Miracle-dz/UniFAR-FTUs huggingface dataset:
Dendritic domain-specific sampling of long-range axons shapes feedforward and feedback connectivity of L5 neurons

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, whereas higher-order areas are thought to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axodendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of male mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feedback inputs may thus need revisiting. SIGNIFICANCE STATEMENT Perception and learning depend on the ability of the brain to shape neuronal representations across all processing stages. Long-range connections across different hierarchical levels enable diverse sources of contextual information, such as predictions or motivational state, to modify feedforward signals. Assumptions regarding the organization of this hierarchical connectivity have not been extensively verified. Here, we assess the synaptic connectivity of brain-wide projections onto pyramidal neurons in the visual cortex of mice. Using trans-synaptic viral tracing and subcellular optogenetic circuit mapping, we show that functional synapses do not follow the consistent connectivity rule predicted by their axonal branching patterns. These findings highlight the diversity of computational strategies operating throughout cortical networks and may aid in building better artificial networks.
Distinct Neurophysiological Correlates of the fMRI BOLD Signal in the Hippocampus and Neocortex

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood oxygenation level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modeling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70–150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30–70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex. SIGNIFICANCE STATEMENT The BOLD signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in the frontal and parietal cortices. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.
Zebrafish spinal cord oligodendrocyte formation requires boc function

The axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central nervous system. In addition to its role in patterning ventral progenitors, Shh signaling must be maintained through development to specify pMN progenitors for oligodendrocyte fate. Using a forward genetic screen in zebrafish for mutations that disrupt development of oligodendrocytes, we identified a new mutant allele of boc, which encodes a type I transmembrane protein that functions as a coreceptor for Shh. Embryos homozygous for the bocco25 allele, which creates a missense mutation in a Fibronectin type III domain that binds Shh, have normally patterned spinal cords but fail to maintain pMN progenitors, resulting in a deficit of oligodendrocytes. Using a sensitive fluorescent detection method for in situ RNA hybridization, we found that spinal cord cells express boc in a graded fashion that is inverse to the gradient of Shh signaling activity and that boc function is necessary to maintain pMN progenitors by shaping the Shh signaling gradient.
Angiotensin-II Modulates GABAergic Neurotransmission in the Mouse Substantia Nigra

Abstract GABAergic projections neurons of the substantia nigra reticulata (SNr), through an extensive network of dendritic arbors and axon collaterals, provide robust inhibitory input to neighboring dopaminergic neurons in the substantia nigra compacta (SNc). Angiotensin-II (Ang-II) receptor signaling increases SNc dopaminergic neuronal sensitivity to insult, thus rendering these cells susceptible to dysfunction and destruction. However, the mechanisms by which Ang-II regulates SNc dopaminergic neuronal activity are unclear. Given the complex relationship between SN dopaminergic and GABAergic neurons, we hypothesized that Ang-II could regulate SNc dopaminergic neuronal activity directly and indirectly by modulating SNr GABAergic neurotransmission. Here, using transgenic mice, slice electrophysiology, and optogenetics, we provide evidence of an AT1 receptor-mediated signaling mechanism in SNr GABAergic neurons where Ang-II suppresses electrically-evoked neuronal output by facilitating postsynaptic GABAA receptors (GABAARs) and prolonging the action potential (AP) duration. Unexpectedly, Ang-II had no discernable effects on the electrical properties of SNc dopaminergic neurons. Also, and indicating a nonlinear relationship between electrical activity and neuronal output, following phasic photoactivation of SNr GABAergic neurons, Ang-II paradoxically enhanced the feedforward inhibitory input to SNc dopaminergic neurons. In sum, our observations describe an increasingly complex and heterogeneous response of the SN to Ang-II by revealing cell-specific responses and nonlinear effects on intranigral GABAergic neurotransmission. Our data further implicate the renin-angiotensin-system (RAS) as a functionally relevant neuromodulator in the substantia nigra, thus underscoring a need for additional inquiry.
Working Memory Representations in Visual Cortex Mediate the Effects of Distraction

Although the contents of working memory (WM) can be decoded from activity in visual cortex, these representations may play a limited role if they are not robust to distraction. Here, we used model-based fMRI to estimate the impact that a distracting visual task had on WM representations in several visual field maps in visual and frontoparietal association cortex. Distraction caused the fidelity of WM representations in all maps to briefly dip when both the memorandum and distractor were jointly encoded by the population activities. Moreover, distraction induced small biases in memory errors which were predicted by biases in neural decoding in early visual cortex, but not other regions. Although distraction briefly disrupts WM representations, the widespread redundancy with which WM information is encoded may protect against catastrophic loss. In early visual cortex, nonetheless, the neural representation of information in WM and behavioral performance were intertwined, solidifying its importance in memory.
Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

Development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are urgently needed to combat the coronavirus disease 2019 (COVID-19). Oxysterols, defined as oxidized derivatives of cholesterol, include endogenous (naturally occurring) cholesterol metabolites as well as semi-synthetic oxysterol derivatives. We have previously studied the use of semi-synthetic oxysterol derivatives as drug candidates for inhibition of cancer, fibrosis, and bone regeneration. In this study, we have screened a panel of naturally occurring and semi-synthetic oxysterol derivatives for anti-SARS-CoV-2 activity, using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy186 displayed antiviral activity comparable to natural oxysterols. In addition, related oxysterol analogues Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fall into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell culture infection assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 with disrupting the formation of double membrane vesicles (DMVs), intracellular membrane compartments associated with viral replication. Oxy210 also inhibited the replication of hepatitis C virus, another RNA virus whose replication is associated with DMVs, but not the replication of the DMV-independent hepatitis D virus. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk developing COVID-19.
Trial-by-trial modulation of express visuomotor responses induced by symbolic or barely detectable cues

Human cerebral cortex can produce visuomotor responses that are modulated by contextual and task-specific constraints. However, the distributed cortical network for visuomotor transformations limits the minimal response time of that pathway. Notably, humans can generate express visuomotor responses that are inflexibly tuned to the target location and occur 80-120ms from stimulus presentation (stimulus-locked responses, SLRs). This suggests a subcortical pathway for visuomotor transformations involving the superior colliculus and its downstream reticulo-spinal projections. Here we investigated whether cognitive expectations can modulate the SLR. In one experiment, we recorded surface EMG from shoulder muscles as participants reached toward a visual target whose location was unpredictable in control conditions, and partially predictable in cue conditions by extrapolating a symbolic cue (75% validity). Valid symbolic cues led to faster and larger SLRs than control conditions; invalid symbolic cues produced slower and smaller SLRs than control conditions. This is consistent with a cortical top-down modulation of the putative subcortical SLR-network. In a second experiment, we presented high-contrast targets in isolation (control) or ~24ms after low-contrast stimuli, which could appear at the same (valid cue) or opposite (invalid cue) location as the target, and with equal probability (50% cue validity). We observed faster SLRs than control with the valid low-contrast cues, whereas the invalid cues led to the opposite results. These findings may reflect exogenous priming mechanisms of the SLR network, potentially evolving subcortically via the superior colliculus. Overall, our results support both top-down and bottom-up modulations of the putative subcortical SLR network in humans. NEW & NOTEWORTHY Express visuomotor responses in humans appear to reflect subcortical sensorimotor transformation of visual inputs, potentially conveyed via the tecto-reticulo-spinal pathway. Here we show that the express responses are influenced both by symbolic and barely detectable spatial cues about stimulus location. The symbolic cue-induced effects suggest cortical top-down modulation of the putative subcortical visuomotor network. The effects of barely detectable cues may reflect exogenous priming mechanisms of the tecto-reticulo-spinal pathway.
Hybridization Dynamics and Extensive Introgression in the Daphnia longispina Species Complex: New Insights from a High-Quality Daphnia galeata Reference Genome

Hybridization and introgression are recognized as an important source of variation that influence adaptive processes; both phenomena are frequent in the genus Daphnia, a keystone zooplankton taxon in freshwater ecosystems that comprises several species complexes. To investigate genome-wide consequences of introgression between species, we provide here the first high-quality genome assembly for a member of the Daphnia longispina species complex, Daphnia galeata. We further re-sequenced 49 whole genomes of three species of the complex and their interspecific hybrids both from genotypes sampled in the water column and from single resting eggs extracted from sediment cores. Populations from habitats with diverse ecological conditions offered an opportunity to study the dynamics of hybridization linked to ecological changes and revealed a high prevalence of hybrids. Using phylogenetic and population genomic approaches, we provide first insights into the intra- and interspecific genome-wide variability in this species complex and identify regions of high divergence. Finally, we assess the length of ancestry tracts in hybrids to characterize introgression patterns across the genome. Our analyses uncover a complex history of hybridization and introgression reflecting multiple generations of hybridization and backcrossing in the Daphnia longispina species complex. Overall, this study and the new resources presented here pave the way for a better understanding of ancient and contemporary gene flow in the species complex and facilitate future studies on resting egg banks accumulating in lake sediment.
Enhanced immunogenicity of a synthetic DNA vaccine expressing consensus SARS-CoV-2 Spike protein using needle-free immunization

The ongoing global pandemic of Coronavirus Disease 2019 (COVID-19) calls for an urgent development of effective and safe prophylactic and therapeutic measures. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein is a major immunogenic and protective protein, and plays a crucial role in viral pathogenesis. In this study, we successfully constructed a synthetic codon-optimized DNA-based vaccine as a countermeasure against SARS-CoV-2; denoted as VIU-1005. The design was based on the synthesis of codon-optimized coding sequence for optimal mammalian expression of a consensus full-length S glycoprotein. The successful construction of the vaccine was confirmed by restriction digestion and sequencing, and the protein expression of the S protein was confirmed by western blot and immunofluorescence staining in mammalian cells. The immunogenicity of the vaccine was tested in two mouse models (BALB/c and C57BL/6J). Th1-skewed systemic S-specific IgG antibodies and neutralizing antibodies (nAbs) were significantly induced in both models four weeks post three injections with 100 μg of the VIU-1005 vaccine via intramuscular needle injection but not intradermal or subcutaneous routes. Importantly, such immunization induced long-lasting IgG response in mice that lasted for at least 6 months. Interestingly, using a needle-free system, we showed an enhanced immunogenicity of VIU-1005 in which lower doses such as 25-50 μg or less number of doses were able to elicit significantly high levels of Th1-biased systemic S-specific IgG antibodies and nAbs via intramuscular immunization compared to needle immunization. Compared to the intradermal needle injection which failed to induce any significant immune response, intradermal needle-free immunization elicited robust Th1-biased humoral response similar to that observed with intramuscular immunization. Furthermore, immunization with VIU-1005 induced potent S-specific cellular response as demonstrated by the significantly high levels of IFN-γ, TNF and IL-2 cytokines production in memory CD8+ and CD4+ T cells in BALB/c mice. Together, our results demonstrate that the synthetic VIU-1005 candidate DNA vaccine is highly immunogenic and capable of inducing long-lasting and Th1-skewed immune response in mice. Furthermore, we show that the use of needle-free system could enhance the immunogenicity and minimize doses needed to induce protective immunity in mice, supporting further preclinical and clinical testing of this candidate vaccine.
CSF metabolites associate with CSF tau and improve prediction of Alzheimer's disease status

INTRODUCTION Cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) are biomarkers of Alzheimer’s disease (AD), yet much is unknown about AD-associated changes in tau metabolism and tau tangle etiology. METHODS We assessed the variation of t-tau and p-tau explained by 38 previously identified CSF metabolites using linear regression models in middle-age controls from the Wisconsin Alzheimer’s Disease Research Center, and predicted AD/mild cognitive impairment (MCI) vs. an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO). RESULTS The 38 CSF metabolites explained 70.3% and 75.7% of the variance in t-tau and p-tau. Of these, 7 LASSO-selected metabolites improved the prediction ability of AD/MCI vs. older controls (AUC score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model. DISCUSSION These tau-correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.
Properties of flexible water models

We have studied the influence of flexibility on liquid water properties for two different potentials of intramolecular motion. Care has first been taken to explore thoroughly the simulation conditions to obtain reliable results free from artificial influences. Grafting an intramolecular potential on top of an originally rigid model introduces minor changes in the structure of the liquid at room temperatures. Dynamic properties are sensitive to the choice of intramolecular potential, but a general trend is that flexibility slows down the molecular motion. For flexible water the dynamic retardation is caused by the increase of the dipole moment, which increases the energetic coupling to the surrounding liquid, and by the intramolecular distortion, giving rise to a larger radius of gyration compared with the equilibrium monomer value. Experimental vibrational frequencies are not accurately reproduced with either the harmonic or anharmonic intramolecular potential studied. In contrast, for a nonpolar system o.
Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Alexander disease (AxD) is a devastating leukodystrophy caused by gain of function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report we introduce a new rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with approximately 15 % dying of unknown cause between 6 to 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long lasting suppression, reverses GFAP pathology, and depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. This is the first report of an animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease. We use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.