Biology subjects

Adam, Y.

Publications and source records attributed to Adam, Y..

12 recordsLinked to original sources

bioRxiv2026

Direct voltage imaging of peripheral axons in vivo reveals ongoing nociceptor firing in healthy mice

The electrical output of a neuron is generated and conducted along its axon, yet the axon has remained largely inaccessible to direct measurement of membrane potential in intact tissue. Genetically encoded voltage indicators have enabled optical recording of membrane potential dynamics from neuronal cell bodies and dendrites in vivo, but direct voltage imaging of identified axons in the living animal has remained largely unexplored. This gap is especially consequential for nociceptive neurons, whose signals are generated and propagated at peripheral terminals far from the soma. Here, we expressed genetically encoded voltage indicators in trigeminal neurons and, using high-speed widefield imaging with holographic targeted illumination, recorded membrane-voltage dynamics directly from corneal nociceptive terminal arbors and their parent axons in vivo, in intact tissue. Individual terminals responded to capsaicin and menthol with depolarization accompanied by trains of spiking activity. Unexpectedly, a substantial fraction generated ongoing action-potential-like firing in the absence of an applied stimulus. This firing was sodium-channel-dependent, synchronized across sister terminal branches, and shared its dynamics with the parent axon. Ongoing terminal firing persisted during lidocaine delivery to the trigeminal ganglion, supporting a peripheral origin distal to the ganglion, and was abolished by inhibition of NaV1.8 or HCN/Ih conductances. Thus, direct voltage imaging reveals ongoing and spatially coordinated electrical activity within intact peripheral sensory arbors. More broadly, this approach provides access to the generation and integration of neuronal output within fine axonal compartments in vivo.

neuroscience↗

bioRxiv2025

Hepatoprotective Effects of Vernonia amygdalina Leaf Extract: In Vivo and In Silico Evidence Against Ethanol-Induced Liver Injury

Alcoholic liver disease (ALD) remains a major global health burden with limited therapeutic options. In this study, we investigated the hepatoprotective effects of Vernonia amygdalina (VA) leaf extract against ethanol-induced liver injury using integrated in vivo and in silico approaches. Wistar rats were exposed to ethanol to induce liver damage, followed by treatment with VA extract (100-300 mg/kg) or silymarin (50 mg/kg). Liver function indices were evaluated through biochemical analysis. Network pharmacology analysis was performed to identify active compounds and their protein targets, and molecular docking assessed the binding affinities of key compounds. Ethanol exposure markedly increased serum SGOT, SGPT, ALKP, and total bilirubin while decreasing total protein and albumin. VA treatment significantly corrected these alterations in a dose-dependent manner. At 300 mg/kg, VA reduced SGPT from 110.31 to 88.65 U/mL, ALKP from 52.20 to 28.14 U/mL, and total bilirubin from 1.19 to 0.59 g/dL. Network pharmacology revealed flavonoids and sesquiterpene lactones as key active compounds targeting ALD-relevant proteins, including AKT1, CASP3, and HSP90AA1. Molecular docking demonstrated strong binding affinities (-9.5 kcal/mol) of cryptolepine, luteolin, and apigenin with AKT1 and HSP90AA1. VA provides both biochemical and mechanistic protection against ethanol-induced liver damage, highlighting its therapeutic potential in ALD management.

pharmacology and toxicology↗

bioRxiv2025

Voltage Imaging of CA1 Pyramidal Cells and SST+ Interneurons Reveals Stability and Plasticity Mechanisms of Spatial Firing

Hippocampal place cells (PCs) are important for spatial coding and episodic memory. PCs representations are modulated upon transitioning between environments (global remapping) but also change with repeated exposure to familiar spaces (representational drift). To gain insights into the mechanistic basis for this unique balance between circuit plasticity and stability, we used voltage imaging to longitudinally record the subthreshold and spiking activity of pyramidal neurons (PNs) and somatostatin-positive (SST) interneurons in CA1 during virtual navigation. A fraction of cells from both populations showed spatial representations, but many SSTs were speed-tuned or fired uniformly across space. Intracellular recordings revealed increased theta power and asymmetric ramp-like depolarization in PN place fields, while SSTs exhibited symmetric depolarization with no theta increase. Longitudinal recordings across weeks demonstrated representational drifts in both populations, although SSTs exhibited remarkably stable firing and subthreshold properties. Transition to a novel environment induced remapping in both populations, accompanied by increase in SST activity and reduction in PNs. These results provide new insights into how hippocampal circuits balance representational stability with experience-dependent plasticity.

neuroscience↗

bioRxiv2025

Bright and Photostable Voltage Sensors Derived from mBaoJin

Genetically encoded voltage indicators (GEVIs) are powerful tools for monitoring neuronal activity, but their application, particularly for long-term recordings in vivo, is often limited by photobleaching under the required high illumination intensities. This constraint restricts the total duration of continuous or trial-based experiments, crucial for studying processes like synaptic plasticity or circuit dynamics during behavior. Here, we introduce ElectraON and ElectraOFF, a pair of green fluorescent eFRET-based GEVIs engineered by incorporating a photostability-enhanced derivative of the bright monomeric fluorescent protein mBaoJin with Ace opsin variants. Critically, Electras demonstrate over 6-fold improved photostability compared to state-of-the-art eFRET GEVIs, pAce, and Ace-mNeon2, under one-photon illumination, while characterized by bright green fluorescence, millisecond kinetics, and good membrane localization. This enhanced stability translates to a 3-to >10-fold extension in functional recording duration, maintaining reliable spike detection in both cultured neurons in vitro and sparsely labeled neurons in the awake mouse cortex in vivo. We demonstrated sustained in vivo recordings exceeding 30 minutes, with instances surpassing one hour. Furthermore, Electras show functionality under scanless two-photon excitation in cultured cells. These highly photostable indicators significantly extend the temporal window for voltage imaging, broadening the scope of accessible biological questions.

neuroscience↗

bioRxiv2025

All-optical electrophysiology reveals behavior-dependent dynamics of excitation and inhibition in the hippocampus

Understanding how neuronal integration is modulated by behavior is a fundamental goal in neuroscience. We combined voltage imaging with optogenetic depolarization to reveal how changes in excitatory (E) and inhibitory (I) inputs, modulate the spiking output, subthreshold dynamics, and gain of key genetically defined cell types in the CA1 region of the hippocampus. We imaged pyramidal cells (PCs), vasoactive intestinal peptide (VIP), somatostatin (SST), and parvalbumin (PV) interneurons (INs) and found that locomotion reduced firing in PCs and VIP INs while increasing activity in SST and PV cells. Prolonged optical depolarization experiments and simulations revealed that intracellular theta oscillations are predominantly driven by inhibitory inputs in PCs and VIP cells. Firing rate-laser intensity (F-I) curves revealed distinct gain modulation across cell types, with a divisive gain reduction in PC bursting during locomotion, while simple spikes are unaffected. A two-compartment model suggested that this results from a balanced E/I input increase to somatic and dendritic compartments. These findings reveal how behavioral state-dependent coordination of excitation and inhibition governs hippocampal neuronal dynamics and output-specific gain modulation.

neuroscience↗

bioRxiv2024

Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins in Plasmodium berghei during erythrocytic development

BackgroundThe life cycle of Plasmodium parasites is intricate and multistage, alternating between dynamic environments. Temporal regulation of transcription by stage-specific transcription factor binding at particular regulatory regions within gene promoters facilitates its progression. As a result, each new developmental stage is endowed with its unique gene sets, whose just-in-time expression enables the parasite to completely adapt to the necessary circumstances. Our understanding of these transcriptome-level regulatory processes is limited, and more so, a thorough examination of the entire life cycle in the experimentally tractable rodent model organism P. berghei is lacking. ResultsWe performed a genome-wide analysis of RNA-Seq data from different developmental stages of P. berghei. Integrated data from the human malaria parasites P. falciparum and P. vivax demonstrated that Plasmodium parasites have a unique transcriptional signature. We identified the sets of genes differentially expressed at each stage, clustered them based on similarities of their expression profiles, and predicted the regulatory motifs governing their expression. We interpreted the motifs using known binding sites for established eukaryotic transcription factors, including those of the ApiAP2s, and identified eight potentially novel motifs. Additionally, we expanded the annotation of another motif--AGGTAA--found in genes exclusive to erythrocytic development and identified members of the PfMORC and GCN5 complexes among its possible interacting proteins. ConclusionThis study provides new insights into gene usage and its regulation during P. berghei development.

bioinformatics↗

bioRxiv2023

A deep population reference panel of tandem repeat variation

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

genomics↗

bioRxiv2021

Neuronal activity drives pathway-specific depolarization of astrocyte distal processes

Astrocytes are glial cells that interact with neuronal synapses via their distal processes, where they remove glutamate and potassium (K+) from the extracellular space following neuronal activity. Astrocyte clearance of both glutamate and K+ is voltage-dependent, but astrocyte membrane potential (Vm) has been thought to be largely invariant. As a result, these voltage-dependencies have not been considered relevant to astrocyte function. Using genetically encoded voltage indicators enabling the measurement of Vm at distal astrocyte processes (DAPs), we report large, rapid, focal, and pathway-specific depolarizations in DAPs during neuronal activity. These activity-dependent astrocyte depolarizations are driven by action potential-mediated presynaptic K+ efflux and electrogenic glutamate transporters. We find that DAP depolarization inhibits astrocyte glutamate clearance during neuronal activity, enhancing neuronal activation by glutamate. This represents a novel class of sub-cellular astrocyte membrane dynamics and a new form of astrocyte-neuron interaction. One Sentence SummaryGenetically encoded voltage imaging of astrocytes shows that presynaptic neuronal activity drives focal astrocyte depolarization, contributing to activity-dependent inhibition of glutamate uptake.

neuroscience↗

bioRxiv2020

High fidelity estimates of spikes and subthreshold waveforms from 1-photon voltage imaging in vivo

The ability to probe the membrane potential of multiple genetically defined neurons simultaneously would have a profound impact on neuroscience research. Genetically encoded voltage indicators are a promising tool for this purpose, and recent developments have achieved high signal to noise ratio in vivo with 1-photon fluorescence imaging. However, these recordings exhibit several sources of noise that present analysis challenges, namely light scattering, out-of-focus sources, motion, and blood flow. We present a novel signal extraction methodology, Spike-Guided Penalized Matrix Decomposition-Nonnegative Matrix Factorization (SGPMD-NMF), which resolves supra- and sub-threshold voltages with high fidelity, even in the presence of correlated noise. The method incorporates biophysical constraints (shared soma profiles for spiking and subthreshold dynamics) and optical constraints (smoother spatial profiles from defocused vs. in-focus sources) to cleave signal from background. We validated the pipeline using simulated and composite datasets with realistic noise properties. We demonstrate applications to mouse hippocampus expressing paQuasAr3-s or SomArchon, mouse cortex expressing SomArchon or Voltron, and zebrafish spine expressing zArchon1.

neuroscience↗

bioRxiv2018

Wide-area all-optical neurophysiology in acute brain slices

Optical tools for simultaneous perturbation and measurement of neural activity open the possibility of mapping neural function over wide areas of brain tissue. However, spectral overlap of actuators and reporters presents a challenge for their simultaneous use, and optical scattering and out-of-focus fluorescence in tissue degrade resolution. To minimize optical crosstalk, we combined an optimized variant (eTsChR) of the most blue-shifted channelrhodopsin reported to-date with a nuclear-localized red-shifted Ca2+ indicator, H2B-jRGECO1a. To perform wide-area optically sectioned imaging in tissue, we designed a structured illumination technique that uses Hadamard matrices to encode spatial information. By combining these molecular and optical approaches we made wide-area maps, spanning cortex and striatum, of the effects of antiepileptic drugs on neural excitability and on the effects of AMPA and NMDA receptor blockers on functional connectivity. Together, these tools provide a powerful capability for wide-area mapping of neuronal excitability and functional connectivity in acute brain slices.

neuroscience↗

bioRxiv2018

All-optical electrophysiology reveals brain-state dependent changes in hippocampal subthreshold dynamics and excitability

A technology to record membrane potential from multiple neurons, simultaneously, in behaving animals will have a transformative impact on neuroscience research1. Parallel recordings could reveal the subthreshold potentials and intercellular correlations that underlie network behavior2. Paired stimulation and recording can further reveal the input-output properties of individual cells or networks in the context of different brain states3. Genetically encoded voltage indicators are a promising tool for these purposes, but were so far limited to single-cell recordings with marginal signal to noise ratio (SNR) in vivo4-6. We developed improved near infrared voltage indicators, high speed microscopes and targeted gene expression schemes which enabled recordings of supra- and subthreshold voltage dynamics from multiple neurons simultaneously in mouse hippocampus, in vivo. The reporters revealed sub-cellular details of back-propagating action potentials, correlations in sub-threshold voltage between multiple cells, and changes in dynamics associated with transitions from resting to locomotion. In combination with optogenetic stimulation, the reporters revealed brain state-dependent changes in neuronal excitability, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behavior.

neuroscience↗

bioRxiv2017

Two-photon photoactivated voltage imaging in tissue with an Archaerhodopsin-derived reporter

Robust voltage imaging in tissue remains a technical challenge. Existing combinations of genetically encoded voltage indicators (GEVIs) and microscopy techniques cannot simultaneously achieve sufficiently high voltage sensitivity, background rejection, and time resolution for highresolution mapping of sub-cellular voltage dynamics in intact brain tissue. We developed a pooled high-throughput screening approach to identify Archaerhodopsin mutants with unusual photophysical properties. After screening ~105 cells, we identified a novel GEVI, NovArch, whose 1-photon near infrared fluorescence is reversibly enhanced by weak 2-photon excitation. Because the 2-photon excitation acts catalytically rather than stoichiometrically, high fluorescence signals, optical sectioning, and high time resolution are achieved simultaneously, at modest 2-photon laser power. We developed a microscopy system optimized for NovArch imaging in tissue. The combination of protein and optical engineering enhanced signal contrast sufficiently to enable optical mapping of back-propagating action potentials in dendrites in acute mouse brain slice.

neuroscience↗