bioRxiv Subject Collection: Neuroscience's Journal
[Most Recent Entries]
[Calendar View]
Thursday, August 21st, 2025
| Time |
Event |
| 3:47p |
Imaging cellular activity simultaneously across all organs of a vertebrate reveals body-wide circuits
All cells in an animal collectively ensure, moment-to-moment, the survival of the whole organism in the face of environmental stressors. Physiology seeks to elucidate the intricate network of interactions that sustain life, which often span multiple organs, cell types, and timescales, but a major challenge lies in the inability to simultaneously record time-varying cellular activity throughout the entire body. We developed WHOLISTIC, a method to image second-timescale, time-varying intracellular dynamics across cell-types of the vertebrate body. By advancing and integrating volumetric fluorescence microscopy, machine learning, and pancellular transgenic expression of calcium sensors in transparent young Danio rerio (zebrafish) and adult Danionella, the method enables real-time recording of cellular dynamics across the organism. Calcium is a universal intracellular messenger, with a large array of cellular processes depending on changes in calcium concentration across varying time-scales, making it an ideal proxy of cellular activity. Using this platform to screen the dynamics of all cells in the body, we discovered unexpected responses of specific cell types to stimuli, such as chondrocyte reactions to cold, meningeal responses to ketamine, and state-dependent activity, such as oscillatory ependymal-cell activity during periods of extended motor quiescence. At the organ scale, the method uncovered pulsating traveling waves along the kidney nephron. At the multi-organ scale, we uncovered muscle synergies and independencies, as well as muscle-organ interactions. Integration with optogenetics allowed us to all-optically determine the causal direction of brain-body interactions. At the whole-organism scale, the method captured the rapid brainstem-controlled redistribution of blood flow across the body. Finally, we advanced Whole-Body Expansion Microscopy to provide ground-truth molecular and ultrastructural anatomical context, explaining the spatiotemporal structure of activity captured by WHOLISTIC. Together, these innovations establish a new paradigm for systems biology, bridging cellular and organismal physiology, with broad implications for both fundamental research and drug discovery. | | 5:46p |
Characterizing neuronal cell bodies in human postmortem cerebral white matter tracts
Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing evident neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders. | | 5:46p |
Meta-analysis of genetic mapping studies in mice reveals candidate epilepsy modifier genes that are outside the current drug development landscape
Objective: Despite decades of development in anti-seizure medications, approximately 30% of individuals remain refractory to all treatments, and none of the existing therapies are disease-modifying. Identifying targets outside the current preclinical paradigm is critically important. This study aimed to characterize the landscape of current epilepsy treatments at the level of gene interaction networks and identify novel genetic modifiers of epilepsy as potential novel therapeutic targets. Methods: We performed a functional network analysis to score genes based on their interactions with known epilepsy genes and integrated these functional scores with population-genetic data and drug tractability information. In parallel, we performed a meta-analysis of genome wide association studies of epilepsy-related phenotypes in genetically diverse mice using a large compendium of historical phenotyping data. Genes within mapped loci were prioritized based on functional rankings and genomic evolutionary rate profiling (GERP) was used to identify highly SNPs at evolutionarily constrained positions. Results: Functional network analyses of known epilepsy genes revealed a strong involvement of neurodevelopmental processes in epilepsy pathogenesis, which are not targeted by existing or emerging treatments. Meta-analysis of seizure traits in mice identified 118 non-overlapping loci harboring potential seizure phenotype modifiers. Using functional rankings, we prioritized 168 candidate genes within these loci and used GERP scores to filter down to 75 single-nucleotide polymorphisms as candidate variants within these genes. Among them, five genes -- Ephb2, En2, Cadps2, Igsf21, and Cep170 -- contain regulatory variants in evolutionarily constrained sites. Four of these genes are validated as modifiers of neurological traits, including epilepsy susceptibility. Significance: This study prioritized epilepsy modifier genes that are strongly predicted to influence neurodevelopmental processes that are underrepresented among current therapeutic targets. Furthermore, the identified genes represent novel candidate modifiers with potential clinical relevance. Our systems-level analysis offers a novel view into the potential target landscape, pointing toward promising new directions for disease-modifying treatments. | | 6:15p |
Tactile responses in the mouse perirhinal cortex show invariance to physical features of the stimulus
Sensory processing in the cortex follows a hierarchical structure, transforming fine-grained stimulus features into abstract, invariant representations. These transformations have typically been characterised in visual pathways ranging from primary visual cortex to inferotemporal cortex. Less is known about how stimulus representations are formatted in other modalities and downstream regions such as the perirhinal cortex (PER), which receives processed sensory input from all modalities and is involved in object recognition. To address this, we investigated neural activity along the somatosensory hierarchy in awake, head-fixed mice receiving tactile whisker stimulation on either side of the face. PCA and stimulus-baseline decoding analyses revealed that PER activity was similar across stimulated sides, while this was not the case in primary somatosensory cortex (wS1). We also performed decoding analyses for the side of stimulation and the stimulus' movement direction and found that wS1 and secondary somatosensory cortex could reliably decode both features. In contrast, PER was shown to be invariant to both features. We also clustered neurons based on their response dynamics, which indicated that the majority of PER neurons did not encode the basic stimulus features. These findings demonstrate that PER is a critical node in the somatosensory processing hierarchy, encoding tactile information in an invariant and abstract format. Together, these insights contribute to a more refined understanding of how perceptual processing in PER contributes to the various cognitive processes it is utilised for. | | 6:15p |
Disentangling Respiratory Phase-Dependent and Anticipatory Cardiac Deceleration in a Visual Perception Task
The heart does not beat like a metronome: varying parasympathetic input to the heart leads to constant heart rate variability. Vagal cardiomotor neuron activity is coupled to the respiratory cycle, leading to Respiratory Sinus Arrhythmia (RSA), a permanent oscillation of heart rate synchronized to respiration. Heart rate also temporarily decelerates in specific conditions such as in freezing due to perceived threat, or anticipation of a salient stimulus. Anticipatory Cardiac Deceleration (ACD) is observed consistently in anticipation of a stimulus in perceptual tasks, but its relationship with perceptual performance is debated. Previous quantifications of ACD neglect ongoing heart rate oscillations due to RSA, which may have led to inconsistencies in the ACD-related analyses across studies. Here, we suggest a novel approach to estimate trial-averaged RSA amplitude and respiratory phase-independent cardiac deceleration simultaneously, and apply it to an EEG-ECG dataset from a visual detection task. While the total ACD was not associated with perception, dissociating RSA-based and non-respiratory cardiac modulations revealed that they show opposing effects on perceptual performance. Additionally, we found that participants with higher ACD amplitudes also displayed larger Visual Awareness Negativity potentials, further supporting a contribution of ACD to visual perception. | | 8:18p |
Negative affective traits moderate transcranial direct current stimulation (tDCS) effects on memory
The cognitive effects of transcranial direct current stimulation (tDCS) show considerable inter-individual variability, prompting the need to identify moderators of responsiveness. This study examined whether negative affectivity (such as depressiveness, anxiety, and stress level), conceptualized as both transient states and stable traits, moderates the effects of tDCS on working memory (WM) and associative memory (AM). We pooled data from six sham-controlled experiments involving 144 healthy young adults (351 tDCS sessions) using within-subject crossover designs. Participants completed WM and AM tasks following active anodal tDCS or sham, as well as Depression, Anxiety, and Stress Scale (DASS-21) before each session. We found that trait-level negative affectivity, but not state-level emotional fluctuations, moderated WM. Individuals with higher levels of depression, anxiety, or stress demonstrated greater tDCS-induced WM gains. In contrast, AM benefits were consistent and unaffected by affective traits or states. These findings indicate that psychological traits can shape the variability of tDCS effects. In particular, negative affectivity influences susceptibility to tDCS effects on cognitively demanding tasks that rely heavily on executive control. This effect may stem from negative affectivity's association with downscaled baseline cortical excitability in prefrontal networks, crucial for WM performance, thereby opening the possibility of greater tDCS-induced improvement. These findings provide further support to our growing understanding of the complex interplay between emotional and cognitive processes in shaping individual responses to tDCS and point out that negative affectivity should be taken into consideration when evaluating individual variability of the tDCS (and other non-invasive brain stimulation techniques) effects on memory and cognition. | | 9:31p |
Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuronal Regeneration.
Therapeutic angiogenesis is essential for regenerating brain tissue damaged by stroke, yet it remains an unmet clinical challenge. During brain development, pro-angiogenic genes drive the formation of vascular networks, with their expression tightly regulated in later stages. We found that in adult CNS endothelial cells (ECs), angiogenesis-related genes are epigenetically silenced through histone deacetylase 2 (HDAC2) and the polycomb repressive complex 2 (PRC2). Conditional deletion of Hdac2 in ECs reactivated pro-angiogenic signaling, including Wnt/{beta}-catenin target genes, leading to functional neovascularization with preserved blood-brain barrier (BBB) integrity in the adult brain. In contrast, Ezh2 (PRC2 subunit) deletion reduced vessel density and compromised BBB function. Deletion of Hdac2 and Ezh2 immediately after transient ischemic stroke conferred vascular protection by modulating stroke-induced transcriptional programs in CNS ECs. In contrast, delayed deletion, initiated seven days post-stroke, after significant neuronal loss in the infarct region, induced robust revascularization and promoted post-stroke neurogenesis, with differentiation into both excitatory and inhibitory neurons. These findings highlight CNS EC HDAC2 as a promising therapeutic target for inducing adult brain angiogenesis, facilitating revascularization, and supporting neuronal regeneration following stroke. | | 9:31p |
The neuro-ocular costs of texting during driving
Texting while driving is among the most dangerous forms of distraction, yet the neurophysiological mechanisms linking cognitive load, gaze control, and driving behavior remain poorly understood. Here, EEG, eye tracking, head kinematics, and driving performance were recorded in a naturalistic driving task while participants solved arithmetic problems presented on a dashboard-mounted display under low and high working-memory (WM) load, mimicking real-world interaction with dashboard media. High WM load resulted in slower reaction times, reduced accuracy, prolonged gaze toward the stimulus, increased corrective head rotations, and compensatory reductions in driving speed. Time-frequency analysis revealed robust alpha power suppression (~8-13 Hz) over occipito-parietal regions scaling with WM load and closely paralleling gaze behavior. Source reconstruction further identified a transient, stimulus-locked increase in oscillatory power at ~15 Hz involving the ipsilateral cerebellum and posterior parietal preceding the head rotation onset. These findings illuminate the time course of a neuro-ocular action circuit involving cerebellum and cortex as candidate neurophysiological precursor of upcoming behavioral costs as a result of driver distraction. Bridging cognitive neuroscience and applied traffic research, the present results provide an ecologically valid framework for studying action-attention coupling in realworld behavior. | | 9:31p |
Age-related differences in the cortical motor network during uni-manual and bimanual coordination - an EEG study
Aging is accompanied by various neurophysiological changes that may affect cognitive and motor function. Compared to younger adults, motor performance in older adults engages more brain regions and exhibits elevated neural activity in the motor-related alpha (8-12 Hz) and beta (15-30 Hz) frequency bands of electro-encephalography (EEG) signals. To what extent these functional changes correlate with the quality of motor performance is underexplored. We recorded EEG in 19 young and 19 older adults during unimanual and bimanual visuomotor tasks with different degrees of difficulty. Older participants showed a lower quality of performance than younger adults, especially during asymmetric bimanual tasks. We analyzed source-localized activity in bilateral parietal and (pre-)motor areas to investigate, especially, the hypothesized pivotal role of left premotor cortex (PMCL) activity within the motor network during motor performance. In PMCL, beta activity was indeed significantly affected by age during bimanual performance, while alpha activity was altered in the bilateral (pre-)cuneus. When predicting error of performance via alpha and beta modulations, we found significant associations in bilateral M1 and (pre-)cuneusR during unimanual performance, while in bimanual performance, PMCL and (pre-)cuneusL were also included in the significant association. Our results confirm the importance of PMCL and (pre-)cuneusL for the performance of bimanual tasks, especially when the tasks are challenging. The age-related differences in alpha power in bilateral (pre-)cuneus and their associations with motor performance suggest that altered visuomotor integration has an important contribution to the reduction of the quality of motor performance in older adults. | | 9:31p |
Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy.
Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in developmental delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase (cis-PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, DhddsR37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. DhddsR37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission, and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used off-label to treat genetic movement disorders, drastically reduces seizure susceptibility to pentylenetetrazol in DhddsR37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis-PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel Congenital Disorder of Glycosylation, associated with aberrant levels of neuronal proteins and lipids. | | 9:31p |
Distributed Cortical Network Dynamics of Binocular Convergent Eye Movements in Humans
Neuroimaging studies in humans have localized brain functions to specific brain regions, but a recent shift toward distributed network-based models of brain function promises deeper insights into the network processes that generate brain functionality. Resting-state functional connectivity provides a rich mapping of the brain's network architecture, linking with both underlying structure and task-evoked responses across the whole brain. In this study, we utilized a model based on propagation of task-evoked activations over resting-state functional connectivity networks to identify cortical contributions to localized functional brain activations associated with binocular convergent eye movements. Binocular vision is crucial for daily routine activities, with its impairment leading to significant challenges in daily life. The distributed network-level mechanisms of binocular convergent eye movements remain unknown. Results showed that mapping activity flow over brain connections accurately generated actual brain activations associated with convergent eye movements, which were distinct from those observed during control tasks. The visual and dorsal attention networks dominated the propagation of activations through resting-state connections during convergent eye movements. Submodel analyses further revealed that restricting activity flow to individual networks, such as the visual or dorsal attention systems alone, substantially reduced model accuracy, underscoring the necessity of distributed, whole-brain contributions. In conclusion, highly distributed network pathways are involved in convergent eye movements, with some pathways contributing much more than others, providing important implications for future clinical models of binocular dysfunction. | | 9:31p |
Pathology-Specific Modulation of Corticostriatal Circuitry by Chronic Alcohol Consumption in Alzheimers Disease Mouse Models
Chronic alcohol use is a major modifiable risk factor for Alzheimers disease (AD), yet the mechanisms by which it modulates AD pathophysiology remain unclear. Here, we examined circuit-level and pathological changes in two distinct AD mouse models, humanized Abeta; knock-in (hAPP-KI) (Abeta;-driven) and PS19 (tau-driven), subjected to a chronic intermittent alcohol exposure paradigm. In hAPP-KI mice, alcohol increased Abeta; accumulation and excitatory transmission in the medial prefrontal cortex (mPFC) while reducing corticostriatal transmission and striatal cholinergic output. These alterations were accompanied by enhanced recruitment of microglia around A{beta} plaques. In contrast, alcohol-exposed PS19 mice displayed elevated mPFC-to-dorsomedial striatum (DMS) glutamatergic transmission and increased tau phosphorylation without significant changes in microglial activation or local mPFC excitatory drive. In wild-type mice, microglial depletion enhanced glutamatergic transmission onto cortical neurons, suggesting a homeostatic role for microglia in maintaining excitatory balance. Together, these findings reveal pathology-specific effects of alcohol on circuit dysfunction and propose microglia as an important modulator of alcohol-induced synaptic remodeling in the early stage of AD. | | 10:46p |
Transcriptional Interference Gates Monogenic Odorant Receptor Expression in Ants
Communication is crucial to social life, and in ants, it is mediated primarily through olfaction. Ants have more odorant receptor (OR) genes than any other group of insects, generated through tandem duplications that produce large genomic arrays of related genes. However, how olfactory sensory neurons produce a single functional OR from these arrays remains unclear. In ants, only mRNA from one OR in an array is exported into the cytoplasm, while upstream genes are silent and transcripts from downstream genes remain nuclear. Here, we show that non-canonical readthrough transcription in the downstream direction generates non-translated transcripts. We also find that OR promoters are bidirectional, producing antisense long non-coding RNAs that appear to suppress the expression of upstream genes. Finally, we present evidence that this regulatory architecture is conserved across ants and bees, suggesting that this mechanism for functionally monogenic OR expression is widespread in insects with expanded OR repertoires. |
|