bioRxiv Subject Collection: Neuroscience's Journal
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Monday, November 24th, 2025
| Time |
Event |
| 5:36a |
Lipid Nanoparticles Enable mRNA Delivery to Diverse Cell Types of the Inner Retina
Lipid nanoparticles (LNPs) have emerged as a promising platform for retinal genetic therapy, offering a non-viral alternative to adeno-associated viruses (AAVs). While LNPs can transfect outer retinal cells, their tropism for inner retinal cell types remains insufficiently characterized. Here, we systematically assessed cellular tropism of conventional LNPs encapsulating chemically modified mRNA encoding mCherry in murine retinal explants and dissociated retinal cells. We compared quasi-subretinal and quasi-intravitreal administrations and evaluated how retinal degeneration and inner limiting membrane (ILM) integrity influence LNP-mediated transfections. We observed that LNPs efficiently transfected Muller glia under all experimental conditions. In addition, LNPs transfected several other retinal cell types, including neurons in dissociated cells and explants, and vascular cells exclusively in explants. Subretinal delivery resulted in significantly higher transfection rates than intravitreal administration, and overall efficiency was higher in degenerate as compared to non-degenerate healthy retinas. In healthy retinas, removal of ILM-associated barriers significantly increased transfection efficiency following intravitreal administration. Together, these findings demonstrate that conventional LNPs can transfect a broader range of retinal cell types than previously recognized and highlight LNPs as a versatile tool for mRNA delivery to the retina, with applications in gene supplementation, gene editing, and regenerative therapies for inner retinal disorders. | | 9:49a |
Dynamic methylation changes in Alzheimers disease-related genes during mindfulness practice - a proof-of-concept study
BackgroundMindfulness meditation has gained significant attention in the context of Alzheimers disease (AD) due to its potential effects on the prevention of cognitive decline and overall psychological well-being. The epigenetic landscape of this complex neurodegenerative disorder can be influenced by environmental factors. Mindfulness practices could actively shape the biological response to AD by modifying the underlying molecular mechanisms through epigenetic regulation.
MethodsA group of 17 long-term mindfulness meditators (MMs) and 17 sex- and age-matched controls were recruited. Experienced MMs participated in a 1-month Vipassana meditation retreat. Blood DNA methylation levels of differentially methylated genes (ABCA7, ADAM10, APOE, HOXA3, NXN, TREM2 and TREML2) previously validated in a predictive AD-model found analyzed by bisulfite pyrosequencing.
ResultsAn increase in DNA methylation was observed for ADAM10, APOE, HOXA3 and TREM2 in MMs with respect to controls. Furthermore, significant differences were found for ABCA7, ADAM10, APOE and HOXA3 in MMs after retreat.
ConclusionsDNA methylation changes identified for ADAM10 and HOXA3 in MMs are in the opposite direction to those occurring in AD and may constitute a protective epigenetic alteration. Mindfulness practice could counteract DNA methylation of key AD genes as a possible preventive strategy or non-pharmacological intervention in AD patients. | | 9:49a |
Comparative Analysis of FOXP2 Expression in the Thalamus of Mice, Rats, and Macaques: Implications for the Evolution of Language Circuits.
FOXP2 is a transcription factor essential for the development and function of neural circuits involved in language. Although its expression has been extensively characterized in the cortex and basal ganglia, its organization within the adult thalamus remains poorly understood. In this study, we present a comparative analysis of FoxP2 protein expression across thalamic nuclei in mice, rats, and macaques, with a focus on nuclei associated with higher-order cognitive functions and language-related circuits in humans. We found that FoxP2 is expressed in most thalamic nuclei across species, with a consistent absence in the reticular nucleus and zona incerta. Expression was highest in midline and intralaminar nuclei, whereas the anterior group showed low and variable expression among species. Macaques exhibited broader and, in some nuclei, more intense FoxP2 expression, particularly in associative regions such as the pulvinar, lateral geniculate, and parts of the ventral group, indicating increased specialization of thalamocortical pathways. This distribution suggests a conserved role for FoxP2 in shaping thalamic circuits supporting sensorimotor integration, attention, memory, and linguistic processing. Phylogenetic comparisons further indicate that enhanced FoxP2 expression in associative thalamic territories in primates, likely intensified in humans, may have contributed to the evolution of neural circuits required for speech and language. These findings provide molecular and anatomical insights into how FoxP2 helps organize thalamocortical networks relevant both to language function and to neuropsychiatric disorders involving thalamocortical dysconnectivity. | | 9:49a |
WWOX deficiency uncovers a cell-autonomous mechanism impairing myelin repair
Remyelination is essential for neuronal function and plasticity, and its failure contributes to multiple sclerosis (MS) and other neurodegenerative disorders. Yet, the molecular programs governing oligodendrocyte precursor cell (OPC) differentiation and remyelination remain incompletely defined. Here, we identify the WW domain-containing oxidoreductase (WWOX) as a critical cell-autonomous regulator of oligodendrocyte differentiation and myelin repair. Reanalysis of single-nucleus RNA sequencing from MS lesions revealed WWOX as one of the most significantly dysregulated oligodendroglial genes. Conditional deletion of Wwox in oligodendroglia impaired OPC differentiation, favouring aberrant proliferation and blocking myelin regeneration after cuprizone-induced demyelination. Single-nucleus transcriptomics confirmed profound transcriptional reprogramming in WWOX-deficient oligodendroglia during remyelination, with enrichment of WNT and TGF{beta} signalling and cell cycle programs. Mechanistically, WWOX physically interacts with the master transcription factor SOX10 via its WW1 domain, stabilising SOX10 protein and sustaining its downstream myelin gene network. Loss of WWOX reduced SOX10 stability and activity, providing a direct mechanistic link to defective OPC differentiation. Together, our findings uncover WWOX as an essential orchestrator of remyelination and position the WWOX-SOX10 axis as a promising therapeutic target for enhancing myelin repair in MS and related demyelinating disorders. | | 11:45a |
Independent Lateralization of Language, Attention, and Numerical Cognition Across Task and Rest
Hemispheric functional complementarity is a core organizational principle of the human brain, yet the extent to which lateralization in one domain constrains that of others remains unclear. Two main accounts have been proposed: the causal hypothesis, in which dominance for one function drives complementary dominance in another, and the statistical hypothesis, in which each function lateralizes independently. Using multimodal fMRI in 287 participants from the BIL&GIN cohort, we examined whether language lateralization phenotypes, defined as typical (left-dominant) or atypical (right-dominant), predict hemispheric asymmetries in visuospatial attention and numerical cognition. Task-based activation was measured during line bisection, mental calculation, and numerical interval comparison, and analyzed within domain-specific, functionally defined network atlases. Resting-state functional connectivity metrics were also assessed in the same networks. Across both attention and numerical domains, typical individuals for language showed stronger asymmetries, whereas atypical individuals exhibited weaker, more bilateral patterns. Critically, atypical participants did not show mirror-reversed asymmetries, and language phenotype did not influence intrinsic connectivity metrics in non-language networks. These findings challenge the notion that atypical lateralization represents an inversion of the canonical template and argue against a universal reciprocal link between language dominance and other cognitive domains. Instead, our results support a domain-specific model in which lateralization profiles are shaped by distinct developmental and functional constraints, highlighting the need for multimodal, multi-domain approaches to brain asymmetry. | | 11:45a |
Localized mRNAs and protein synthesis in cortical layer 1
Cortical layer 1 plays an essential role for brain function, integrating many streams of information and undergoing synaptic plasticity during learning. Yet, we understand little of the underlying molecular processes, and whether they are specialized to achieve layer-specific functions. Here, we show that layer 1 and its synapses are metabolically active. Using laser capture RNA-sequencing and fluorescence in situ hybridization, we report an abundance of synaptic transcripts localized to layer 1. We purified layer 1 excitatory and inhibitory synapses and characterized their enriched transcriptomes, identifying candidate proteins that can be locally synthesized to maintain and regulate synaptic transmission in layer 1. Furthermore, we find significant differences between the transcriptome of synapses in layer 1 and in deeper, somatic layers, suggesting that local translation might confer specialized function. Finally, by comparing our tissue data with the transcriptome from the hippocampal CA1 strata, we discover a strong similarity between cortical layer 1 and stratum lacunosum moleculare, suggesting that these distal layers share a common molecular environment. Together, our results establish that local protein synthesis is an important mechanism for layer 1, and provide the first comprehensive characterization of the transcripts localized to layer 1 and its synapses. | | 11:45a |
A cross-species spatial transcriptomic atlas of the human and non-human primate basal ganglia
The basal ganglia are interconnected subcortical nuclei with complex topographical organization that orchestrate goal-directed behaviors and are implicated in neurodegenerative movement disorders. We generated a cellular-resolution, spatial transcriptomic atlas of the basal ganglia in human, rhesus macaque, and common marmoset, sampling over one million cells in each species. By integrating spatial data with a cross-species, consensus snRNA-seq cell type taxonomy, this atlas reveals conserved principles of molecular organization within and across structures. The cellular architecture is complex but highly stereotyped, with gene expression gradients superimposed onto discrete compartments. Extensive spatial sampling illuminates 3D gradients of molecular organization in the striatum and reveals cell type-specific core and shell compartments in the primate internal globus pallidus, which is conserved with mouse. This unified, cross-species spatial transcriptomic atlas will be a foundational resource for characterizing the molecular and functional organization of the basal ganglia and their roles in health and disease. | | 11:45a |
Spatial patterning of transcriptional and regulatory programs in the primate subcortex
Mammalian brain cell identity is shaped by intrinsic factors and external context. We present a spatially resolved transcriptomic and gene regulatory atlas of cell types found across all subcortical brain regions in a primate - the marmoset monkey. Dense sampling and cross-species integrations revealed spatially precise neuronal assemblies, including in complex structures such as hypothalamus. We find chromatin accessibility and transcriptional identity are spatially tuned within and across subcortical structures. Spatial gradients within subfields of the hippocampal formation are predominantly orchestrated by graded transcription factors coupled with graded enhancers. The primate-expanded population of GABAergic neurons in the thalamus shares transcriptional and regulatory syntax with neurons in superior colliculus, reflecting an evolutionary adaptation compared with rodents. We show that unexpected transcriptional convergence, such as between striatal GABAergic medium spiny neurons and telencephalic glutamatergic neurons, can arise when distinct gene regulatory networks impinge on the same downstream genes. | | 11:45a |
Learning dynamically regulates stimulus discrimination of ventral striatal D1 receptor expressing neurons
Animals encounter a barrage of sensory stimuli, but only a subset of these are associated with appetitive outcomes, highlighting the importance of neural mechanisms for learning to distinguish reward-paired from unpaired cues. The ventral striatum plays a critical role in both reinforcement learning and stimulus discrimination, but the effect of learning on the selectivity of different cell types remains unclear. Here we examined ventral striatal D1 and D2 medium spiny neuron (MSN) firing properties as mice learned to distinguish between reward-paired and unpaired cues. As learning progressed within a single session, D1 MSN selectivity increased linearly with behavioral selectivity, while D2 MSNs exhibited only modest, behaviorally uncorrelated changes in activity. Altered D1 MSN selectivity was primarily attributed to attenuated excitatory responses to the unrewarded cue, and increasing D1 MSN activity during the unrewarded cue impaired behavioral selectivity. Together, these findings reveal significantly more dynamic contributions of D1 MSNs to stimulus discrimination learning. | | 5:38p |
Less is more: uncompensated gravity torques for intuitive EMG-based assistance with a robotic exoskeleton
Despite extensive investigation on the use of electromyographic (EMG) activity to control active exoskeletons over the past decade, designing intuitive assistive controllers that seamlessly integrate with natural human motor control have yet to be realized. While existing EMG-based controllers often achieve substantial reduction in muscle effort, they frequently incur increased cognitive and attentional load for the user, thereby compromising the overall efficacy of the assistance. Here we introduce a novel EMG-based assistive controller founded upon neuroscience principles, specifically the observation that humans naturally exploit gravity torque to facilitate movement control. Therefore, deviating from conventional compensation strategies, our approach purposely leaves a fraction of the predicted human gravity torque uncompensated so that users can still take advantage of gravity as they would without assistance. Through a load-carrying arm movement task, we show that enabling gravity exploitation improves traditional EMG-based assistance by achieving a significant reduction in muscle effort, while concurrently yielding superior kinematic performance (i.e., faster, smoother movements) and enhanced subjective user experience. These findings demonstrate that integrating principles from neural motor control into assistive controllers allows to implement a favorable tradeoff between muscle effort reduction and functional usability. | | 7:34p |
Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II
High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus. |
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