bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, December 27th, 2023
| Time |
Event |
| 4:42a |
Feeding-state dependent modulation of reciprocally interconnected inhibitory neurons biases sensorimotor decisions in Drosophila
The feeding state of an animal will change behavioral priorities and thus influences even non-feeding related decisions. How is the influence of the feeding state transmitted to non-feeding related circuits and what are the circuit mechanisms involved in biasing non-feeding related decisions remains an open question. By combining calcium imaging, neuronal manipulations, behavioral analysis, and computational modeling we determined that the competitive interactions between different behavioral responses to a mechanical stimulus are biased by the feeding state and found that this is achieved by differentially modulating two different types of reciprocally connected inhibitory neurons promoting opposing actions. The modulation of these inhibitory neurons influences the activity in the output layer of the network towards encoding more frequently an active type of response and less frequently a protective type of response in larvae fed on sugar compared to those fed on a balanced diet. The information about the internal state is conveyed to the inhibitory neurons through homologues of the vertebrate neuropeptide Y known to be involved in regulating feeding behavior. | | 4:42a |
Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke
Reactive neuroglia critically shape the brain's response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition and microenvironment of the early ischemic lesion. Here we generated a single cell resolution transcriptomics dataset of the injured brain during the acute recovery from permanent middle cerebral artery occlusion. This approach unveiled infarction and subtype specific molecular signatures in oligodendrocyte lineage cells and astrocytes, which ranged among the most transcriptionally perturbed cell types in our dataset. Specifically, we characterized and compared infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and heterogeneous reactive astrocyte populations. Our analyses unveiled unexpected commonalities in the transcriptional response of oligodendrocyte lineage cells and astrocytes to ischemic injury. Moreover, OPCs and reactive astrocytes were involved in a shared immuno-glial cross talk with stroke specific myeloid cells. In situ, osteopontin positive myeloid cells accumulated in close proximity to proliferating OPCs and reactive astrocytes, which expressed the osteopontin receptor CD44, within the perilesional zone specifically. In vitro, osteopontin increased the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition and microenvironment of infarcted brain tissue in the early stages of recovery. | | 5:41a |
Machine Learning Based Modelling of Human and Insect Olfaction Screens Millions of compounds to Identify Pleasant Smelling Insect Repellents
The rational discovery of behaviorally active odorants is impeded by a lack of understanding on how the olfactory system generates percept or valence for a volatile chemical. In previous studies we showed that chemical informatics could be used to model prediction of ligands for a large repertoire of odorant receptors in Drosophila (Boyle et al., 2013). However, it remained difficult to predict behavioral valence of volatiles since the activities of a large ensembles of odor receptors encode odor information, and little is known of the complex information processing circuitry. This is a systems-level challenge well-suited for Machine-learning approaches which we have used to model olfaction in two organisms with completely unrelated olfactory receptor proteins: humans (~400 GPCRs) and insects (~100 ion-channels). We use chemical structure-based Machine Learning models for prediction of valence in insects and for 146 human odor characters. Using these predictive models, we evaluate a vast chemical space of >10 million compounds in silico. Validations of human and insect behaviors yield very high success rates. The discovery of desirable fragrances for humans that are highly repulsive to insects offers a powerful integrated approach to discover new insect repellents. | | 8:17a |
Identification, Characterization, and Mitigation of a Simultaneous Multi-Slice fMRI Signal Artifact: Multiband Artifact Regression in Simultaneous Slices (MARSS)
Simultaneous multi-slice (multiband) acceleration in fMRI has become widespread, but may be affected by novel forms of signal artifact. Here, we demonstrate a previously unreported artifact manifesting as a shared signal between simultaneously acquired slices in all resting-state and task-based multiband fMRI datasets we investigated, including publicly available consortium data. We propose Multiband Artifact Regression in Simultaneous Slices (MARSS), a regression-based detection and correction technique that successfully mitigates this shared signal in unprocessed data. We demonstrate that the signal isolated by MARSS correction is likely non-neural, appearing stronger in neurovasculature than grey matter. We show that MARSS correction leads to study-wide increases in signal-to-noise ratio, decreases in cortical coefficient of variation, and mitigation of systematic artefactual spatial patterns in participant-level task betas. Finally, we demonstrate that MARSS correction has substantive effects on second-level t-statistics in analyses of task-evoked activation. We recommend that investigators apply MARSS to all multiband fMRI datasets. | | 8:17a |
Naturalistic Movies and Encoding Analysis Redefine Areal Borders in Primate Visual Cortex
Accurate definition of the borders of cortical visual areas is essential for the study of neuronal processes leading to perception. However, data used for definition of areal boundaries has suffered from issues related to resolution, uniform coverage, or suitability for objective analysis, leading to ambiguity. Here, we present a novel approach that combines widefield optical imaging, presentation of naturalistic movies, and encoding model analysis, to objectively define borders in the primate extrastriate cortex. We applied this method to test conflicting hypotheses about the third-tier visual cortex, where areal boundaries have remained controversial. The results support a hypothesis whereby an area contains representations of both the upper and lower contralateral quadrants (DM) is located immediate anterior to V2, and unveil pronounced tuning preferences in the third-tier areas. High-density electrophysiological recordings with a Neuropixels probe confirm these findings. Our encoding-model approach offers a powerful, objective way to disambiguate areal boundaries. | | 8:17a |
Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer's disease in females
Nearly two-thirds of patients with Alzheimer's are women. Identifying therapeutics specific for women is critical to lowering their elevated risk for developing this major cause of adult dementia. Moreover, targeting epigenetic processes that regulate multiple cellular pathways is advantageous given Alzheimer's multifactorial nature. Histone acetylation is an epigenetic process heavily involved in memory consolidation. Its disruption is linked to Alzheimer's. Through our computational studies, we predicted that RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) has repurposing potential for Alzheimer's. RG2833 is a histone deacetylase HDAC1/3 inhibitor, that is FDA-approved, orally bioavailable, and permeates the blood-brain-barrier. We investigated the RG2833 therapeutic potential in TgF344-AD rats, which are a model of Alzheimer's that exhibits age-dependent progression, thus mimicking this aspect of Alzheimer's patients that is difficult to establish in animal models. We investigated the RG2833 effects on cognitive performance, gene expression, and AD-like pathology in 11-month TgF344-AD female and male rats. A total of 89 rats were used: wild type n = 45 (17 females, 28 males), and TgF344-AD n = 44 (24 females, 20 males) across multiple cohorts. No obvious toxicity was detected in the TgF344-AD rats up to 6 months of RG2833-treatment starting at 5 months of age administering the drug in rodent chow at ~30mg/kg of body weight. We started treatment early in the course of pathology when therapeutic intervention is predicted to be more effective than in later stages of the disease. The drug-treatment significantly mitigated hippocampal-dependent spatial memory deficits in 11-month TgF344-AD females but not in males, compared to wild type littermates. This female sex-specific drug effect has not been previously reported. RG2833-treatment failed to ameliorate amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. However, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug-treatment in females upregulated the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at P < 0.05, false discovery rate < 0.05, and fold-change [≥] 1.5. Our data suggest that histone modifying therapeutics such as RG2833 improve cognitive behavior by modulating the expression of immediate early, neuroprotective and synaptic plasticity genes. Our preclinical study supports that RG2833 has therapeutic potential specifically for female Alzheimer's patients. RG2833 evaluations using other AD-related models is necessary to confirm our findings. | | 9:30a |
Neural entrainment to both target and distracting speech causally contributes to speech perception in a multi-speaker scenario
Segregating important stimuli from distractors is crucial for successful speech perception. Neural activity aligned to speech, also termed neural entrainment, is thought to be instrumental for this purpose. However, the relative contribution of neural entrainment to target and distractors in speech perception remained unclear. In this study, we used transcranial alternating current stimulation (tACS) to manipulate entrainment to two simultaneously presented sequences of rhythmic speech while participants attended to one of them. A random temporal relationship between speech streams allowed us to disentangle effects of tACS on target and distractor processing, and to examine their combined effect on a behavioural measure of speech perception. We found that the phase relation between tACS and both target and distracting speech modulated word report accuracy, and to a similar degree. The phasic modulation of target processing correlated with that of the distractor across subjects, and their combined effect on speech perception was stronger than each of the two alone. In contrast to our expectation, the tACS phases leading to most accurate perception were uncorrelated between target and distracting speech modulations. Together, our results suggest that entrainment to target and distracting speech jointly and causally contributes to speech perception. They also demonstrate how effect sizes might be increased in future work and for technological or clinical applications. | | 3:20p |
Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism
Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further disrupts sleep in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation in 16p11.2 deletion mice. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings reveal that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD. | | 4:30p |
Impaired activation of the prefrontal executive network during working memory processing in multiple sclerosis
AbstractIn multiple sclerosis (MS), working memory (WM) impairment occurs soon after disease onset and significantly affects the patients quality of life. Functional imaging research in MS aims to investigate the neurophysiological underpinnings of WM impairment. In this context, we utilized a data-driven technique, the time delay embedded- hidden Markov model (TDE-HMM), to extract spectrally defined functional networks in magnetoencephalographic (MEG) data acquired during a WM visual-verbal n-back task. We observed that two networks show an altered activation in RR-MS patients. First, the activation of an early theta prefrontal network linked to stimulus encoding and attentional control significantly decreased in RR-MS compared to HC. This diminished activation correlated with reduced accuracy in task performance in the MS group, suggesting an impaired encoding and learning process. Secondly, a frontoparietal network characterized by beta coupling is activated between 300 and 600 ms after stimulus onset; this resembles the characteristic event-related P300, a cognitive marker extensively explored in EEG studies. The activation of this network is amplified in patients treated with benzodiazepine, in line with the well-known benzodiazepine-induced beta enhancement. Altogether, the TDE-HMM technique extracted task-relevant functional networks showing disease-specific and treatment- related alterations, revealing potential new markers to assess and track WM impairment in MS.
HighlightsO_LIWe decomposed the brain dynamics underlying a WM n-back task in data-driven, spectrally defined whole-brain networks in both healthy controls and people with relapsing-remitting-MS (pwMS).
C_LIO_LIPwMS showed a significantly decreased activation of an early theta prefrontal network linked to stimulus encoding and attentional control.
C_LIO_LIThe weaker activation of this prefrontal theta network is correlated with worse task performance.
C_LIO_LIA beta frontoparietal network with a P300-like temporal evolution was significantly modulated by the use of benzodiazepines.
C_LIO_LIThe model distinguished disease-induced and treatment-induced dynamic network alterations.
C_LI |
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