Biology subjects

Nikitina, A. A.

Publications and source records attributed to Nikitina, A. A..

6 recordsLinked to original sources

bioRxiv2026

Neuronal Population Effects of Ketamine on Human Brain Organoids

Ketamines rapid neuropsychiatric actions emerge from interactions that span receptors, cells, and circuits, but their net effects on human neuronal population dynamics remain incompletely defined. Here we combine human dorsal forebrain organoids with high-density microelectrode arrays (MEAs) to quantify ketamines effects from spikes to networks. In 6-month-old organoids, acute ketamine (20{square}g/mL) abolished population bursting while neuronal firing continued mostly unchanged. Spike sorting revealed that mean firing rates declined but not silenced after ketamine Reductions were concentrated within a subset of burst-driver units previously defined as "backbone". Functional connectivity, estimated with the spike time tiling coefficient (STTC), decreased globally after ketamine. Backbone units displayed elevated connectivity at baseline but were functionally disconnected by ketamine. Graph construction from STTC uncovered widespread network reconfiguration, characterized by redistribution of edges from backbone to non-backbone units leading to loss of hubs and less-interconnected communities. Re-exposure after chronic ketamine treatment no longer silenced population bursting, indicating tolerance. Together, these results show that ketamine acutely silences human organoid networks by disconnecting backbone units, while chronic exposure induces tolerance to re-silencing while reducing the number of backbone units and leaving the network less active and less connected. The organoid-MEA platform provides a scalable, human-relevant system for dissecting circuit-level drug effects.

neuroscience↗

bioRxiv2025

Inherent coupling of perceptual judgments to actions in the mouse cortex

Neural activity during perceptual tasks is distributed across many cortical regions, but it remains unclear where perceptual judgments are made and whether they are encoded independently of the resulting actions. To address these questions, we designed a vibrotactile detection task in which mice flexibly switched between standard and reversed contingency blocks, requiring them to lick when a stimulus was present or absent, depending on the block. A cortex-wide optogenetic screen revealed that the premotor cortex is important for perceptual judgments rather than the ability to lick. However, coding of perceptual judgments in the premotor cortex and other cortical regions was coupled to actions rather than being independent of them. Finally, we identified a subset of premotor cortex cells whose activity encoded the current block identity. Based on these findings, we propose a model in which vibrotactile perceptual judgments are inherently, but flexibly, coupled to actions via cortical activity.

neuroscience↗

bioRxiv2025

Rescuing Ischemic Brain Injury by Rewiring Mitochondrial Electron Flow

Mitochondrial metabolic flux alterations are critical drivers of acute ischemia-reperfusion (IR) brain injury. Reverse electron transfer (RET), defined as the upstream flow of electrons from the quinone pool to complex I, is a major source of pathological reactive oxygen species (ROS) under stress conditions. In an in vivo brain IR model, oxygen deprivation induces the buildup of RET-supporting substrates, with glycerol 3-phosphate identified as the dominant contributor in addition to succinate. Rapid oxidation of these substrates by brain mitochondria upon reoxygenation drives massive ROS production, while also leading to over-reduction and dissociation of the complex I flavin mononucleotide (FMN) cofactor. The resulting FMN-deficient complex I becomes catalytically impaired, unable to oxidize NADH or to produce ROS. To mitigate RET and preserve complex I function, we used transgenic mice xenotopically expressing alternative oxidase (AOX). This enzyme bypasses complexes III and IV by directly oxidizing the reduced quinone pool and passing electrons onto molecular oxygen. AOX expression did not alter complex I abundance, supercomplexes assembly, or basal respiration rates, but effectively diverted electrons from the quinone pool, decreasing RET flux via complex I and limiting ROS generation during IR. For the first time we showed that AOX expression and attenuation of RET preserved complex I FMN binding, suppressed oxidative stress, and conferred neuroprotection in vivo. Our findings reveal a novel strategy for rewiring mitochondrial electron flux to mitigate initial IR brain injury, highlighting modulation of the quinone pool by AOX as a potential therapeutic strategy for IR.

biochemistry↗

bioRxiv2025

Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes

The APOE3-Christchurch (APOE3-Ch) variant has been linked to reduced Alzheimers Disease (AD) risk, but its protective mechanisms remain unclear. This study explores the neuroprotective phenotype of APOE3-Ch astrocytes, focusing on lipid metabolism and tau processing. APOE3-Ch astrocytes demonstrate enhanced tau oligomer uptake via HSPG- and LRP1-mediated pathways, facilitated by elevated HSPG expression, and achieve superior tau degradation through lysosomal pathways and proteasomal pathways, in contrast to wild-type astrocytes, which primarily use proteasomal mechanisms. Transcriptomic analysis reveals upregulation of genes involved in endocytosis and cell projection assembly, explaining enhanced tau uptake and clearance in APOE3-Ch astrocytes. Lipidomic profiling identifies reduced levels of pathological lipids such as ceramides and gamma-linolenic acid (GLA), potentially mitigating neuroinflammation. These findings provide insight into the protective mechanisms of APOE3-Ch astrocytes and underscore their potential as therapeutic targets for tauopathy and neurodegeneration in AD. TeaserAPOE3-Christchurch astrocytes enhance tau clearance and mitigate neurotoxic lipid accumulation, unveiling protective mechanisms against Alzheimers.

neuroscience↗

bioRxiv2022

Mass spectrometry imaging reveals early metabolic priming of cell lineage in differentiating human induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) hold great promise in regenerative medicine; however, few algorithms of quality control at the earliest stages of differentiation have been established. Despite lipids having known functions in cell signaling, their role in pluripotency maintenance and lineage specification is underexplored. We investigated changes in iPSC lipid profiles during initial loss of pluripotency over the course of spontaneous differentiation using co-registration of confocal microscopy and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. We identified lipids that are highly informative of the temporal stage of the differentiation and can reveal lineage bifurcation occurring metabolically. Several phosphatidylinositol species emerged from machine learning analysis as early metabolic markers of pluripotency loss, preceding changes in Oct4. Manipulation of phospholipids via PI 3-kinase inhibition during differentiation manifested in spatial reorganization of the colony and elevated expression of NCAM-1. In addition, continuous inhibition of phosphatidylethanolamine N-methyltransferase during differentiation resulted in increased pluripotency maintenance. Our machine learning analysis highlights the predictive power of metabolic metrics for evaluating lineage specification in the initial stages of spontaneous iPSC differentiation.

bioengineering↗

bioRxiv2022

Integration of imaging modalities with lipidomic characterization to investigate MSCs potency metrics

Mesenchymal stem cells (MSCs) are widely used as therapeutics targets for numerous autoimmune diseases. However, MSC therapies have had limited success so far in clinical trials, mainly being heterogenous population it is difficult to determine MSCs efficiencies. It is critical to understand internal signaling of individual MSCs population that directly affect the cell phenotype. Lipid signaling is closely associated with cell shape so, a holistic approach to understand how changes in lipid metabolites trickles all the way to single cell phenotype could reveal deeper understanding of MSCs functional regulation. So, we aim to evaluate lipid metabolic profiles of single cell MSCs with known variability in immune regulation and explore the phenotypic changes that occur because of differences in lipid signaling. We use longitudinal label free phase imaging strategies to obtain cell phenotypic features which are directly correlated with single cell lipid metabolome obtained using advanced MALDI-MSI technique. Correlation maps indicate associations between lipid signaling and phenotypic changes in MSCs. Moreover, a novel machine learning clustering approach detects the heterogeneity in the MSCs subpopulation then methodically see how each heterogenous population is being impacted by the changes in lipid profiles which could be linked to the functional behaviors of the cell.

cell biology↗