Biology subjects

Cohen, L.

Publications and source records attributed to Cohen, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinsons disease

Approximately 90% of Parkinson's disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly synuclein (Syn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between Syn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of Syn preformed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic Syn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1-3 month following injection of PFFs into the OB. Following PFF injection, Syn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1-3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes (Il-1{beta} ; and Il-6), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking Syn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD.

neuroscience↗

bioRxiv2026

Constricted pupil states index neural replay during wakeful rest in humans

Neural replay has been linked to skill consolidation during wakeful rest, yet its physiological context in humans remains poorly understood. In animals, hippocampal ripples and associated replay occur more frequently within intrinsically oriented brain states associated with constricted pupils, suggesting that pupil dynamics may index neural replay events in humans. We combined magnetoencephalography-derived sequence replay with pupillometry in 25 participants learning a motor sequence across alternating intervals of practice and rest. Replay was indexed by smaller-pupil states, and replay timing clustered on the constricting phase of slow pupil fluctuations. More frequent replay accompanied larger cumulative offline gains during early learning, while smaller rest pupil was associated with better performance when practice resumed. Multivariate pupil features predicted replay-associated states across and within individuals while preceding pupil dynamics showed modest predictive ability to identify the precise onset of individual replay events. Here, we show that constricted-pupil states index neural replay during wakeful rest in humans, linking replay-associated physiology with early motor learning.

neuroscience↗

bioRxiv2026

HSPD1 promotes neuroblastoma by augmenting MYCN expression

MYCN amplification is associated with poor outcomes in neuroblastoma (NB). MYCN encodes a transcription factor that induces the expression of mitochondrial one-carbon enzymes and chaperones, promoting metabolic reprogramming and aggressiveness in NB tumor cells. While the contribution of MYCN to changes in the mitochondrial proteome is well established, how mitochondrial proteostasis contributes to MYCN activity remains poorly understood. Mitochondrial HSP60 (HSPD1) is a conserved mitochondrial chaperone promoting the mitochondrial one-carbon pathway and mitochondrial translation by folding the one-carbon enzyme MTHFD2 and preventing aggregation of mitochondrial ribosomal proteins. Here, we show that HSPD1 depletion in MYCN-amplified NB cells led to reduced mitochondrial translation, MYCN expression, and tumorigenesis in vitro and in vivo. In addition, HSPD1 mRNA and protein correlate with MYCN expression in NB tumors. These results establish HSPD1 as a promising target for the treatment of MYCN-amplified NB.

cancer biology↗

bioRxiv2026

Early sensory deprivation drives local reorganization of sensory integration within a conserved global hierarchy

The human brain processes sensory information through a hierarchical system, from primary to higher-level regions, integrating inputs across modalities to support perception and cognition. While early sensory loss triggers widespread neuroplastic changes, its impact on integration across the cortical hierarchy remains unclear. Here, we examined the cortical reorganization of individuals with early blindness and deafness using a sensory integration framework that quantifies how brain regions prioritize different sensory inputs across the hierarchy. We found that early sensory deprivation drives highly localized reorganization adjacent to the deprived primary cortical areas: extrastriate cortex in early blindness and the superior temporal cortex in early deafness. These findings were further corroborated by analysis of the functional gradients, which found reorganization within these sensory regions. Notably, the hierarchy was largely preserved across groups. However, the sensory integration framework uniquely detected reorganization in language-related regions in deaf individuals with knowledge of a visual communication system known as cued speech. The specific differences between early deaf and hearing individuals remained restricted to superior temporal cortex. Together, our findings demonstrate that early sensory deprivation drives targeted reorganization adjacent to the affected primary sensory cortex, while preserving the overall hierarchy of cortical integration.

neuroscience↗

bioRxiv2026

Fronto-temporal structural alterations in congenital aphantasia

Congenital aphantasia is characterized by a lifelong self-reported absence of voluntary visual imagery despite preserved visual knowledge, offering a natural model for dissociating sensory representation from conscious imagery. Functional imaging evidence suggests that this dissociation may arise from altered top-down interactions between higher-order control systems and high-level visual cortex, but its structural correlates remain unknown. Here, using diffusion and structural MRI in 18 individuals with congenital aphantasia and 18 matched visualisers, we tested two competing accounts of aphantasia: one predicting structural differences in visual pathways, the other predicting differences in higher-order associative networks. Across multimodal analyses of white-matter tract microstructure, functional-ROI tractography, graph-theoretic network organization, and cortical morphometry, aphantasia was associated with structural differences in frontotemporal and cingulate white-matter tracts, including the uncinate fasciculus, posterior interparietal callosal fibres, and dorsal cingulum, and in frontotemporal cortical regions, including the anterior insula, anterior prefrontal cortex, and medial temporal cortex, together forming a candidate neuroanatomical signature for the broad cognitive-affective profile of aphantasia. By contrast, we found no reliable group differences in early visual cortex, major visual tracts, or the direct structural connections of the core imagery network. Congenital aphantasia therefore exhibits a pattern of structural alterations centered on frontotemporal and cingulate systems, sparing the principal visual pathways. Given the modest sample size, these findings are exploratory and hypothesis-generating and require replication in larger cohorts; they nonetheless suggest that higher-order systems supporting integration and conscious access, rather than visual representations themselves, may contribute to the absence of conscious imagery in congenital aphantasia.

neuroscience↗

bioRxiv2026

Context-dependent determinants of CRISPR-Cas9 editing efficiency revealed through cross-species endogenous editing analysis

Accurate prediction of CRISPR-Cas9 guide RNA (gRNA) editing efficiency remains limited, particularly outside human systems, where models trained on exogenous human datasets show poor generalization. We analyzed Cas9 efficiency and repair outcomes using novel endogenous editing data from four human cell types, two tomato cell types, and cells from giant river prawn and black soldier fly. While integrating publicly available predictors via ensemble frameworks improved performance, our analysis revealed hundreds of novel features affecting activity. Crucially, dominant features related to sites competition for gRNA, and local geometric properties varied across systems, highlighting the strong context dependence of Cas9 efficiency and arguing against a universal model. Interestingly, codon usage bias-based features also emerged as informative predictors, as they are proxies for chromatin accessibility. In contrast, trends in repair outcomes remained conserved. This work provides essential resources for more generalizable CRISPR guide design.

synthetic biology↗

bioRxiv2026

Expert Motor Synergies Emerge Predominantly Offline During Early Skill Learning

Everyday skilled actions depend on the formation of coordinated motor synergies that integrate multiple digits into stable, low-dimensional control units. Although initial practice of a new skill leads to rapid performance improvements, it is unclear whether the underlying movement kinematics reorganize on a similar timescale and in a way that directly relates to these gains. It also remains uncertain whether such reorganization occurs mainly during active practice or instead during brief rest breaks. Here, we tracked the temporal evolution of multi-digit synergy formation during early learning of a naturalistic keypress skill. Initial practice rapidly sculpted the motor repertoire toward higher-order, temporally compressed and overlapping multi-digit synergies. These synergies emerged after only minutes of practice and continued to be expressed along the full training session. Notably, they were primarily shaped across brief rest breaks and robustly predicted individual skill proficiency. Across learning, distinct synergy subtypes emerged, differing in their heuristic prevalence. Rarely expressed synergies reflected transient novice patterns, synergies expressed at intermediate levels could index exploratory and trial-initiation strategies, and highly expressed synergies emerged later to dominate performance, reflecting the consolidation and expansion of skilled motor control. Together, these findings indicate that skilled performance is supported by the early formation of a compact repertoire of expert multi-digit synergies that emerge preferentially across rest periods and predict subsequent skill gains. They further raise the hypothesis that explicitly training such expert synergies alongside task goals could enhance learning in domains such as the arts, sport, and neurorehabilitation. HighlightsExpert multi-digit synergies form during early skill learning Higher-order synergies emerge across brief rest breaks Fatigue spares expert synergy use during early learning Skill gains mirror multi-digit synergy expression eTOC blurb"Expert multi-digit synergies emerge early in motor learning, strengthen across brief rest breaks, track skill gains, and resist fatigue"

neuroscience↗

bioRxiv2026

The mitochondrial chaperone HSPD1 folds MTHFD2 independently of its co-chaperone HSPE1

Acquiring new cellular states entails metabolic reprogramming driven by changes in the expression of cytosolic and mitochondrial metabolic enzymes. Most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria in a linear form, after which they are folded by a network of mitochondrial chaperones and co-chaperones. Which mitochondrial protein is dependent upon which chaperone for its folding is largely unknown. HSPD1/HSPE1 (HSP60/HSP10) are evolutionarily conserved mammalian homologues of the bacterial proteins GroEL/GroES, forming a chamber-and-lid chaperonin to facilitate the folding of client proteins. We used gene knockdown and SILAC-based proteomics to identify HSPD1 client proteins. We found that HSPD1 supports the expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2), a key essential protein in the mitochondrial one-carbon (1C) pathway, in cells and tumors, and directly folds MTHFD2, independently of its co-chaperone HSPE1. HSPD1 interacts with MTHFD2 in mitochondria, and MTHFD2 is degraded by LONP1 in HSPD1 knockdown cells. Consequently, we observed reduced nucleotide and S-adenosylmethionine (SAM) levels in HSPD1 knockdown and found minimal overlap in the transcriptional and metabolic cellular responses to HSPD1 vs. HSPE1 depletion. In C. elegans, knockout of HSP60 triggers the mitochondrial stress response in the gut, while HSP10 knockout triggers the mitochondrial stress response in muscle tissue. Our data support that HSPD1 is an MTHFD2 chaperone and that, in addition to working together, HSPD1 and HSPE1 have distinct biological functions.

cell biology↗

bioRxiv2025

Expansion of Working Memory Capacity Supports Early Skill Learning

Motor skill learning depends on refining action sequences through practice, yet how learning unfolds moment-to-moment within trials remains unclear. Here, healthy participants learned generative sequential keypress skills at different speeds. Within trials, we identified reproducible high initial skill (HIS) segments, brief epochs of elevated performance followed by decline, that emerged only during learning of repeating sequences and were absent during practice of pseudo-randomized, non-repeating sequences. HIS keypress content scaled with execution speed and increased with practice. This expansion of HIS segment content continued after overall performance plateaued. Neural analyses showed increased theta-gamma phase-amplitude coupling ({theta}/{gamma} PAC) and beta-band bursts during HIS segments. Hippocampal {theta}/{gamma} PAC predicted HIS content, suggesting a mechanism for binding successive actions into progressively larger skill-memory representations during early learning. Together, these findings identify expansion of skill memory, rather than fatigue, as a key driver of early skill learning.

neuroscience↗

bioRxiv2025

Whole-transcriptome-scale and isoform-resolved spatial imaging of single cells in complex tissues

Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved, whole-transcriptome-scale analysis of single cells with high spatial resolution. Here, we introduce a spatial transcriptomics method based on a novel in situ RNA amplification strategy, enabling short RNA sequence detection and hence spatially resolved expression profiling of individual cells at the whole-transcriptome scale with splice-isoform resolution. Using this approach, we imaged [~]33,000 distinct RNAs--including [~]23,000 genes and [~]10,000 isoform-defining transcripts--in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed a rich spatial diversity and cell-type specificity in isoform usage across numerous genes and identified brain structures particularly enriched for specific isoform usage. We anticipate broad application of this method for molecular and cellular analysis of tissues, unlocking previously inaccessible discoveries in cell and organismal biology.

genomics↗

bioRxiv2025

Eccentric cycling enhances primary motor cortex excitability

Acute aerobic exercise (AAE) can modulate primary motor cortex (M1) excitability. To date, studies evaluating its effects have focused almost exclusively on concentric cycling. Critically, we found that eccentric AAE enhances motor learning more than concentric AAE, possibly explained by enhanced frontal-parietal brain activation during eccentric cycling. Yet, M1 excitability mechanisms underlying this eccentric AAE-enhanced motor learning remain unknown. Thus, this study aimed to evaluate the effect of eccentric cycling AAE on M1 excitability using transcranial magnetic stimulation (TMS). Thirty adults performed three 20 min-conditions: i) eccentric cycling AAE, ii) concentric cycling AAE, and iii) rest. Cycling AAE was carried out at a workload corresponding to 70% of peak heart rate (%HRpeak) measured during concentric incremental cycling exercise. TMS assessments were conducted before (Pre), immediately (Post0) and 20 minutes after (Post20) AAE/rest to evaluate changes in corticospinal excitability (CSE) and short-interval intracortical inhibition (SICI). Overall, we found CSE increased and intracortical inhibition (SICI) was reduced at Post20 to a comparable extent following eccentric and concentric cycling AAE compared to rest. Also, %HRpeak, muscle pain and perceived effort were lower during eccentric cycling AAE compared to concentric cycling AAE. Our results showed that eccentric cycling impacted M1 excitability change to a comparable degree as concentric cycling, while requiring less cardiovascular response, eliciting less muscle pain and lower perceived effort. Taken together, our results suggest that eccentric cycling AAE may be a valuable intervention to modulate M1 excitability for populations with limited cardiovascular capacity and may have potential implications in clinical and sports-related contexts.

neuroscience↗

bioRxiv2025

Heterogeneous NF-κB activation and enhancer features shape transcription in Drosophila immunity

Conserved NF-{kappa}B signaling pathways shape immune responses in animals. In mammals, NF-{kappa}B activation patterns and downstream transcription vary with stimulus, cell type, and stochastic differences among identically treated cells. Whether animals without adaptive immunity exhibit similar heterogeneity or rely on distinct immune strategies remains unknown. We engineered Drosophila melanogaster S2* reporter cells as an immune-responsive model to monitor the dynamics of an NF-{kappa}B transcription factor, Relish, and downstream transcription in single, living cells. Following immune stimulation, Relish exhibits diverse nuclear localization dynamics that fall into distinct categories, with both the fraction of responsive cells and their activation speed rising with stimulus dose. Pre-stimulus features, including Relish nuclear fraction, predict a cells responsiveness to stimulation. Simultaneous measurement of Relish and downstream transcription revealed that the probability of transcriptional bursts from immune-responsive enhancers correlates with Relish nuclear fraction. The number of NF-{kappa}B binding sites tunes transcriptional activity among immune enhancers. Our study uncovers heterogeneity in NF-{kappa}B activation and target gene expression within Drosophila, illustrating how dynamic NF-{kappa}B behavior and enhancer architecture tune gene regulation.

molecular biology↗

bioRxiv2025

Brain-computer interface training fosters perceptual skills to detect errors

Accurate perception of visuo-motor errors is essential for perceptual and sensorimotor learning so that corrective actions are performed timely to maintain stability and goal-directed behavior. However, a key challenge remain: conventional, behavioral perceptual training -- typically based on response accuracy feedback-- is limited in improving sensitivity to small, subtle errors. While prior approaches have focused on modulating sensory regions to enhance perceptual learning, we propose an alternative approach: targeting a cognitive neural marker, namely the error positivity (Pe), a component of the error-related potential (ErrP) that primarily originates in the anterior cingulate cortex (ACC), a key region involved in decision-making. We hypothesize that the Pe, which reflects conscious awareness of errors, serves as a modifiable neural correlate of error perception. To address the performance bottlenecks seen in conventional, behavioral perceptual training, we show that real-time feedback on ErrP presence or absence during perceptual training over five longitudinal days enhances the Pe component and improves participants ability to detect small visuo-motor errors --an outcome not achieved through conventional, behavioral perceptual training. These findings offer new neurophysiological insights into error perception and learning, and establish ErrP-based BCI interventions as a promising tool for accelerating perceptual learning, particularly in contexts where subtle error detection is critical.

bioengineering↗

bioRxiv2025

Face-, color-, and word-specific patches in the human orbitofrontal cortex

The human ventral occipitotemporal cortex (VOTC) contains multiple category-specific areas, organized along posterior-to-anterior and medial-to-lateral axes. However, the role of regions beyond the VOTC in category-specific processing remains less explored. Here, we report the presence of face-, color-and word-specific patches in the human orbitofrontal cortex (OFC) and systematically describe their location, activity amplitude, category selectivity, representational content, and functional connectivity. We compare these features with those of corresponding VOTC category-specific patches. Our findings reveal that these multi-category OFC patches follow a similar medial-lateral organization to those in the VOTC, and face-and color-specific patches form continuous functional gradients with VOTC patches. These results suggest that the OFC contains a topographic organization similar to, but at a higher hierarchical level than, the VOTC object categorization system. One Sentence SummaryFace-, color-, and word-specific patches are present in the human orbitofrontal cortex and form a continuous functional hierarchy with corresponding patches in the ventral occipitotemporal cortex.

neuroscience↗

bioRxiv2024

Seeing speech: neural mechanisms of cued speech perception in prelingually deaf and hearing users

For many deaf people, lip-reading plays a major role in verbal communication. However, lip movements are by nature ambiguous, so that lip reading does not allow for a full understanding of speech. The resulting language access difficulties may have serious consequences on language, cognitive and social development. Cued speech (CS) was developed to eliminate this ambiguity by complementing lip-reading with hand gestures, giving access to the entire phonological content of speech through the visual modality alone. Despite its proven efficiency for improving linguistic and communicative abilities, the mechanisms of CS perception remain largely unknown. The goal of the present study is to delineate the brain regions involved in cued speech perception and identify their role in visual and language-related processes. Three matched groups of participants were scanned during two fMRI experiments: Prelingually deaf users of cued speech, hearing users of cued speech, and naive hearing controls. In Experiment 1, we presented videos of silent CS sentences, isolated lip movements, isolated gestures, plus CS sentences with speech sounds and meaningless CS sentences. In Experiment 2, we presented pictures of faces, bodies, written words, tools, and houses in order to understand the contribution of category-specific visual regions to CS perception. We delineated a number of mostly left-hemisphere brain regions involved in CS perception. We first found that language areas were activated in all groups by both silent CS sentences and isolated lip movements, and by gestures in deaf participants only. Despite overlapping activations when perceiving CS, several findings differentiated experts from novices. As such, CS expertise was associated with a leftward functional lateralization of the lateral occipital cortex, possibly driven by the expert identification of hand gestures. The Visual Word Form Area, which supports the interface between vision and language during reading, did not contribute to CS perception. Moreover, the integration of lip movements and gestures took place in a temporal language-related region in deaf users, and in movement-related regions in hearing users, reflecting their different profile of expertise in CS comprehension and production. Finally, we observed a strong involvement of the Dorsal Attentional Network in hearing users of CS, and identified the neural correlates of the variability in individual proficiency. Cued speech constitutes a novel pathway for accessing core language processes, halfway between speech perception and reading. The current study provides a delineation of the common and specific brain structures supporting those different modalities of language input, paving the way for further research.

neuroscience↗

bioRxiv2024

Cingulate and striatal hubs are linked to early skill learning

Early skill learning develops in the context of activity changes in distributed cortico-subcortical regions. Here, we investigated network hubs--centers of information integration and transmission--within the brain network supporting early skill learning. We recorded magnetoencephalographic (MEG) brain activity in healthy human subjects who learned a moderately difficult sequence skill with their non-dominant left hand. We then computed network hub strength by summing top 10% functional connectivity over 86 parcellated brain regions (AAL3 atlas) and five brain oscillatory frequency bands (alpha, low-, high-beta, low- and high-gamma). Virtually all skill gains developed during rest intervals of early learning (micro-offline gains). MEG hub strength in the alpha band (8-13Hz) in bilateral anterior cingulate (ACC) and caudate and in the low-beta band (13-16Hz) in bilateral caudate and right putamen correlated with micro-offline gains. These regions linked strongly with the hippocampus, parahippocampal cortex, and lingual and fusiform gyri. Thus, alpha and low-beta brain oscillatory activity in cingulate and striatal regions appear to contribute as hubs of information integration and transmission during early skill learning. Significance StatementEarly learning of moderately difficult skill sequences develops over periods of rest interspersed with practice (micro-offline gains). We demonstrate here a link between alpha and low-beta oscillatory activity in a cingulate-hippocampo-striato network hubs and rest intervals of early learning.

neuroscience↗

bioRxiv2024

Optimized Plaque Assay for Detecting Chronically Infecting Viruses of Haloarchaea

Archaeal viruses predominantly exhibit a chronic lifestyle, where viral particles are released without causing host cell death. Therefore, conventional plaque assays, which are well-suited for identifying lytic viruses, usually fail to detect chronically infecting viruses due to their non-lytic nature. To address this limitation, we developed an optimized plaque assay protocol for detecting chronically infecting viruses of haloarchaea, particularly species within the Haloferax genus. By enhancing viral diffusibility and infectivity through adjustments in agar concentration and lowering incubation temperature, this modified protocol improved plaque formation, enabling the detection of viruses that cause mild growth delays. We demonstrate successful plaque formation for two chronically infecting viruses, Haloferax volcanii pleomorphic virus 1 (HFPV-1) and lemon-shaped virus 48N (LSV-48N), on representative Haloferax strains and highlight the potential for isolating novel viruses from environmental samples. This improved plaque assay is an effective method for the detection and quantification of chronically infecting archaeal viruses, providing a new tool for discovering new viral families in extreme environments.

microbiology↗

bioRxiv2024

Sequence action representations contextualize during rapid skill learning

Activities of daily living rely on our ability to acquire new motor skills composed of precise action sequences. Here, we asked if the millisecond-level neural representation of an action performed at different contextual sequence locations within a skill differentiates or remains stable during early motor learning. We first optimized machine learning decoders predictive of sequence-embedded finger movements from magnetoencephalographic (MEG) activity. Using this approach, we found that the neural representation of the same action performed in different contextual sequence locations, progressively differentiated--primarily during rest intervals of early learning (offline)--correlating with skill gains. In contrast, representational differentiation during practice (online) did not reflect learning. The regions contributing to this representational differentiation evolved with learning, shifting from the contralateral pre- and post-central cortex during early learning (trials 1-11) to increased involvement of the superior and middle frontal cortex once skill performance plateaued (trials 12-36). Thus, the neural substrates supporting finger movements and their representational differentiation during early skill learning differ from those supporting stable performance during the subsequent skill plateau period. Representational contextualization extended to Day 2, exhibiting specificity for the practiced skill sequence. Altogether, our findings indicate that sequence action representations contextually differentiate during early skill learning, an issue relevant to brain-computer interface applications in neurorehabilitation.

neuroscience↗