bioRxiv Subject Collection: Neuroscience's Journal
 
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Wednesday, June 12th, 2024

    Time Event
    12:30a
    Mutant HTT protein decreases with CAG repeat expansion: implications for therapeutics and bioassays.
    Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in the HTT protein. The mutant CAG repeat is unstable and expands in specific brain cells and peripheral tissues throughout life. Genes involved in the DNA mismatch repair pathways, known to act on expansion, have been identified as genetics modifiers, therefore, it is the rate of somatic CAG repeat expansion that drives the age of onset and rate of disease progression. In the context of an expanded CAG repeat, the HTT pre-mRNA can be alternatively processed to generate the HTT1a transcript, that encodes the aggregation prone and highly pathogenic HTT1a protein. This may be a mechanism through which somatic CAG repeat expansion exerts its pathogenic effects, as the longer the CAG repeat, the more HTT1a and HTT1a is produced. The allelic series of knock-in mouse models: HdhQ20, HdhQ50, HdhQ80, HdhQ111, CAG140 and zQ175 with polyQ expansions of 20, 50, 80, 111 140 and ~190 can be used to model the molecular and cellular consequences of CAG repeat expansion within a single neuron. By western blot of cortical lysates, we found that mutant HTT levels decreased with increasing CAG repeat length; mutant HTT was only 23% and 10% of wild-type levels in CAG140 and zQ175 cortices, respectively. To identify the optimal bioassays for detecting the full-length HTT and HTT1a isoforms, we interrogated the pairwise combinations of seven well-characterized antibodies on both the HTRF and MSD platforms. In total we tested 32 HTRF and 32 MSD assays to detect full-length mutant HTT, HTT1a, total mutant HTT (full-length HTT and HTT1a) and total full-length HTT (mutant and wild type). None of these assays recapitulated the full-length mutant HTT levels as measured by western blot. We recommend using isoform- and species- specific assays that detect either full-length mutant HTT, HTT1a or wild-type HTT as opposed to those that detect more than one isoform simultaneously. Our finding that as the CAG repeat expands, full-length mutant HTT levels decrease, whilst HTT1a and HTT1a levels increase has implications for therapeutic strategies. If mutant HTT levels in cells containing (CAG)200 are only 10% of wild-type, HTT-lowering strategies targeting full-length HTT at sequences 3 prime to intron 1 HTT will predominantly lower wild-type HTT, as mutant HTT levels in these cells are already depleted. These data support a therapeutic strategy that lowers HTT1a and depletes levels of the HTT1a protein.
    12:30a
    High-affinity detection of endogenously biotinylated neuroligin-1 at excitatory and inhibitory synapses using a tagged knock-in mouse strain
    Neuroligins (NLGNs) are important cell adhesion molecules mediating trans-synaptic contacts between neurons. However, the high-yield biochemical isolation and visualization of endogenous NLGNs have been hampered by the lack of efficient antibodies to these proteins. Thus, to reveal their sub-cellular distribution, binding partners, and synaptic function, NLGNs have been extensively manipulated using knock-down, knock-out, or over-expression approaches, overall leading to controversial results. As an alternative to the manipulation of NLGN expression level, we describe here the generation of a new transgenic mouse strain in which native NLGN1 was N-terminally tagged with a small biotin acceptor peptide (bAP) that can be enzymatically biotinylated by the exogenous delivery of biotin ligase. After showing that knock-in mice exhibit normal behavior as well as similar synaptic number, ultrastructure, transmission properties, and protein expression levels when compared to wild type counterparts, we exploited the fact that biotinylated bAP-NLGN1 can be selectively isolated or visualized using high-affinity streptavidin conjugates. Using immunoblotting and immunofluorescence, we show that bAP-NLGN1 binds both PSD-95 and gephyrin and distributes equally well at excitatory and inhibitory synapses, challenging the historical view that NLGN1 is exclusively localized at excitatory synapses. Using super-resolution fluorescence microscopy and electron microscopy, we further highlight that bAP-NLGN1 forms in the synaptic cleft a subset of nanodomains each containing a few NLGN1 dimers, while the number of nanodomains per synapse positively scales with the post-synapse size. Overall, our study not only provides a novel, extensively characterized transgenic mouse model which will be made available to the scientific community, but also an unprecedented view of the nanoscale organization of endogenous NLGN1.
    12:30a
    TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy.
    Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimers disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenic C. elegans model expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT in C. elegans causes neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with loss of pgrn-1, the C. elegans ortholog of human PGRN. Neither full nor partial loss of pgrn-1 altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout of spop-1, sut-2, and sut-6 resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.
    12:30a
    Central Amygdala Astrocyte Plasticity Underlies GABAergic Dysregulation in Ethanol Dependence
    Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 also did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, astrocytic GAT3 does not appear necessary for the drinking related phenotypes associated with dependence.
    12:30a
    The Drosophila tyramine-beta-hydroxylase gene encodes multiple isoforms with different functions
    The Tyramine-beta-hydroxylase (Tbh) is required for octopamine synthesis. To better understand the function of Tbh in neurotransmitter synthesis, we analyzed the molecular genetic organization of the Drosophila melanogaster Tbh gene and found that the Tbh gene encodes multiple transcripts. The transcripts differ in their 5UTR, which results in proteins that differ in their size and putative phosphorylation sites, suggesting that the Tbh function is regulated at translational and posttranslational levels. We generated a new Tbh mutant - TbhDel3 - using FLP/FRT recombination mutagenesis to remove the translational start site still that is present in TbhnM18mutants. The TbhDel3 mutants share ethanol tolerance and larval locomotion defects with the TbhnM18 mutants. But, they differ in terms of their cellular stress response. To develop normal levels of ethanol tolerance, Tbh is required in a subset of Tbh expressing neurons in the adult brain, which was identified using a newly generated Tbh-Gal4 driver. Taking advantage of a newly generated Tbh antibody serum, we show that one Tbh isoform is expressed in a group of peptidergic Hugin-positive and noradrenergic neurons uncoupling Tbh function from octopamine synthesis. The existence of different functional Tbh isoforms impacts our understanding of the regulatory mechanisms of neurotransmitter synthesis and the function of the octopaminergic neurotransmitter system in cellular processes and the regulation of behavior.
    12:30a
    Universal statistics of hippocampal place fields across species and dimensionalities
    Hippocampal place cells form a spatial map by selectively firing at specific locations in an animal's environment. Until recently the hippocampus appeared to implement a simple coding scheme for position, in which each neuron is assigned to a single region of space in which it is active. Recently, new experiments revealed that the tuning of hippocampal neurons to space is much less stereotyped than previously thought: in large environments, place cells are active in multiple locations and their fields vary in shape and size across locations, with distributions that differ substantially in different experiments. It is unknown whether these seemingly diverse observations can be explained in a unified manner, and whether the heterogeneous statistics can reveal the mechanisms that determine the tuning of neural activity to position. Here we show that a surprisingly simple mathematical model, in which firing fields are generated by thresholding a realization of a random Gaussian process, explains the statistical properties of neural activity in quantitative detail, in bats and rodents, and in one-, two-, and three-dimensional environments of varying sizes. The model captures the statistics of field arrangements, and further yields quantitative predictions on the statistics of field shapes and topologies, which we verify. Thus, the seemingly diverse statistics arise from mathematical principles that are common to different species and behavioral conditions. The underlying Gaussian statistics are compatible with a picture in which the synaptic connections between place cells and their inputs are random and highly unstructured.
    12:30a
    Endogenous opioids facilitate stress-induced binge eating via an insular cortex-claustrum pathway
    Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating behaviors are largely unreported. The endogenous dynorphin (dyn)/kappa opioid receptor (KOR) opioid neuropeptide system has been well-established to be a crucial mediator of the anhedonic component of stress. Here, we aimed to dissect the basis of dynorphinergic control of stress-induced binge-like eating behavior. We first established a mouse behavioral model for stress-induced binge-like eating behaviors. We found that mice exposed to stress increased their food intake of familiar palatable food (high fat, high sugar, HPD) compared to non-stressed mice. Following a brain-wide analysis, we isolated robust cFos-positive cells in the Claustrum (CLA), a subcortical structure with highly abundant KOR expression, following stress-induced binge-eating behavior. We report that KOR signaling in CLA is necessary for this elevated stress-induced binge eating behavior using local pharmacology and local deletion of KOR. In vivo calcium recordings using fiber photometry revealed a disinhibition circuit structure in the CLA during the initiation of HPD feeding bouts. We further established the dynamics of endogenous dynorphinergic control of this behavior using a genetically encoded dynorphin biosensor, Klight. Combined with 1-photon single-cell calcium imaging, we report significant heterogeneity with the CLA population during stress-induced binge eating and such behavior attenuates local dynorphin tone. Furthermore, we isolate the anterior Insular cortex (aIC) as the potential source of endogenous dynorphin afferents in the CLA. By characterizing neural circuits and peptidergic mechanisms within the CLA, we uncover a pathway that implicates endogenous opioid regulation stress-induced binge eating.
    1:48a
    Longitudinal sex-at-birth and age analyses of cortical structure in the ABCD Study
    While the brain continues to develop during adolescence, such development may depend on sex-at-birth. However, the elucidation of such differences may be hindered by analytical decisions (e.g., covariate selection to address body/brain-size differences) and the typical reporting of cross-sectional data. To further evaluate adolescent cortical development, we analyzed data from the Adolescent Brain Cognitive Development StudySM, whose cohort of 11,000+ youth participants with biannual neuroimaging data collection can facilitate understanding neuroanatomical change during a critical developmental window. Doubly considering individual differences in the context of group-level effects, we analyzed regional changes in cortical thickness, sulcal depth, surface area, and volume between two timepoints (~2 years apart) in 9- to 12-year-olds assigned male or female sex-at-birth. First, we conducted linear mixed-effects models to gauge how controlling for intracranial volume, whole-brain volume (WBV), or a summary metric (e.g., mean cortical thickness) influenced interpretations of age-dependent cortical change. Next, we evaluated the relative changes in thickness and surface area as a function of sex-at-birth and age. Here, we showed that WBV (thickness, sulcal depth, volume) and total cortical surface area were more optimal covariates; controlling for different covariates would have substantially altered our interpretations of overall and sex-at-birth-specific neuroanatomical development. Further, we provided evidence to suggest that aggregate change in how cortical thickness is changing relative to surface area is generally comparable across those assigned male or female sex-at-birth, with corresponding change happening at slightly older ages in those assigned male sex-at-birth. Overall, these results help elucidate neuroanatomical developmental trajectories in early adolescence.
    1:48a
    Palytoxin Evokes Reversible Spreading Depolarization in the Locust CNS
    Spreading depolarization (SD) describes the near-complete depolarization of CNS neural cells as a consequence of chemical, electrical, and metabolic perturbations. It is well-established as the central mechanism underlying insect coma and various mammalian neurological dysfunctions. Despite significant progress in our understanding, the question remains: which cation channel, if any, generates SD in the CNS? Previously, we speculated that the sodium-potassium ATPase (NKA) might function as a large-conductance ion channel to initiate SD in insects, potentially mediated by a palytoxin (PLTX)-like endogenous activator. In the current study, we evaluate the effectiveness and properties of PLTX as an SD initiator in L. migratoria. Whereas bath-applied PLTX failed to ignite SD, direct injection into the neuropil triggered SD in 57% of the preparations. Notably, PLTX-induced SD onset was significantly more rapid compared to ouabain injection and azide controls, though their electrophysiological features remained similar. Furthermore, PLTX-induced SD was recoverable and resulted in a greater frequency of repetitive SD events compared to ouabain. Surprisingly, prior PLTX treatment disrupted the onset and recovery of subsequent SD evoked by other means. PLTX injection could attenuate the amplitude and hasten the onset time of azide-induced SD. Such an effect is associated with a complete inhibition at higher doses of subsequent anoxic SD induced through azide treatment or submersion. These results show that PLTX can trigger repetitive and reversible SD-like events in locusts and simultaneously interfere with anoxic SD occurrence. We suggest that the well-documented NKA pump conversion into an open non-selective cationic channel is a plausible mechanism of SD activation in the locust CNS, warranting additional investigations.
    1:48a
    Enhancing Retromer Complex Stability Ameliorates Synaptic Dysfunction in a Mouse Model ofAlzheimer's Disease
    Synaptic dysfunction is an early hallmark of Alzheimers disease, characterized by the disruption of synaptic transmission and plasticity. Central to these processes is endosomal trafficking, mediated by the retromer complex, which orchestrates the movement of vesicle contents for recycling to the plasma membrane, return to the Golgi, or degradation. Variants of VPS35, the cargo recognition component of the retromer complex, have been linked to neurodegenerative diseases, including Parkinsons disease (PARK17, D620N mutation) and Alzheimers disease (L625P mutation). While substantial research has focused on Parkinsons, the role of VPS35 in Alzheimers has been less explored. This study investigates the acute neuroprotective effects of retromer-stabilizing compounds in the 5xFAD mouse model of Alzheimers. Our results reveal that stabilization of the retromer complex not only mitigates pathogenic production mechanisms but also compensates for early synaptic dysfunction and microglial activation. Specifically, we observed significant modulation of genes involved in long-term potentiation and a reduction in abnormal retromer-associated cargos. These findings highlight the potential of retromer stabilisation as atherapeutic strategy to address fundamental pathological pathological processes in Alzheimers disease
    1:48a
    Modeling differences in neurodevelopmental maturity of the reading network using support vector regression on functional connectivity data
    The construction of brain growth charts trained to predict age based on morphometric and/or functional properties of the brain ("brain-age prediction") has the potential to inform neuroscientists and clinicians alike about children's neurodevelopmental trajectories. When applied to both typically and atypically-developing populations - such as those with specific learning disorders - results may be informative as to whether a particular condition is associated with atypical maturation of specific brain networks. Here, we focus on the relationship between reading disorder (RD) and maturation of functional connectivity (FC) patterns in the prototypical reading/language network across development using a cross-sectional sample of N = 742 participants aged 6-21 years. A support vector regression model is trained to predict chronological age from FC data derived from (1) a whole-brain model, as well as (2) multiple "reduced" models, which are trained on FC data generated from a successively smaller number of regions in the brain's reading network. We hypothesized that the trained models would show systematic underestimation of brain network maturity (i.e., lower FC-based age predictions) for poor readers, particularly for the models trained with reading/language regions. Exploratory results demonstrated that the most important whole-brain ROIs and connections are derived from the dorsal attention and somatosensory motor networks. Comparisons of the different models' predictions reveal that while the whole-brain model outperforms the others in terms of overall prediction accuracy, all models are effective at predicting brain maturity, including the one trained with the smallest amount of FC data. In addition, all models demonstrate some degree of moderation in the reliability of their age predictions as a function of reading ability, with predictions for both poor and exceptional readers being more accurate relative to those for typical readers.
    1:48a
    The maturation of infant and toddler visual cortex neural activity and associations with fine motor performance
    Our understanding of how visual cortex neural processes mature during infancy and toddlerhood is limited. Using magnetoencephalography (MEG), the present study investigated the development of visual evoked responses (VERs) in both cross-sectional and longitudinal samples of infants and toddlers 2 months to 3 years. Brain space analyses focused on N1m and P1m latency, as well as the N1m-to-P1m amplitude. Associations between VER measures and developmental quotient (DQ) scores in the cognitive/visual and fine motor domains were also examined. Results showed a nonlinear decrease in N1m and P1m latency as a function of age, characterized by rapid changes followed by slower progression, with the N1m latency plateauing at 6-7 months and the P1m latency plateauing at 8-9 months. The N1m-to-P1m amplitude also exhibited a non-linear decrease, with strong responses observed in younger infants (~2-3 months) and then a gradual decline. Associations between N1m and P1m latency and fine motor DQ scores were observed, suggesting that infants with faster visual processing may be better equipped to perform fine motor tasks. The present findings advance our understanding of the maturation of the infant visual system and highlight the relationship between the maturation of visual system and fine motor skills.
    1:48a
    A scalable and modular computational pipeline for axonal connectomics: automated tracing and assembly of axons across serial sections
    Progress in histological methods and in microscope technology has enabled dense staining and imaging of axons over large brain volumes, but tracing axons over such volumes requires new computational tools for 3D reconstruction of data acquired from serial sections. We have developed a computational pipeline for automated tracing and volume assembly of densely stained axons imaged over serial sections, which leverages machine learning-based segmentation to enable stitching and alignment with the axon traces themselves. We validated this segmentation-driven approach to volume assembly and alignment of individual axons over centimeter-scale serial sections and show the application of the output traces for analysis of local orientation and for proofreading over aligned volumes. The pipeline is scalable, and combined with recent advances in experimental approaches, should enable new studies of mesoscale connectivity and function over the whole human brain.
    1:48a
    BASOPHILS ACTIVATE PRURICEPTOR-LIKE VAGAL SENSORY NEURONS.
    Vagal sensory neurons convey sensations from internal organs along the vagus nerve to the brainstem. Pruriceptors are a subtype of neurons that transmit itch and induce pruritus. Despite extensive research on the molecular mechanisms of itch, studies focusing on pruriceptors in the vagal ganglia still need to be explored. In this study, we characterized vagal pruriceptor neurons by their responsiveness to pruritogens such as lysophosphatidic acid, {beta}-alanine, chloroquine, and the cytokine oncostatin M. We discovered that lung-resident basophils produce oncostatin M and that its release can be induced by engagement of Fc{varepsilon}RI. Oncostatin M then sensitizes multiple populations of vagal sensory neurons, including Tac1+ and MrgprA3+ neurons in the jugular ganglia. Finally, we observed an increase in oncostatin M release in mice sensitized to the house dust mite Dermatophagoides pteronyssinus or to the fungal allergen Alternaria alternate, highlighting a novel mechanism through which basophils and vagal sensory neurons may communicate during type I hypersensitivity diseases such as allergic asthma.
    1:48a
    C-LTMRs mediate wet dog shakes via the spinoparabrachial pathway
    Mammals perform rapid oscillations of their body- "wet dog shakes" -to remove water and irritants from their back hairy skin. The somatosensory mechanisms underlying this stereotypical behavior are unknown. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to hairy skin of mice. Unmyelinated low-threshold mechanoreceptors (C-LTMRs) were strongly activated by oil droplets and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial (SPB) neurons, and optogenetically inhibiting SPB neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR-spinoparabrachial pathway mediates wet dog shakes for rapid and effective removal of foreign particles from back hairy skin.
    2:16a
    Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient
    Microglia play critical roles in the brain physiology and pathology. CSF1R is primarily expressed in microglia. The mono-allelic CSF1R mutation causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a lethal neurological disease and no rational cure in clinical trials. There are no animal models mimicking human ALSP. In this study, we first developed mouse models based on human ALSP hotspot mutations. We then utilized microglia replacement by bone marrow transplantation (Mr BMT) to replace the Csf1r-deficient microglia in ALSP mice by Csf1r-normal donor cells. With pathogenic gene correction, Mr BMT efficiently attenuated the pathologies. Previously, an ALSP patient received traditional bone marrow transplantation (tBMT) due to a misdiagnosis of metachromatic leukodystrophy. The disease progress was halted for 15 years with unknown reasons. We demonstrated that tBMT in ALSP is equivalent to or close to Mr BMT, achieving efficient microglia replacement and therefore attenuating the ALSP progress in the mouse model. Next, we applied tBMT to replace CSF1R-deficient microglia in human patients. Our clinical results show that after microglia replacement, the ALSP course is effectively halted. Together, microglia replacement corrects the pathogenic gene and thus halts the disease progress in the mouse model and human patients. This study strongly demonstrates clinical potentials of microglia replacement in neurological disease treatments.
    2:16a
    The spatial organization of ascending auditory pathway microstructural maturation from infancy through adolescence using a novel fiber tracking approach
    Auditory perception is established through experience-dependent stimuli exposure during sensitive developmental periods; however, little is known regarding the structural development of the central auditory pathway in humans. The present study characterized the regional developmental trajectories of the ascending auditory pathway from the brainstem to the auditory cortex from infancy through adolescence using a novel diffusion MRI-based tractography approach and along-tract analyses. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to quantify the magnitude and timing of auditory pathway microstructural maturation. We found spatially varying patterns of white matter maturation along the length of the tract, with inferior brainstem regions developing earlier than thalamocortical projections and left hemisphere tracts developing earlier than the right. These results help to characterize the processes that give rise to functional auditory processing and may provide a baseline for detecting abnormal development.
    3:30a
    Echo-locate: Cerebellar activity predicts vocalization in fruit bats
    Echolocating bats exhibit remarkable auditory behaviors, enabled by adaptations within and outside their auditory system. Yet, research in echolocating bats has focused mostly on brain areas that belong to the classic ascending auditory pathway. This study provides direct evidence linking the cerebellum, an evolutionarily ancient and non-classic auditory structure, to vocalization and hearing. We report that in the fruit-eating bat Carollia perspicillata, external sounds can evoke cerebellar responses with latencies below 20 ms. Such fast responses are indicative of early inputs to the bat cerebellum. In vocalizing bats, distinct spike train patterns allow the prediction with over 85% accuracy of the sound they are about to produce, or have just produced, i.e., communication calls or echolocation pulses. Taken together, our findings provide evidence of specializations for vocalization and hearing in the cerebellum of an auditory specialist.
    3:30a
    Impact of cardiometabolic factors and blood beta-amyloid on the volume of white matter hyperintensities in dementia-free subjects with cognitive complaints
    Introduction: White matter hyperintensities (WMH) in Alzheimer disease (AD) have traditionally been associated with cerebrovascular diseases. Amyloid beta deposition reportedly contributes to WMHs, however, this relationship remains unclear in dementia free subjects with cognitive complaints (CC). Here, we explored the relationship between WMHs and cardiometabolic and amyloid beta blood biomarkers in a community based cohort of Latin American CC participants. Methods: We recruited 112 individuals with CC (69 92 YO, 90 females) with available plasma amyloid beta biomarkers and cardiometabolic markers (systolic diastolic blood pressure and glycaemia). WMHs were quantified using a lesion segmentation tool based on SPM12 and segmented using the John Hopkins University (JHU) Atlas and ALVIN segmentation for periventricular and subcortical white matter. Linear multiple regression models were fitted to assess total WMH lesions and the segmented tract, using demographics, cardiometabolic, and amyloid beta blood biomarker measures as independent variables. Results: After multiple comparison corrections, diastolic blood pressure was associated with WMHs, specifically in the right anterior thalamic radiation, left cingulum, minor forceps, and subcortical ALVIN segmentation. Glycaemia was associated with WMH volume in forceps major, forceps minor, and right fronto occipital fasciculi. Conversely, amyloid beta blood biomarkers and systolic blood pressure showed no association with WMH overall or in specific tracts. Conclusion: Our findings suggest that, in dementia free CC individuals, WMH volume was more related to cardiometabolic factors, whereas amyloid beta blood biomarkers might be of less relevance. Dementia prevention strategies in individuals might be a useful focus for managing high peripheral vessel resistance and endothelial damage due to hypertension and hyperglycaemia.
    3:30a
    Modulation of beta oscillatory dynamics in motor and frontal areas during physical fatigue
    Beta-band oscillations have been suggested to promote the maintenance of the current motor (or cognitive) set, thus signaling the status quo of the system. While this hypothesis has been reliably demonstrated in many studies, it fails to explain changes in beta-band activity due to the accumulation of physical fatigue. In the current study, we aimed to reconcile the functional role of beta oscillations during physical fatigue within the status quo theory. Using an innovative EEG design, we identified two distinct beta-band power dynamics in the motor areas as fatigue rises: (i) an enhancement at rest, supposedly promoting the resting state, and (ii) a decrease during contraction, thought to reflect the increase in motor cortex activation necessary to cope with the muscular fatigue. We then conducted effective connectivity analyses, which revealed that the modulations during contractions were driven by frontal areas. Finally, we implement a biologically plausible model to replicate and characterize our results mechanistically. Together, our findings anchor the physical fatigue paradigm within the status quo theory, thus shedding light on the functional role of beta oscillations in physical fatigue. We further discuss a unified interpretation that might explain the conflicting evidence previously encountered in the physical fatigue literature.
    6:35p
    Differences in fMRI-based functional connectivity during abstinence or interventions between heroin-dependent individuals and healthy controls
    The substantial personal, societal, and economic impacts of opioid addiction drive research investigating how opioid addiction affects the brain, and whether therapies attenuate addiction-related metrics of brain function. One useful approach to characterise the effects of opioid addiction on the brain is functional connectivity (FC). FC assesses the pairwise relationship of brain region function over time. This work is a systematic narrative review of studies investigating the effect of abstinence or interventions on FC in people who are dependent on heroin (HD) and healthy controls (HC). We found that HD typically showed weaker FC between three functional networks: the Executive Control Network, Default Mode Network, and the Salience Network. Abstinence and Transcranial Magnetic Stimulation (TMS) both attenuated differences in FC between HD and HC, often by increasing FC in HD. We critically assessed the clinical relevance of these results and the impact of study methods on the robustness of study results. We concluded with practical suggestions to improve the translational potential of neuromodulatory interventions (e.g., noninvasive brain stimulation) targeting the neural correlates of opioid addiction.
    7:49p
    Sex, racial, and APOE-ϵ4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease
    INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 {+/-} 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-{epsilon}4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-{epsilon}4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-{epsilon}4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.
    9:47p
    Identifying factors that contribute to collision avoidance behaviours while walking in a natural environment
    Busy walking paths, like in a park, a sidewalk in a city centre, or a shopping mall, frequently necessitate collision avoidance behaviour. Lab-based research has shown how a variety of situation-specific factors (e.g., distraction, object/pedestrian proximity) and person-specific factors (e.g., pedestrian size, age), typically studied independently, affect avoidance behaviour. What happens in the real world is unclear. Thus, we filmed unscripted pedestrian walking behaviours on a busy ~3.5 m urban path adjacent to the water. We leveraged deep learning algorithms to identify and extract walking trajectories of pedestrians and had unbiased raters characterize interaction details. Here we analyzed over 500 situations where two pedestrians approached each other from opposite ends (i.e., one-on-one pedestrian interactions). We found that smaller medial-lateral distance between approaching pedestrians and a lower number of surrounding pedestrians (i.e., smaller crowd size) predicted an increase in the likelihood of a subsequent path deviation. Furthermore, we found that whether a pedestrian looked distracted or held, pushed, or pulled something while walking predicted the medial-lateral distance between pedestrians at the time of crossing. Although pedestrians maintained a larger personal space boundary compared to lab settings, this is likely because of the outdoor path's width. Overall, our results suggest that collision avoidance behaviours in lab and real-world environments share similarities and offer insights relevant to developing more accurate computational models for realistic pedestrian movement.
    11:46p
    The first interneuron of the mouse visual system is tailored to the natural environment through morphology and electrical coupling
    The topographic complexity of the mouse retina has long been underestimated, as obvious specializations, like a fovea or visual streak, are absent. However, anatomical and functional gradients exist. It was recently shown that receptive fields of retinal ganglion cells change their shape along the dorso-ventral retinal axis. These variations likely reflect the non-uniform statistics of the visual environment which vary dramatically from ground to sky. Horizontal cells are the first visual interneurons and dictate the synaptic signaling between photoreceptors and bipolar cells by lateral interactions, thereby shaping the receptive fields of down-stream neurons. Thus, we asked whether regional specializations are present at this earliest stage of synaptic circuitry, i.e. at the level of horizontal cells. We analyzed horizontal cell density distributions, morphological properties, localization of gap junction proteins, and the spatial extent of horizontal cell electrical coupling across complete retinas. All of these horizontal cell key features were asymmetrically organized along the dorso-ventral axis. Dorsal horizontal cells were less densely distributed, had larger dendritic trees, and electrical coupling was more extensive than in their ventral counterparts. The steepest change along this gradient occurred at the opsin transition zone of photoreceptors, i.e. the mouse visual horizon. Therefore, our results show that the cellular and synaptic organization of the mouse visual system are adapted to the visual environment at the earliest possible level, and that horizontal cells are well suited to form the cellular substrate for the global gradient previously described for the receptive field structures of retinal ganglion cells.
    11:46p
    A General Framework for Characterizing Optimal Communication in Brain Networks
    Communication in brain networks is the foundation of cognitive function and behavior. A multitude of evolutionary pressures, including the minimization of metabolic costs while maximizing communication efficiency, contribute to shaping the structure and dynamics of these networks. However, how communication efficiency is characterized depends on the assumed model of communication dynamics. Traditional models include shortest path signaling, random walker navigation, broadcasting, and diffusive processes. Yet, a general and model-agnostic framework for characterizing optimal neural communication remains to be established. Our study addresses this challenge by assigning communication efficiency through game theory, based on a combination of structural data from human cortical networks with computational models of brain dynamics. We quantified the exact influence exerted by each brain node over every other node using an exhaustive multi-site virtual lesioning scheme, creating optimal influence maps for various models of brain dynamics. These descriptions show how communication patterns unfold in the given brain network if regions maximize their influence over one another. By comparing these influence maps with a large variety of brain communication models, we found that optimal communication most closely resembles a broadcasting model in which regions leverage multiple parallel channels for information dissemination. Moreover, we show that the most influential regions within the cortex are formed by its rich-club. These regions exploit their topological vantage point by broadcasting across numerous pathways, thereby significantly enhancing their effective reach even when the anatomical connections are weak. Our work provides a rigorous and versatile framework for characterizing optimal communication across brain networks and reveals the most influential brain regions and the topological features underlying their optimal communication.
    11:46p
    Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine Alpha-Adrenergic Receptor Signaling
    Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimer's disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.
    11:46p
    Minimizing command timing volatility is a key factor in skilled actions
    Variability between movements prevents the best athletes from making a perfect shot every time. While fluctuations in the amplitude of neural sensory inputs and motor outputs are thought to be primarily responsible, they only account for a fraction of the observed variability. Here, we propose that a significant portion of the variability is due to imprecisely timed motor commands. This command timing volatility theory best explained the three peaks observed in the force variability's time-series in discrete reaching movements and during periodic force control. Furthermore, we show how the timing volatility in the non-dominant arm's muscles is larger than in the dominant arm, then develop a variability index that estimates the arm's timing volatility via its variability during circle tracing. The difference in the variability index between the left and right hands accurately predicts the Edinburgh Quotient, suggesting a relationship between handedness and the command timing volatility of the left- and right-hands. Lastly, we constructed a simulation of reaching movements made by an arm controlled by muscles whose command timing was made incrementally more volatile. As timing volatility increased, aiming became less precise and movements jerkier. Such impairments during reaching are reported in patients with different neuronal diseases that damage any brain regions critical to motor timing, suggesting that essential aspects of these symptoms may be caused by excessive timing volatility. Our theory provides a unifying computational perspective of movement variability in healthy and diseased individuals that is essential to understanding the control of movements.

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