bioRxiv Subject Collection: Neuroscience's Journal

The cortical heartbeat-evoked potential is modulated by heart rate in a task and mental effort dependent manner
Periods of slow heart rate are associated with increased sensory sensitivity. Accordingly, cardiac deceleration occurs when individuals orient their attention in anticipation of a sensory stimulus they might have to respond to (attentive anticipation). Cardiac deceleration might be important to optimize sensory processing. However, it is unclear which mechanism connects heart rate with the neuronal processing of external stimuli. In this study, we investigated if cardiac deceleration evoked by attentive anticipation as well as ongoing fluctuations in heart rate were associated with changes in the heartbeat-evoked potential (HEP), a cortical response evoked by the heartbeat which amplitude modulations are associated with sensory sensitivity. We studied these phenomena in young and older people [N = 33 (26 women) and 29 (23 women); mean age 23 and 61 years], using a previously described dataset including electroencephalograms (EEG), electrocardiograms (ECG), and pupilograms which were acquired during an auditory cued simple reaction time task, an auditory cued go/no-go task, and a passive task condition. While the period of attentive anticipation between the cue and the target characterized by cardiac deceleration was not related with significant changes in the HEP, ongoing heart rate fluctuations affected HEP amplitude. Interestingly, the effect of heart rate on the HEP increased with task difficulty and was associated with the amplitude of task-related pupil responses suggesting a link with mental effort. Thus, the impact of ongoing heart rate fluctuations on the HEP depends on cognitive state and this effect might link heart rate with the neural processing of external stimuli.

mTORC1 ACTIVATION IN PRESUMED CLASSICAL MONOCYTES:OBSERVED CORRELATES WITH HUMAN SIZE VARIATION AND NEUROPSYCHIATRIC DISEASE
Background: Gain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. Methods: Twenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response. Results: mTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance. Conclusions: The data illustrates the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response.

Hypothalamic dopamine neuron activity is modulated by caloric states and amphetamine abuse in zebrafish larvae
Dopaminergic (DA) neuron activity is affected by reward and stress-inducing entities such as food and drugs of abuse, and different DA neuron populations can respond distinctly to these stimuli. Interaction between both stimuli significantly alters the dynamics of DA release in different DA populations. Additionally, these stimulating entities can affect the interconnections among different DA populations by impairing their correspondence with each other. However, limited studies have been performed that could point to the effect of interaction between AMPH and caloric states on DA neurons and their inter-correlation. This study explores the individual and interactive effect of two caloric states, ad-libitum fed (AL) and food deprived (FD), and acute exposure to a stimulant drug (amphetamine) in two different DA neurons in the hypothalamus of zebrafish larvae. We used a transgenic zebrafish line Tg(th2:GCaMP7s), which expresses a calcium indicator (GCaMP7s) in A11(Posterior Tuberculum) and a part of A14 (Caudal Hypothalamus and Intermediate Hypothalamus) DA populations located in the hypothalamus of the larval zebrafish. The larvae were subjected to acute FD and ad AL feeding followed by acute treatment with 0.7uM and 1.5uM doses of AMPH. We recorded calcium activity and quantified fluorescence change, activity duration, peak rise/fall time, and latency in the spikes of the DA neurons. Our results show that baseline DA neuron activity amplitude, spike duration, and correlation between inter- and intra-DA neurons were higher in the FD than in the AL state. Dose-dependent AMPH treatment further increased the activity intensity of the aforementioned parameters in the neuron spikes in the FD state. The DA activity correlation and spike latency were dose-dependently impaired in both DA populations. These results suggest that different DA populations in the brain exhibit a similar activity trend in response to caloric states and AMPH, where the AMPH-mediated intensity change in the activity was dose-dependent.

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1a/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1 is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.

Single-Cell Peripheral Immunoprofiling of Lewy Body Disease in a Multi-site Cohort
Studies implicated peripheral organs involvement in the development of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinsons Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). This study characterized peripheral immune responses unique to LBD at single-cell resolution. Peripheral mononuclear cell (PBMC) samples were collected from sites across the U.S. The diagnosis groups comprise healthy controls (HC, n=164), LBD (n=132), Alzheimers disease dementia (ADD, n=98), other neurodegenerative disease controls (NDC, n=21), and immune disease controls (IDC, n=14). PBMCs were activated with three stimulants, stained by surface and intracellular signal markers, and analyzed by flow cytometry, generating 1,184 immune features. Our model classified LBD from HC with an AUROC of 0.90. The same model distinguished LBD from ADD, NDC, IDC, or other common conditions associated with LBD. Model predictions were driven by pPLC{gamma}2, p38, and pSTAT5 signals from specific cell populations and activations.

Histological comparison of repeated mild weight drop and lateral fluid percussion injury models of traumatic brain injury (TBI) in female and male rats.
Traumatic brain injury (TBI) heterogeneity has led to the development of several preclinical models, each modeling a distinct subset of outcomes. Selection of an injury model should be guided by the research question and the specific outcome measures of interest. Consequently, there is a need for conducting direct comparisons of different TBI models. Here, we used immunohistochemistry to directly compare the outcomes from two common models, lateral fluid percussion (LFP) and repeat mild weight drop (rmWD), on neuropathology in adult female and male Wistar rats. Specifically, we used immunohistochemistry to measure the effects of LFP and rmWD on cerebrovascular and tight junction disruption, inflammatory markers, mature neurons and perineuronal nets in the cortical site of injury, cortex adjacent to injury, dentate gyrus, and the CA2/3 area of the hippocampus. Animals were randomized into either LFP or rmWD groups. The LFP group received a craniotomy prior to LFP (or corresponding sham procedure) three days later, while rmWD animals underwent either weight drop or sham (isoflurane only) on each of those four days. After a recovery period of 7 days, animals were euthanized, and brains were harvested for analysis of RECA-1, claudin-5, GFAP, Iba-1, CD-68, NeuN, and wisteria floribunda lectin. Overall, our observations revealed that the most significant disruptions were evident in response to LFP, followed by craniotomy-only, while rmWD animals showed the least residual changes compared to isoflurane-only controls. These findings support consideration of rmWD as a mild, transient injury. LFP leads to longer-lasting disruptions that are more closely associated with a moderate TBI. We further show that both craniotomy and LFP produced greater disruptions in females relative to males at 7 days post-injury. These findings support the inclusion of a time-matched experimentally-naive or anesthesia-only control group in preclinical TBI research to enhance the validity of data interpretation and conclusions.

Open-Source Platform for Kinematic Analysis of Mouse Forelimb Movement
We present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. The protocol describes how to assemble the box, train mice to perform the task and process the video with the custom software pipeline to analyze forepaw kinematics. All the schematics, 3D models, code and assembly instructions are provided in the open GitHub repository.

Model mimicry limits conclusions about neural tuning and can mistakenly imply unlikely priors
In a recent issue of Nature Communications, Harrison, Bays, and Rideaux use electroencephalography (EEG) to infer population tuning properties from human visual cortex, and deliver a major update to existing knowledge about the most elemental building block of visual perception: orientation tuning. Using EEG together with simulations in an approach they refer to as 'generative forward modeling', the authors adjudicate between two competing population tuning schemes for orientation tuning in visual cortex. They claim that a redistribution of orientation tuning curves can explain their observed pattern of EEG results, and that this tuning scheme embeds a prior of natural image statistics that exhibits a previously undiscovered anisotropy between vertical and horizontal orientations. If correct, this approach could become widely used to find unique neural coding solutions to population response data (e.g., from EEG) and to yield a 'true' population tuning scheme deemed generalizable to other instances. However, here we identify major flaws that invalidate the promise of this approach, which we argue should not be used at all. First, we will examine the premise of Harrison and colleagues, to subsequently explain why 'generative forward modeling' cannot circumvent model mimicry pitfalls and can deliver many possible solutions of unknowable correctness. Finally, we show a tentative alternative explanation for the data.

The role of hidden hearing loss in tinnitus: insights from early markers of peripheral hearing damage
Since the presence of tinnitus is not always associated with audiometric hearing loss, it has been hypothesized that hidden hearing loss may act as a potential trigger for increased central gain along the neural pathway leading to tinnitus perception. In recent years, the study of hidden hearing loss has improved with the discovery of cochlear synaptopathy and several objective diagnostic markers. This study investigated three potential markers of peripheral hidden hearing loss in subjects with tinnitus: extended high-frequency audiometric thresholds, the auditory brainstem response, and the envelope following response. In addition, speech intelligibility was measured as a functional outcome measurement of hidden hearing loss. To account for age-related hidden hearing loss, participants were grouped according to age, presence of tinnitus, and audiometric thresholds. Group comparisons were conducted to differentiate between age- and tinnitus-related effects of hidden hearing loss. All three markers revealed age-related differences, whereas no differences were observed between the tinnitus and non-tinnitus groups. However, the older tinnitus group showed improved performance on low-pass filtered speech in noise tests compared to the older non-tinnitus group. These low-pass speech in noise scores were significantly correlated with tinnitus distress, as indicated using questionnaires, and could be related to the presence of hyperacusis. Based on our observations, cochlear synaptopathy does not appear to be the underlying cause of tinnitus. The improvement in low-pass speech-in-noise could be explained by enhanced temporal fine structure encoding or hyperacusis. Therefore, we recommend that future tinnitus research takes into account age-related factors, explores low-frequency encoding, and thoroughly assesses hyperacusis.

The Switchmaze: an open-design device for measuring motivation and drive switching in mice
Animals need to switch between motivated behaviours, like drinking, feeding or social interaction, to meet environmental availability, internal needs and more complex ethological needs such as hiding future actions from competitors. Inflexible, repetitive behaviours are a hallmark of many neuropsychiatric disorders. However, how the brain orchestrates switching between the neural mechanisms controlling motivated behaviours, or drives, is unknown. This is partly due to a lack appropriate measurement systems. We designed an automated extended home-cage, the Switchmaze, using open source hardware and software. In this study, we use it to establish a behavioural assay of motivational switching, measured as the ratio of single probe entries to continuous exploitation runs. Behavioural transition analysis is used to further dissect altered motivational switching. As proof-of-concept, we show environmental manipulation, and targeted brain manipulation experiments which altered motivational switching without effect on traditional behavioural parameters. Chemogenetic inhibition of the prefrontal-hypothalamic axis increased the rate of motivation switching, highlighting the involvement of this pathway in drive switching. This work demonstrates the utility of open-design in understanding animal behaviour and its neural correlates.

Negative relationship between inter-regional interaction and regional power: a resting fMRI study
Background: Regional neural response and network property used to be treated separately. However, evidence has suggested an intimate relationship between the regional and inter-regional profiles. This research aimed to investigate the influence of functional connectivity on regional spontaneous activity. Methods: Thirty-six and sixty datasets of structural magnetic resonance imaging (sMRI) and resting state functional MRI (rsfMRI) were selected from the NKI and CAN-BIND database, respectively. The cerebral cortex in rsfMRI was parcellated by MOSI (modular analysis and similarity measurements), which enables multi-resolution exploration. For each parcellated cluster, the mean amplitude of low-frequency fluctuation (ALFF) and its average functional connectivity strength with the remaining cortical analogs were computed. Correlation analyses were exploited to examine their relationship. Supplementary analysis was applied to CAN-BIND EEG data (1 to 30 Hz). Results: Negative correlation coefficients between inter-regional interaction and regional power were noticed in both MRI datasets. One-sample t-tests revealed robust statistics across different analytic resolutions yielded by MOSI, with individual P values at the level 10^-4 to 10^-5. The results suggested that the more intense crosstalk a neural node is embedded in, the less regional power it manifests, and vice versa. The negative relationship was replicated in EEG analysis but limited to delta (1 to 4 Hz) and theta (4 to 8 Hz) frequencies. Conclusions: We postulate that inhibitory coupling is the mechanism that bridges the local and inter-regional properties, which is more prominent in the lower spectra. The interpretation warrants particular caution since noise may also contribute to the observation.

Dynamic formation of a posterior-to-anterior peak-alpha-frequency gradient driven by two distinct processes
Peak-alpha frequency varies across individuals and mental states, but it also forms a negative gradient from posterior to anterior regions in association with increases in cortical thickness and connectivity reflecting the cortical hierarchy in temporal integration. Tracking the spatial standard deviation of peak-alpha frequency in scalp EEG, we observed that the posterior-to-anterior gradient dynamically formed and dissolved. Periods of high spatial standard deviation yielded robustly negative posterior-to-anterior gradients (the gradient state) while periods of low spatial standard deviation yielded globally converged peak-alpha frequency (the uniform state). Our analyses suggest that the fluctuations between the gradient and uniform states are associated with two separate variables: (1) coordinated variations in peak-alpha frequency in anterior regions and (2) coordinated variations in peak-alpha power in central regions driven by posterior regions. These variables each accounted for ~25% of the state fluctuations, were uncorrelated with each other, and together accounted for ~50% of the state fluctuations. These results reflect general mechanisms as they replicated while participants engaged in a variety of behavioral tasks with their eyes closed (breath focus, vigilance, working memory, mental arithmetic, and generative thinking). Overall, our results suggest that the spatial pattern of peak-alpha frequency dynamically fluctuates between the gradient state, potentially facilitating information influx and temporal integration toward anterior regions, and the uniform state, potentially facilitating global communication, with the state fluctuations controlled by at least two distinct mechanisms, an anterior mechanism that directly adjusts peak-alpha frequencies and a posterior mechanism that indirectly adjusts them by influencing synchronization.

Label-free and reference region-free X-ray cross-beta index for quantifying protein aggregates of neurodegenerative diseases
Background and objectives: Recent advancements in therapies targeting various protein aggregates, ranging from oligomers to fibrils, in neurodegenerative diseases exhibit considerable promise. This underscores the imperative for robust quantitative methods capable of accurately detecting and quantifying these biomarker aggregates across different structural states, even when present in sparse quantities during the early stages of the disease continuum. In response to this exigency, we propose and assess an X-ray-based quantitative metric designed for the global and region-specific detection and quantification of oligomers and fibrils within tissues. This methodology proves applicable to a broad spectrum of neurodegenerative diseases, including Alzheimer's and Parkinson's. Notably, unlike positron emission tomography (PET)-based biomarker quantification methods, our approach obviates the need for a contrast agent or a reference region. Methods: We assessed the proposed metric, termed X-ray cross-beta aggregate index (XbetaAI), in a sheep brain model and brain tissue phantoms, incorporating synthetic oligomers and fibrils characterized against amyloid beta-42 and alpha-synuclein aggregates. Detection of these biomarkers utilized laboratory-based monochromatic, and polychromatic X-ray sources, specifically targeting the cross-beta substructure of protein aggregates. We employed a peak-location, knowledge-based material decomposition approach to extract target signals from the complex X-ray scattering spectrum originating from a mixture of tissue, water, and aggregate signals. Results: Clinically relevant quantities of oligomers and fibrils were detected in tissues from different brain regions using the laboratory-based X-ray scattering method, without the need for a contrast agent. The signals from protein aggregates were successfully recovered from composite X-ray scattering spectra through material decomposition, eliminating the need for a reference region. The area under the peak of the decomposed inter-{beta} strand signal correlated well with aggregate burden in synthetically diseased brain tissues. The X-ray cross-{beta} aggregate index (X{beta}AI) accurately quantified aggregate burden in heterogeneous tissues across various brain regions and effectively tracked the deposition increments in specific tissue regions. Conclusion: Our study introduces a novel metric, for both regional and global quantification of protein aggregates linked to various protein misfolding diseases, including synucleinopathies.

AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2-targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.

Aging is associated with a modality-specific decline in taste
Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer's Disease (AD). In many cases, chemosensory deficits are harbingers of neurodegenerative disease, and understanding the mechanistic basis for these changes may provide insight into the fundamental dysfunction associated with aging and neurodegeneration. The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on chemosensation remain largely unexplored in this model, particularly with respect to taste. To determine whether the effects of aging on taste are conserved in flies, we compared the response of flies to different appetitive tastants. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons, revealing modality-specific deficits in taste. Selective expression of the human amyloid beta (A{beta}) 1-42 peptide bearing the Arctic mutation (E693E) associated with early onset AD in the neurons that sense sugars and fatty acids phenocopies the effects of aging, suggesting that the age-related decline in response is localized to gustatory neurons. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies, suggesting that reduced sucrose response does not derive from neurodegeneration. Conversely, expression of the amyloid peptide in sweet-sensing taste neurons resulted in reduced innervation of the primary fly taste center. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes, including a reduction in odorant-binding protein class genes that are also expressed in taste sensilla. Together, these findings suggest that deficits in taste detection may result from signaling pathway-specific changes, while different mechanisms underly taste deficits in aged and AD model flies. Overall, this work provides a model to examine cellular deficits in neural function associated with aging and AD.

Individualized functional connectivity markers associated with motor and mood symptoms of Parkinson's disease
Parkinson's disease (PD) is a complex neurological disorder characterized by many motor and non-motor symptoms. While most studies focus on the motor symptoms of the disease, it is important to identify markers that underlie different facets of the disease. In this case-control study, we sought to discover reliable, individualized functional connectivity markers associated with both motor and mood symptoms of PD. Using functional MRI, we extensively sampled 166 patients with PD (64 women, 102 men; mean age=61.8 years, SD=7.81) and 51 healthy control participants (32 women, 19 men; mean age=55.68 years, SD=7.62). We found that a model consisting of 44 functional connections predicted both motor (UPDRS-III: Pearson r=0.21, FDR-adjusted p=0.006) and mood symptoms (HAMD: Pearson r=0.23, FDR-adjusted p=0.006; HAMA: Pearson r=0.21, FDR-adjusted p=0.006). Two sets of connections contributed differentially to these predictions. Between-network connections, mainly connecting the sensorimotor and visual large-scale functional networks, substantially contributed to the prediction of motor measures, while within-network connections in the insula and sensorimotor network contributed more so to mood prediction. The middle to posterior insula region played a particularly important role in predicting depression and anxiety scores. We successfully replicated and generalized our findings in two independent PD datasets. Taken together, our findings indicate that sensorimotor and visual network markers are indicative of PD brain pathology, and that distinct subsets of markers are associated with motor and mood symptoms of PD.

Older individuals do not show task specific variations in EEG band power and finger force coordination
Abstract Background: Controlling and coordinating finger force is crucial for performing everyday tasks and maintaining functional independence. Aging naturally weakens neural, muscular, and musculoskeletal systems, leading to compromised hand motor function. This decline reduces cortical activity, finger force control and coordination in older adults. Objective: To examine the relationship between EEG band power and finger force coordination in older individuals and compare the results with young adults. Methods: Twenty healthy young adults aged 20 to 30 (mean:26.96, Std:2.68) and fourteen older adults aged 58 to 72 (mean:62.57, Std:3.58) participated in this study. Participants held the instrumented handle gently for five seconds then lifted and held it for an additional five seconds in the two conditions: fixed (thumb platform secured) and free condition (thumb platform may slide on slider). Results: In the older individuals there was no difference observed in the finger force synergy indices, and EEG beta band power between the two task conditions. However, in the young group synergy indices and EEG beta band power were less in free condition compared to fixed condition. Additionally, in the fixed condition, older adults showed a reduced synergy indices and reduced EEG beta band power than the young adults. Conclusion: Older participants showed consistent synergy indices and beta band power across conditions, unlike young adults who adjusted strategies based on tasks. Young adults exhibited task-dependent finger force synergy indices contrasting with older individuals. These results suggest that the EEG beta band power may serve as a marker for finger force coordination rather than indicating the magnitude of force.

ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3'UTR Length
UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.

A multiple Arc (mArc) tagging system to uncover the organizational principles of multiple memories
Engrams or memory traces are the neuronal ensembles that collectively store individual experiences. Genetic strategies based on immediate early genes (IEGs), such as Arc/Arg3.1, allow us to tag the ensembles active during memory encoding and compare them to those active during retrieval. However, these strategies only allow for the tagging of one neural ensemble. Here, we developed a multiple Arc (mArc) system that allows for the tagging of two Arc+ ensembles. We validated this system by investigating how context, time, and valence influence neuronal ensemble reactivation in the dentate gyrus (DG). We show that similar contextual and valenced experiences are encoded in overlapping DG ensembles. We also find that ensembles are modulated by time, where experiences closer in time are encoded in more similar ensembles. These results highlight the dynamic nature of DG ensembles and show that the mArc system provides a powerful approach for investigating multiple memories in the brain.

A systematic analysis of the joint effects of ganglion cells, lagged LGN cells, and intercortical inhibition on spatiotemporal processing and direction selectivity
Simple cells in the visual cortex process spatial as well as temporal information of the visual stream and enable the perception of motion information. Previous work suggests that the direction selectivity of V1 simple cells is associated with a temporal offset in the thalamocortical input stream through lagged and non-lagged cells of the lateral geniculate nucleus (LGN), but also with intercortical inhibition. While there exists a large corpus of models for spatiotemporal receptive fields, the majority of them built-in the spatiotemporal dynamics by utilizing a combination of spatial and temporal functions and thus, do not explain the emergence of spatiotemporal dynamics on basis of network dynamics emerging in the retina and the LGN. In order to better comprehend the emergence of spatiotemporal processing and direction selectivity, we used a spiking neural network to implement the visual pathway from the retina to the primary visual cortex. By varying different functional parts in our network, we demonstrate how the direction selectivity of simple cells emerges through the interplay between two components: tuned intercortical inhibition and a temporal offset in the feedforward path through lagged LGN cells. Further, we observe that direction-selective simple cells are linked to a particular spiking pattern in a local excitatory-inhibitory circuit: If the stimulus moves in the non-preferred direction of a simple cell, inhibitory neurons with a different spatial position or tuning spike earlier, preventing the simple cell to spike. However, in the preferred direction, these inhibitory cells spike later, enabling the simple cell to spike.

Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain.
The brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.

Serotonin drives aggression and social behaviours of laboratory mice in a semi-natural environment
Aggression is an adaptive social behaviour crucial for the stability and prosperity of social groups. When uncontrolled, aggression leads to pathological violence that disrupts group structure and individual well-being. The comorbidity of uncontrolled aggression across different psychopathologies makes it a potential endophenotype of mental disorders with the same neurobiological substrates. Serotonin plays a critical role in the regulation of impulsive and aggressive behaviours, and mice lacking brain serotonin, due to the ablation of a rate-limiting enzyme of serotonin synthesis (Tryptophan hydroxylase 2, TPH2), are a potential model of pathological aggression. Home cage monitoring allows for the continuous observation and quantification of social and non-social behaviours in group-housed, freely-moving mice. Using an ethological approach, we investigated the impact of central serotonin ablation on everyday expression of social and non-social behaviours and their correlations in undisturbed, group-living Tph2-deficient and wildtype mice. By training a machine learning algorithm on behavioural time series, allogrooming, struggling at feeder and eating emerged as key behaviours dissociating one genotype from the other. Although Tph2-deficient mice showed characteristics of pathological aggression and decreased communication compared to wildtype animals, they still showed affiliative behaviours to normal levels. Altogether, such distinct and dynamic phenotype of Tph2-deficient mice influenced the group's structure and the dynamic of its hierarchical organization, which emerged later. These aspects were analysed using social network analysis and the Glicko rating methods. This study demonstrates the importance of the ethological approach for understanding the global impact of pathological aggression on different aspects of life, both at the individual and the group level. Home cage monitoring allows the observation of the natural behaviours of the mice in a semi-natural habitat and provides an accurate representation of real-world phenomena and pathological mechanisms. The results of this study provide insights into the neurobiological substrate of pathological aggression and their potential role in complex brain disorders.

Independent regulation of early trafficking of NMDA receptors by ligand-binding domains of the GluN1 and GluN2A subunits
The essential role of N-methyl-D-aspartate receptors (NMDARs) in excitatory neurotransmission is underscored by numerous pathogenic variants in the GluN subunits, including those identified in their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs; however, whether it controls the structure of LBDs or the functionality of NMDARs is unknown. Using alanine substitutions combined with microscopy and electrophysiology, we found that surface expression of GluN1/GluN2A receptors, the primary NMDAR subtype in the adult forebrain, strongly correlates with EC50 values for glycine and Lglutamate. Interestingly, co-expression of both GluN1 and GluN2A subunits with alanine substitutions led to an additive reduction in the surface number of GluN1/GluN2A receptors, as did co-expression of both GluN1 and GluN2A subunits containing closed cleft conformation of LBDs. The synchronized ER release confirmed the altered regulation of early trafficking of GluN1/GluN2A receptors bearing alanine substitutions in the LBDs. Furthermore, the human versions of GluN1/GluN2A receptors containing pathogenic GluN1-S688Y, GluN1-S688P, GluN1-D732E, GluN2A-S511L, and GluN2A-T690M variants exhibited distinct surface expression compared to the corresponding alanine substitutions. Mutant cycles of GluN1-S688, GluN1-D732, GluN2A-S511, and GluN2A-T690 residues revealed, in most cases, a weak correlation between surface expression of the mutant GluN1/GluN2A receptors and their EC50 values for glycine or L-glutamate. Consistent with our experimental data, molecular modeling and dynamics showed that the ER quality control machinery likely perceives structural changes of the LBDs but not the functionality of GluN1/GluN2A receptors.

A spatial model of autophosphorylation of CaMKII in a glutamatergic spine suggests a network-driven kinetic mechanism for bistable changes in synaptic strength.
Activation of N-methyl-D-aspartate-type glutamate receptors (NMDARs) at synapses in the CNS triggers changes in synaptic strength that underlie memory formation in response to strong synaptic stimuli. The primary target of Ca2+ flowing through NMDARs is Ca2+/calmodulin dependent protein kinase II (CaMKII) which forms dodecameric holoenzymes that are highly concentrated at the postsynaptic site. Activation of CaMKII is necessary to trigger long-term potentiation of synaptic strength (LTP), and is prolonged by autophosphorylation of subunits within the holoenzyme. Here we use MCell4, an agent-based, stochastic, modeling platform to model CaMKII holoenzymes placed within a realistic spine geometry. We show how two mechanisms of regulation of CaMKII, 'Ca2+-calmodulin-trapping (CaM-trapping)' and dephosphorylation by protein phosphatase-1 (PP1) shape the autophosphorylation response during a repeated high-frequency stimulus. Our simulation results suggest that autophosphorylation of CaMKII does not constitute a bistable switch. Instead, prolonged but temporary, autophosphorylation of CaMKII may contribute to a biochemical-network-based 'kinetic proof-reading' mechanism that controls the induction of synaptic plasticity.

Hexagons all the way down: Grid cells as a conformal isometric map of space
The brain's ability to navigate is often attributed to spatial cells in the hippocampus and entorhinal cortex. Grid cells, found in the entorhinal cortex, are known for their hexagonal spatial activity patterns and are traditionally believed to be the neural basis for path integration. However, recent studies have cast grid cells as a distance-preserving representation. We further investigate this role in a model of grid cells based on a superposition of plane waves. In a module of such grid cells, we optimise their phases to form a conformal isometry (CI) of two-dimensional flat space. With this setup, we demonstrate that a module of at least seven grid cells can achieve a CI, with phases forming a regular hexagonal arrangement. This pattern persists when increasing the number of cells, significantly diverging from a random uniform distribution. In particular, when optimised for CI, the phase distribution becomes distinctly regular and hexagonal, offering a clear experimentally testable prediction. Moreover, grid modules encoding a CI maintain constant energy expenditure across space, providing a new perspective on the role of energy constraints in normative models of grid cells. Finally, we investigate the minimum number of grid cells required for various spatial encoding tasks, including a unique representation of space, the population activity forming a torus, and achieving a CI, where we find that all three are achieved when the module encodes a CI. Our study not only underscores the versatility of grid cells beyond path integration but also highlights the importance of geometric principles in neural representations of space.

The correlation between Rate of Force Development Maximal Strength and Electromyography Variables of Basketball Athletes.
The rate of force development (RFD), is seen as a determining characteristic in fast actions present in basketball. However, we observed different relationships between RFD and maximum strength, as well as different relationships between RFD and neuromuscular variables according to the evaluated population. The aim of the present study is to evaluate the degree of determination of maximum strength (Tmax) and neuromuscular recruitment variables (RMS), Absolute Energy (AE) and the motor units firing frequencies (MPF) in rate of force development (RFD) for basketball athletes. Nine basketball athletes from the same team (mean {+/-} SD; age: 20.8 {+/-} 2.08 years; body mass: 84.33 {+/-} 8.80kg; height: 1.86 {+/-} 0.095 meters; practice time: 11.67 {+/-} 1.65 years) were evaluated through maximum isometric contraction with highest value of maximum force among 3 attempts. The RFD were evaluated and correlated with the RMS and AE values and the MPF values of the electromyographic signal at instants 0-50; 50-100, 100-150 and 150-200 milliseconds. The results show a reduction in RFD and MPF over the evaluated time windows and also a correlation between MPF and TDF in the 0-50ms time window (R2 0.67 p<0.05). The results show no relationship between RFD and RMS and AE, in addition to these variables not showing significant reductions in the evaluated time windows. The levels of RFD show to be more related to the firing frequency of the motor units than the maximum force and the level of recruitment of the motor units.