bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, January 10th, 2024
| Time |
Event |
| 4:37a |
Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the of AD-BXD Mouse Population
Alzheimer's disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of-onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity seen in human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. By comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXD. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with a substantially higher level of GR expression. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. Using the paraclique enrichment method, we found four coexpression modules related to cell structure, protein folding, and postsynaptic densities that correlated with the quantitative resilience score in aged 5XFAD mice. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus. | | 5:33p |
Traveling waves shape neural population dynamics enabling predictions and internal model updating
The brain generates predictions based on statistical regularities in our environment. However, it is unclear how predictions are optimized through iterative interactions with the environment. Because traveling waves (TWs) propagate across the cortex shaping neural excitability, they can carry information to serve predictive processing. Using human intracranial recordings, we show that anterior-to-posterior alpha TWs correlated with prediction strength. Learning about priors altered neural state space trajectories, and how much it altered correlated with trial-by-trial prediction strength. Learning involved mismatches between predictions and sensory evidence triggering alpha-phase resets in lateral temporal cortex, accompanied by stronger alpha phase-high gamma amplitude coupling and high-gamma power. The mismatch initiated posterior-to-anterior alpha TWs and change in the subsequent trials state space trajectory, facilitating model updating. Our findings suggest a vital role of alpha TWs carrying both predictions to sensory cortex and mismatch signals to frontal cortex for trial-by-trial fine-tuning of predictive models. | | 5:33p |
Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment
Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3 untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTPB2 as a critical trans-acting factor mediating 3APA of synaptic genes in SCZ subjects. Functional characterization of PTPB2 in iNs confirmed its key role in 3APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3APA as one common molecular mechanism that underlies synaptic impairments in SCZ. | | 5:33p |
Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation
Background and ObjectivesSpatially-selective vagus nerve stimulation (sVNS) offers a promising solution to mitigate the off-target effects associated with traditional VNS, potentially serving as a precise method for addressing chronic heart failure (HF) by specifically targeting efferent cardiac fibers. This approach holds the potential to enhance therapeutic outcomes by avoiding off-target effects and eliminating the current need for time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. Methods and Results: By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179{+/-}55{degrees} SD microCT, p<0.05 and 200{+/-}137{degrees} SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. Cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability to selectively elicit therapeutic-related effect (heart rate decrease) without stimulating afferent-related reflexes. Conclusions: By investigating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating HF, myocardial infarction and other conditions, allowing for therapeutic effect to be achieved much sooner.
Condensed AbstractSpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart failure (HF) with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like heart rate decrease without stimulating afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in HF and related conditions. | | 6:48p |
A split-GAL4 driver line resource for Drosophila CNS cell types
Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3063 lines targeting a range of cell types in the adult Drosophila central nervous system and 1020 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines. |
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