bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, April 22nd, 2025
| Time |
Event |
| 7:34a |
Aicardi-Goutieres Syndrome Associated ADAR G1007R mutation dominantly induces neuroinflammation in mouse brain
The ADARG1007R mutation is one of the most frequent mutations found in type six Aicardi-Goutieres Syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients. We report here a mouse model bearing an human equivalent ADARG1007R mutation, and the heterozygous mice recapitulated some pathologic features of ADARG1007R AGS patients, including early-onset brain inflammation in heterozygous individuals and interferon-stimulated gene (ISG) expression within deep brain areas. Furthermore, we demonstrated that brain inflammation could be reversed by deletion of the cellular RNA receptor MDA5, which blocks the cellular RNA sensing signaling pathway. This model provides a unique tool for studying the molecular mechanisms underlying the heterozygous ADARWT/G1007R mutation in AGS brain pathogenesis. It may also be a valuable platform for developing personalized therapies for patients with this specific mutation. | | 12:32p |
Machine Learning-Driven fMRI Analysis for Objective Craving Prediction
Background Craving is a fundamental aspect of substance use disorder (SUD), traditionally assessed through subjective self-report measures. To develop more objective assessments, we created a brain-based marker to predict craving based on machine learning approaches using functional magnetic resonance imaging (fMRI) drug cue reactivity data from 69 participants with methamphetamine use disorders. Methods To predict craving intensity, our analysis demonstrated that utilizing principal component analysis (PCA) and linear regression outperformed other models in terms of Root Mean Squared Error (RMSE). Employing a 5-fold cross-validation strategy with a 20% holdout set, we established the reliability of the model. Additionally, the model successfully classified high and low craving levels and distinguished cue types (neutral vs. drug) based on fMRI data. Results The model achieved an RMSE of 0.983+/- 0.026 (standard deviation), with strong generalization evidenced by an out-of-sample RMSE of 0.985 and statistical significance (p < 0.026; effect size = 0.715; statistical power = 0.639). Key neurobiological signatures included the Parahippocampal Gyrus, Superior Temporal Gyrus, Medioventral Occipital Cortex, and Amygdala (positively associated with craving), as well as the Inferior Temporal Gyrus (negatively associated). Classification of high vs. low craving levels yielded an AUC-ROC of 0.684 +/- 0.084 (out-of-sample AUC-ROC = 0.714), with significant separation (p < 0.04; effect size = 0.831). Additionally, classification of cue types (neutral vs. drug) achieved an AUC-ROC of 0.692 +/- 0.090 (out-of-sample AUC-ROC = 0.693), with p < 0.002, effect size= 0.896, and statistical power = 0.800, highlighting the robustness of the model. Conclusion These findings underscore the potential of neuroimaging and machine learning to provide objective, data-driven insights into the neural mechanisms underlying subjective experience of craving and to inform future clinical applications in SUD. | | 12:32p |
Single Cell Landscape of Sex-specific Drivers of Alzheimers Disease
BackgroundSex differences in Alzheimers disease (AD) have been documented for decades, and many sex-specific molecular contributors to AD have been discovered through bulk omics analysis of brain tissues. RNA sequencing (RNAseq) at single cell resolution provides an opportunity to characterize transcript associations with AD in a cell type-specific matter. Here, we investigated sex-specific gene expression associations with neuropathology and cognitive manifestation of AD (endophenotypes) leveraging a large single-nucleus transcriptomic dataset consisting of 1.64 million nuclei from dorsolateral prefrontal cortex (DLPFC) tissue of 424 unique donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853).
MethodsROS/MAP single-nucleus RNAseq data (snRNA-seq) were processed through a rigorous pipeline. In total, eight major cell types from DLPFC were identified. We first performed sex-stratified and sex-interaction association analyses by fitting negative binomial mixed models in relation to {beta}-amyloid load (A{beta}), paired helical filament tau tangle density (tau), global cognitive performance at last visit, and longitudinal cognitive trajectory. We then conducted gene-set enrichment analysis to identify functional signaling pathways enriched for sex-specific associations. Lastly, we compared differential gene expression patterns and intercellular communication profiles between sexes and diagnostic groups among major cell types. For replication, sex-specific associations were examined using snRNA-seq derived from DLPFC tissue-derived of an independent set of 84 donors from The Seattle Alzheimers Disease Brain Cell Atlas (SEA-AD) study.
Results68% of the ROS/MAP participants were female, and 52% were diagnosed with AD dementia. We first identified several disease-dependent or sex-dependent cell subpopulations. Then we identified 2,660 sex-specific associations involving 2,110 genes with A{beta} (51%), tau (21%), and cognitive performance (29%). 60% female-specific associations were for A{beta}, and 49% male-specific associations were with tau. The vast majority (93%) of female protective associations were from neurons, and most (76%) of female risk associations were from glial cells. Nine of the female-specific associations involving eight unique genes were replicated in the SEA-AD cohort, including ADGRV1 and OR3A3 with A{beta}; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive decline. All replicated associations except TMEM50B were observed in neurons. Furthermore, the preponderance of protective female-specific associations in neurons was also recapitulated in the SEA-AD cohort. Sex-specific associations were enriched for genes in the immune, inflammation, and damage-related stress response pathways, and microglia presented the most sex-specific enriched pathways. Finally, we identified six ITGB1-mediated microglia-specific incoming signals that may play a role in female-specific risk for A{beta} accumulation.
ConclusionOur study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline. We delineate the full scope of sex-specific transcript associations, differential expression, signaling pathway, and cell-cell communication network changes in each major DLPFC cell type, while identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies. | | 12:32p |
Cognitive Mode Detectable with Task-Based fMRI: Default Mode B (DMB)
In the context of task-based functional magnetic resonance imaging (fMRI), cognitive modes can be defined as task-general cognitive/sensory/motor processes which reliably elicit specific blood-oxygen-level-dependent (BOLD) signal pattern configurations. A number of cognitive modes are detectable with task-based fMRI, and here we focus on Default Mode B (DMB), a task-negative and late-trial peaking cognitive mode. The BOLD signal configurations associated with DMB are modulated by a range of tasks, and here we present eight. For each task, we report: (1) specific pattern-based (as opposed to coordinate-based) anatomical details essential for distinguishing DMB from other BOLD-based cognitive modes, and (2) task-induced BOLD signal changes associated with DMB over a range of task conditions. In order to facilitate recognition, we nick-named the anatomical patterns specific to DMB as follows: (1) In Flight, (2) Medial Temporal Dots, (3) Snowman Nose, (4) Angel Wings, and (5) Tripod. Evidence for DMB was derived from the timing and magnitude of task-induced BOLD signal changes induced by the following tasks: working memory, spatial capacity, semantic association, evidence integration, Ravens matrices, autobiographical event simulation, meditation and social perception. It was observed that deactivations in DMB were sensitive to cognitive load during attention to specific features of the external environment, based on evidence from working memory, spatial capacity, semantic association, evidence integration, and Ravens matrices. It was also observed that activations in DMB involved a cognitive process for engaging in mental projection into self-relevant social narratives, based on evidence from autobiographical event simulation, meditation, and social perception. Future research may explore DMB activation over a wider range of tasks in larger samples. | | 12:32p |
Interactions between the medial prefrontal cortex, dorsomedial striatum, and dorsal hippocampus that support rat category learning
Categorization creates memory representations that are efficient, generalizable, and robust to noise. Multiple brain regions have been implicated in categorization, including the prefrontal cortex, striatum, and hippocampus; however, few studies have examined how these regions interact during category learning. We recorded neural activity in the medial prefrontal cortex (PFC), dorsomedial striatum (DMS), and dorsal hippocampus (HPC) while rats learned to categorize distributions of visual stimuli. We found a learning-related shift in contributions from the PFC (with DMS to PFC theta (4-10Hz) interactions) to the HPC (with HPC to DMS and bidirectional PFC-HPC theta interactions). Decision-making depended on DMS and HPC spiking, as well as the PFC to HPC to DMS pathway. Our results provide a framework that characterizes how the PFC-DMS-HPC network interacts during category learning. This is informative for multiple neurological disorders that affect category learning, including Parkinson's Disease, autism, and dementia. | | 12:32p |
Task dependent cortico-cerebellar responses to delayed visual movement feedback
Forward models in the brain issue predictions of sensory movement consequences that can establish self-other distinction through comparison with actual feedback. But forward models can also be updated by sensory prediction errors, as in sensorimotor adaptation. Disentangling the neuronal correlates of processes related to sensorimotor incongruence detection from those related to adaptation can be challenging. Here, we approached this challenge with a novel, virtual reality based hand-target tracking task that allowed us to manipulate the behavioral relevance of delayed visual movement feedback, while recording hemodynamic brain activity with functional magnetic resonance imaging (fMRI). Participants performed continuous right hand grasping movements to track a target oscillation with either their real, unseen hand or with a glove-controlled virtual hand. The movements of the virtual hand were delayed in a roving oddball fashion. Therefore, tracking with the virtual hand (VH task) required visuomotor adaptation, whereas tracking with the real hand (RH task) required ignoring visuomotor delays. VH > RH task execution produced stronger activity in the left posterior parietal cortex (PPC) and the bilateral extrastriate visual cortex. Delays correlated with activity in several regions, prominently including right temporoparietal regions, in both tasks. Crucially, the cerebellum showed a stronger delay dependent activation, and increased functional connectivity with the PPC, in the VH > RH task. Delay changes and errors correlated with activity in the anterior insulae (AI), and more strongly so in the VH>RH task. Thus, the instructed behavioral relevance of delayed visual movement feedback enhanced responses of the cerebellum and PPC, and their communication, likely for visuomotor adaptation. In contrast, temporoparietal regions compared predicted and actual visual movement feedback irrespective of its behavioral relevance, while the AI signaled visual mismatches particularly when these were behaviorally relevant. | | 12:32p |
Combinative protein expression of immediate early genesc-Fos, Arc, and Npas4 along aversive- and reward-related neural networks
Expression of immediate early genes (IEGs) is critical for memory formation and has been widely used to identify the neural substrate of memory traces, termed memory engram cells. However, the types of IEG have been relatively not distinguished in identifying engram cells, as there is limited knowledge about the extent to which different types of IEGs are selectively or concurrently involved in the formation of memory engram. To address this question, we investigated the combinative expression of c-Fos, Arc, and Npas4 proteins using immunohistochemistry following aversive and rewarding experiences across subregions in the prefrontal cortex (PFC), basolateral amygdala (BLA), hippocampal dentate gyrus (DG), and retrosplenial cortex (RSC). Using an automated cell detection algorithm, we found that expression patterns of c-Fos, Npas4, and Arc varied across different brain areas, with a higher increase of IEG expressing cells in the PFC and posterior BLA than in the DG. The combinative expression patterns, along with their learning-induced changes, also differed across brain areas; the co-expression of IEGs increased in the PFC and BLA following learning whereas the increase was less pronounced in the DG and RSC. Furthermore, we demonstrate that different area-to-area functional connectivity networks were extracted by different IEGs. These findings provide insights into how different IEGs and their combinations identify engram cells, which will contribute to a deeper understanding of the functional significance of IEG-tagged memory engram cells. | | 12:32p |
Enhanced reward coding and condition-independent dynamics in optogenetically identified corticostriatal neurons in monkeys
The basal ganglia are considered to be the site where cortical sensorimotor and dopaminergic reward information interact to potentiate and select actions. This had led to the assumption that cortical inputs to the basal ganglia encode sensorimotor states rather than reward or choice signals. We tested this hypothesis by studying the coding properties of neurons in the frontal eye field of monkeys that were optogenetically identified as being connected to the basal ganglia. We found that neurons already contained information about expected rewards and selected actions. Further, the reward and condition-independent modulations were stronger in connected neurons than in other neurons in the same area. These findings indicate that reward, choice, and sensorimotor information are integrated already in the inputs to the basal ganglia, implying that the basal ganglia play a role in manipulating rather than generating reward and choice signals. | | 12:32p |
Postnatal development of the dentate gyrus vascular niche
Lifelong neurogenesis in the dentate gyrus (DG) of the hippocampus supports cognitive and emotional functions in most adult mammals. The subgranular zone (SGZ) of the DG contains dense vasculature where neural stem and progenitor cells (NSPCs) reside in close proximity to local capillaries. This arrangement likely supports NSPCs by providing access to oxygen, circulating molecules, and endothelial-derived factors. While SGZ vessel density and NSPC association with vessels are well established in adulthood, when these niche attributes emerge in development remains unclear. Here, we show that while blood vessel density in the SGZ remained stable from initial layer formation (2 weeks of age) into young adulthood (9 weeks of age) in male and female mice, the average distance from NSPC somas to the nearest blood vessel decreased progressively over postnatal development. This finding was accompanied by a symmetrical compression of proliferating cells within the SGZ, and a gradual shift of quiescent neural stem cell somas towards the granule cell layer of the DG. Our findings imply that the DG neurogenic vascular niche continues to refine postnatally, suggesting that the NSPC vascular niche has a unique functional role in supporting mature adult neurogenesis. | | 12:32p |
Feedforward Extraction of Behaviorally Significant Information by Neocortical Columns
Neurons throughout the neocortex exhibit selective sensitivity to particular features of sensory input patterns. According to the prevailing views, cortical strategy is to choose features that exhibit predictable relationship to their spatial and/or temporal context. Such contextually predictable features likely make explicit the causal factors operating in the environment and thus they are likely to have perceptual/behavioral utility. The known details of functional architecture of cortical columns suggest that cortical extraction of such features is a modular nonlinear operation, in which the input layer, layer 4, performs initial nonlinear input transform generating proto-features, followed by their linear integration into output features by the basal dendrites of pyramidal cells in the upper layers. Tuning of pyramidal cells to contextually predictable features is guided by the contextual inputs their apical dendrites receive from other cortical columns via long-range horizontal or feedback connections. Our implementation of this strategy in a model of prototypical V1 cortical column, trained on natural images, reveals the presence of a limited number of contextually predictable orthogonal basis features in the image patterns appearing in the column's receptive field. Upper-layer cells generate an overcomplete Hadamard-like representation of these basis features: i.e., each cell carries information about all basis features, but with each basis feature contributing either positively or negatively in the pattern unique to that cell. In tuning selectively to contextually predictable features, upper layers perform selective filtering of the information they receive from layer 4, emphasizing information about orderly aspects of the sensed environment and downplaying local, likely to be insignificant or distracting, information. Altogether, the upper-layer output preserves fine discrimination capabilities while acquiring novel higher-order categorization abilities to cluster together input patterns that are different but, in some way, environmentally related. We find that to be fully effective, our feature tuning operation requires collective participation of cells across 7 minicolumns, together making up a functionally defined 150um diameter "mesocolumn." Similarly to real V1 cortex, 80% of model upper-layer cells acquire complex-cell receptive field properties while 20% acquire simple-cell properties. Overall, the design of the model and its emergent properties are fully consistent with the known properties of cortical organization. Thus, in conclusion, our feature-extracting circuit might capture the core operation performed by cortical columns in their feedforward extraction of perceptually and behaviorally significant information. | | 4:49p |
Neuropathological hallmarks during the chronic phase of ischemic stroke in mice and humans
Background: Improvements in acute stroke treatment, including endovascular thrombectomy and critical care management, have increased survival rates post-stroke. However, stroke remains a leading cause of long-term disability and many survivors have significant neurological and cognitive deficits. Despite this, the chronic neurological sequelae and underlying secondary injury mechanisms induced by ischemic stroke remain understudied. Methods: This study examined long-term neurobehavioral recovery and neuropathology at 2- and 6- months post-stroke in young (12-week-old) male C57Bl/6 mice after a 60-minute transient middle cerebral artery occlusion (MCAO) or sham surgery. Behavioral testing included the open field test (OFT), novel object recognition test (NORT), fear conditioning (FC), nesting activity, and tail suspension. Post-mortem brain samples from patients with chronic ischemic stroke were also assessed. Immunohistochemistry (IHC) was performed to assess demyelination (MBP), neuronal apoptosis (TUNEL), and A{beta}42 in human brains. Flow cytometric analysis was performed to assess microglial phenotypes, the chronic neuroimmune landscape, and to evaluate senescent-like phenotypes (SA-{beta}Gal and lipofuscin). Transcriptomic profiling was performed using RNA isolated from the ipsilateral hemisphere in stroke mice. Results: Experimental stroke caused progressive cognitive and motor decline up to 6 months post-MCAO. IHC and flow cytometric analyses revealed a significant increase in TUNEL-positive neurons, cortical and hippocampal gliosis, white matter degradation, senescent cell accumulation, and altered microglial function. IHC analysis of postmortem human brains shows significantly increased levels of microgliosis, senescent cells and amyloid burden. Transcriptomic analysis revealed that pathways involving apoptosis, microglial activation and the complement pathway were chronically upregulated after stroke. Conclusion: Our findings demonstrate that ischemic stroke induces a non-resolving microglial response and accelerated inflamm-aging in the brain, evidenced by premature senescence and elevated production of cytokines within the chronic infarct microenvironment. Senescent-like phenotypes and chronic neurodegenerative disease signatures may contribute to the progressive worsening of cognitive function post-stroke. These results suggest that chronic, ongoing neurodegeneration occurs late after stroke, even in younger mice. Mitigating these detrimental changes may offer viable targets for delayed treatment strategies for stroke. | | 11:15p |
Access to emotional memories: Evidence for a vagal route to boost memory retrieval using non-invasive taVNS
Remembering emotionally significant events is critical for the organisms' behavior and survival. While the mechanisms underlying formation of such memories are well understood and closely linked to the vagus nerve and the brain's arousal system, less is known about its contribution to memory retrieval. The current study tested whether non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) applied during a long-term recognition memory task influenced retrieval of unpleasant and neutral scenes that have been incidentally encoded one week earlier. Results showed that taVNS, compared to a sham condition, selectively enhanced the recollection of unpleasant images. Despite a modest effect size (d = 0.33), these findings provide first human evidence for a direct link of the vagus nerve in emotional memory retrieval, thus extending current theoretical models of emotional memory retrieval and opening a new pathway for memory modulation and non-invasive therapeutic interventions. |
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