavioral variability may be highly context dependent. Going forward, automation of behavioral experiments will likely be essential in teasing out the complex causality of individuality.

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer's Disease Mice.

BACKGROUND: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer's disease (AD) and may coincide with early accumulation of amyloid-ß (Aß) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aß imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. OBJECTIVE: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. METHODS: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aß levels were assessed with advanced protein quantitation techniques. RESULTS: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. CONCLUSION: These data support the premise that retinal Aß is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.

EEG Signals Index a Global Signature of Arousal Embedded in Neuronal Population Recordings.

Electroencephalography (EEG) has long been used to index brain states, from early studies describing activity in the presence and absence of visual stimulation to modern work employing complex perceptual tasks. These studies have shed light on brain-wide signals but often lack explanatory power at the single neuron level. Similarly, single neuron recordings can suffer from an inability to measure brain-wide signals accessible using EEG. Here, we combined these techniques while monkeys performed a change detection task and discovered a novel link between spontaneous EEG activity and a neural signal embedded in the spiking responses of neuronal populations. This "slow drift" was associated with fluctuations in the subjects' arousal levels over time: decreases in prestimulus α power were accompanied by increases in pupil size and decreases in microsaccade rate. These results show that brain-wide EEG signals can be used to index modes of activity present in single neuron recordings, that in turn reflect global changes in brain state that influence perception and behavior.

Erratum: Estimating intracranial pressure using pulsatile cerebral blood flow measured with diffuse correlation spectroscopy: erratum.

[This corrects the article on p. 1462 in vol. 11, PMID: 32206422.].