Biology subjects

Fried, S.

Publications and source records attributed to Fried, S..

6 recordsLinked to original sources

bioRxiv2026

Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice

Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions. Highlights- Four common pesticides in mixture disrupt metabolism in liver cells - Dietary exposure to this pesticide mixture alters hepatic gene expression in mice - The pesticide mixture exacerbates WD-induced disruptions in glucose homeostasis - Pesticides and diet interact in producing the metabolic effects of a pesticide mixture

pharmacology and toxicology↗

bioRxiv2025

Single-Cell and Population-Level Neuromodulation Dynamics in Dual-Electrode Intracortical Stimulation

In neuroprosthetics, intracortical microstimulation (ICMS) recruits cortical networks to evoke brain responses and sensory perceptions. However, multi-electrode ICMS often generates suboptimal percepts compared to single-electrode ICMS, suggesting nonlinear neuromodulation rather than simple summation by multi-electrode ICMS. Yet, the factors and mechanisms underlying this modulation remain poorly understood. To investigate multi-electrode ICMS, we combined two-photon calcium imaging with a well-controlled dual-electrode ICMS in the mouse visual cortex to investigate how neurons integrate converging ICMS inputs at varying intensities. We found that stimulation intensity significantly shapes neuromodulation at both single-cell and population levels. Specifically, low intensities (5-7 {micro}A) have a minimal effect on neural responses. At intermediate intensities (10-15 {micro}A), we observed diverse, nonlinear bipolar modulation--both enhancement and attenuation--at the single-cell level. However, we achieved net enhancement at the population level. At higher intensities (15-20 {micro}A), although the proportion of modulated neurons increased in both enhancement and attenuation directions, the net effect at the population level was neutral (zero modulation). Furthermore, neurons strongly responsive to single-electrode ICMS were more likely to be attenuated, while weaker responding cells exhibited enhanced modulation. The strongest neuromodulatory effects occur at intermediate spatial distances in between the two electrodes. Computational modeling based on spiking neural network composed of adaptive exponential integrate-and-field neurons implicated the importance of inhibitory network dynamics and network variability as key mechanisms. Our experimental data was used to train an advanced deep learning approach, which successfully predicted the neuromodulation patterns induced by dual-electrode ICMS. Our findings reveal intensity- and spatial-dependent rules of neuromodulation by ICMS, providing necessary insights to optimize multi-electrode ICMS for neuroprosthetic applications. Significance statementUnderstanding how cortical neurons integrate concurrent inputs from multi-electrode intracortical microstimulation (ICMS) is essential for advancing neuroprosthetic technologies. We show that dual-electrode ICMS evokes distinct, predictable neuromodulatory effects that depend on (i) stimulation intensity, (ii) a neurons baseline responsiveness to single electrode input, and (iii) its proximity to the electrodes. Low and intermediate intensity dual-electrode ICMS amplifies neural activity compared to single-electrode ICMS, whereas high-intensity stimulation leads to attenuation, limiting net activation.

neuroscience↗

bioRxiv2022

Flexible, Scalable, High Channel Count Stereo-Electrode for Recording in the Human Brain

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on a novel, reconfigurable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents a major new advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology. One-Sentence SummaryA human-grade thin-film depth electrode offers new opportunities in spatial and temporal resolution for recording brain activity.

neuroscience↗

bioRxiv2022

Thermal Effects on Neurons During Stimulation of the Brain

All artificial stimulation of the brain deposits thermal energy in the brain. This occurs through either Joule heating of the conductors carrying current through electrodes and magnetic coils, or through dissipation of energy in the conductive brain. Similarly, temperature affects all biological processes and chemical reactions. Although electrical interaction with brain tissue is inseparable from thermal effects when electrodes are used, magnetic induction enables us to separate Joule heating from induction effects by contrasting AC and DC driving of magnetic coils using the same energy deposition within the conductors. Since mammalian cortical neurons have no known sensitivity to static magnetic fields, and if there is no evidence of effect on spike timing to oscillating magnetic fields, we can presume that the induced electrical currents within the brain are below the molecular shot noise where any interaction with tissue is purely thermal. In this study, we examined a range of frequencies produced from micromagnetic coils operating below the molecular shot noise threshold for electrical interaction with single neurons. We found that small temperature increases and decreases of 1{degrees}C caused consistent transient suppression and excitation of neurons during temperature change. Numerical modeling of the biophysics demonstrated that the Na-K pump, and to a lesser extent the Nernst potential, could account for these transient effects. Such effects are dependent upon compartmental ion fluxes, and the rate of temperature change. A new bifurcation is described in the model dynamics that accounts for the transient suppression and excitation; in addition, we note the remarkable similarity of this bifurcations rate dependency with other thermal rate-dependent tipping points in planetary warming dynamics. Furthermore, bifurcations in the steady state dynamics leading to stable firing suppression are described for slightly higher temperatures. These experimental and theoretical findings demonstrate that stimulation of the brain must take into account small thermal effects that are ubiquitously present in electrical and magnetic stimulation. More sophisticated models of electrical current interaction with neurons combined with thermal effects will be required in order to more accurately enable model-based control of neuronal circuitry.

biophysics↗

bioRxiv2022

Periductal bile acid exposure causes cholangiocyte injury and fibrosis

IntroductionBile duct integrity is essential for the maintenance of the structure and function of the biliary tree. We previously showed that cholangiocyte injury in a toxic model of biliary atresia leads to increased monolayer permeability. Increased epithelial permeability was also shown in other cholangiopathies. We hypothesized that after initial cholangiocyte injury, leakage of bile acids into the duct submucosa propagates cholangiocyte damage and fibrosis. We thus aimed to determine the impact of bile acid exposure on cholangiocytes and the potential therapeutic effect of a non-toxic bile acid. Materials and methodsExtrahepatic bile duct explants were isolated from adult and neonatal BALB/c mice. Explants were cultured with or without glycochenodeoxycholic acid and ursodeoxycholic acid. They were then fixed and stained. ResultsExplants treated with glycochenodeoxycholic acid demonstrated cholangiocyte injury with monolayer disruption and partial lumen obstruction compared to control ducts. Massons trichrome stains revealed increased collagen fibers. Myofibroblast marker -SMA stains were significantly elevated in the periductal region. The addition of ursodeoxycholic acid resulted in decreased cholangiocyte injury and reduced fibrosis. ConclusionsBile acid leakage into the submucosa after initial cholangiocyte injury may serve as a possible mechanism of disease propagation and progressive fibrosis in cholangiopathies.

physiology↗

bioRxiv2022

Magnetic Stimulation Allows Focal Activation of the Mouse Cochlea

Cochlear implants (CIs) strive to restore hearing to those with severe to profound hearing loss by artificially stimulating the auditory nerve. While most CI users can understand speech in a quiet environment, hearing that utilizes complex neural coding (e.g., appreciating music) has proved elusive, probably because of the inability of CIs to create narrow regions of spectral activation. Several novel approaches have recently shown promise for improving spatial selectivity, but substantial design differences from conventional CIs will necessitate much additional safety testing before clinical viability is established. Outside the cochlea, magnetic stimulation from small coils (micro-coils) has been shown to confine activation more narrowly than that from conventional micro-electrodes, raising the possibility that coil-based stimulation of the cochlea could improve the spectral resolution of CIs. To explore this, we delivered magnetic stimulation from micro-coils to multiple locations of the cochlea and measured the spread of activation utilizing a multi-electrode array inserted into the inferior colliculus; responses to magnetic stimulation were compared to analogous experiments with conventional micro-electrodes as well as to the responses to auditory monotones. Encouragingly, the extent of activation with micro-coils was [~]60% narrower than that from electric stimulation and largely similar to the spread arising from acoustic stimulation. The dynamic range of coils was more than three times larger than that of electrodes, further supporting a smaller spread of activation. While much additional testing is required, these results support the notion that coil-based CIs can produce a larger number of independent spectral channels and may therefore improve functional performance. Further, because coil-based devices are structurally similar to existing CIs, fewer impediments to clinical translational are likely to arise.

neuroscience↗