bioRxiv Subject Collection: Neuroscience's Journal

Pursuing reconsolidation in ethanol-CPP: memory reactivation in different conditions did not trigger destabilization
Consolidated memories can return to a labile state during retrieval, through destabilization, and must be reconsolidated to persist. Associative memories of contextual cues paired with hedonic effects of drugs of abuse exert a pivotal role in maintaining maladaptive behaviors in addiction. Thus, impairment of reconsolidation of drug-associated memories may provide a potential strategy to reduce drug-seeking and relapse in addiction. It is critical to understand the conditions under which a consolidated memory becomes labile and may undergo reconsolidation. After inducing ethanol Conditioned Place Preference (CPP; 2 g/kg ethanol, i.p.) in male mice, we examined different parameters during the reactivation session that could turn memory susceptible to disruption by systemic injection of the protein synthesis inhibitor cycloheximide (CHX, 100 mg/kg, i.p.). Reactivation with free access to the apparatus (similarly to a Test session, for 10, 5, or 3 min) or Reactivation sessions restricted to ethanol-paired compartment with no ethanol (for 10 or 5 min), or with the administration of a low dose of ethanol (5 min session), failed to reduce ethanol-preference after CHX administration. These findings suggest that boundary conditions constraint memory in ethanol-CPP to undergo reconsolidation.

Spatiotemporal structure and substates in emotional facial expressions
Facial expressions are tools for modulating social interaction, from the display of overt expressions to subtle cues like a raised eyebrow that accompanies speech. How this complex signalling capacity is achieved remains only partially explored. An overlooked factor is the dynamic form of facial expressions signalling, particularly how facial actions combine and recombine over time to produce nuanced expressions and enrich speech. Previous research has focused largely on the static aspects of facial behaviour, reflecting the theoretical and methodological challenges in modelling the production and perception of dynamic social signals. Drawing on theories of motor control we leveraged facial-motion tracking and spatiotemporal dimensionality reduction to investigate the structure and function of facial signalling dynamics. We show that despite the complexity of facial expressions, their emotion-signalling function is achieved through a few fundamental dynamic patterns with subtle yet diagnostic kinematic differences. Classification analysis further show that spatiotemporal components reliably differentiate emotion signals in Expressions only and Emotive-speech conditions. The underlying spatiotemporal structure represents an efficient encoding strategy, optimising the transmission and perception of facial social signals. These insights have implications for understanding normative and atypical face-to-face signalling and inform the optimal design of non-verbal expressive capabilities in artificial social agents. This work also contributes new methods for analysing facial movements, applicable to broader aspects human multimodal social communication. Keywords: Facial expressions, movement, spatiotemporal, dimensionality reduction, emotion, signalling.

Are you talking to me? How the choice of speech register impacts listeners' hierarchical encoding of speech.
Speakers accommodate their speech to meet the needs of their listeners, producing different speech registers. One such register is Foreigner-Directed Speech (FDS), which is the way native speakers address non-native listeners, typically characterized by features such as slow speech rate and phonetic exaggeration. Here, we investigated how register impacts the cortical encoding of speech at different levels of language integration. Specifically, we tested the hypothesis that enhanced comprehension of FDS compared with Native-Directed Speech (NDS) involves more than just a slower speech rate, influencing speech processing from acoustic to semantic levels. Electroencephalography (EEG) signals were recorded from Spanish native listeners, who were learning English (L2 learners), and English native listeners (L1 listeners) as they were presented with audio-stories. Speech was presented in English in three different speech registers: FDS, NDS and a control register (Slow-NDS) which is slowed down version of NDS. We measured the cortical tracking of acoustic, phonological, and semantic information with a multivariate temporal response function analysis (TRF) on the EEG signals. We found that FDS promoted L2 learners' cortical encoding at all the levels of speech and language processing considered. First, FDS led to a more pronounced encoding of the speech envelope. Second, phonological encoding was more refined when listening to FDS, with phoneme perception getting closer to that of L1 listeners. Finally, FDS also enhanced the TRF-N400, a neural signature of lexical expectations. Conversely FDS impacted acoustic but not linguistic speech encoding in L1 listeners. Taken together, these results support our hypothesis that FDS accommodates speech processing in L2 listeners beyond what can be achieved by simply speaking slowly, impacting the cortical encoding of sound and language at different abstraction levels. In turn, this study provides objective metrics that are sensitive to the impact of register on the hierarchical encoding of speech, which could be extended to other registers and cohorts.

Inferring Ligand-Receptor Interactions between GABAergic and Glutamatergic neurons during somatosensory cortex development
The cerebral cortex hosts a diverse array of excitatory and inhibitory neuron types, each characterized by distinct positional and synaptic connectivity patterns, yet the molecular mechanisms driving this stereotyped organization remain largely unknown. To identify ligand-receptor (LR) pairs that regulate interactions and connectivity between cortical neurons during embryonic and postnatal development, we tracked the transcriptional dynamics of all genes across all cortical neuron types at 17 time points spanning the entire course of cortical development. Using this data, we built a comprehensive bioinformatic atlas to infer significant LR-mediated interactions among all neuron types throughout cortical maturation. This atlas not only validated observations but also served as a powerful tool for hypothesis generation, revealing the critical role of two cadherin superfamily members in mediating perisomatic inhibition of deep and superficial layer excitatory neurons by neighboring parvalbumin-expressing basket cells.

The contributions of biological maturity and experience to fine motor development in adolescence
Fine motor function develops into adulthood, but little is known about the differential effects of biological maturation and experience on speed and complex sequential performance of the hand. To determine maturity levels, ultrasonic bone age (BA) was assessed in 225 adolescents (123 females; BA range: 9.9 to 17.9 years). The role of experience was evaluated based on chronological age (CA, range: 11.1 to 16.5 years), musical instrumental experience, and handedness. Multiple linear regression modeling showed that BA is the strongest predictor of sequential motor performance, while CA influenced motor speed when no musical instrumental experience was present. When present, the amount of highly specific musical instrumental experience becomes the main predictor of sequential performance.

Mapping Contributions of the Anterior Temporal Semantic Hub to the Processing of Abstract and Concrete Verbs
Multiple representation theories of semantic processing propose that word meaning is supported by simulated sensorimotor experience in modality-specific neural regions, as well as in cognitive systems that involve processing of linguistic, emotional, and introspective information. According to the Hub and Spoke Model of Semantic Memory, activity from these distributed cortical areas feeds into a primary semantic hub located in the ventral anterior temporal lobe (vATL). Though a substantial amount of research has tested this model in terms of concrete noun representation, there is less known about how this model can account for the representation of verb meaning, and in particular the meaning of abstract verbs which convey important information, for example, about socioemotional dynamics. In the present pre-registered study, we examined whether different types of abstract verbs (mental, emotional, nonembodied) and concrete (embodied) verbs all engage the vATL, and also whether they differentially recruit a broader set of distributed neurocognitive systems (consistent with multiple representation theories). Finally, we investigated whether there is information about different verb types distributed across the broader ATL region, consistent with a Graded Semantic Hub Hypothesis. We collected data from 30 participants who completed a syntactic classification task (is it a verb? Yes or no) and a numerical judgement task which served as an active but less semantic baseline task. Whole brain univariate analyses revealed consistent BOLD signal throughout the canonical semantic network, including the left inferior frontal gyrus, left middle temporal gyrus, and the vATL. All types of abstract verbs engaged the vATL except for mental state verbs. Finally, a multivariate pattern analysis revealed clusters within the ATL that were differentially engaged when processing each type of abstract verb. Our findings extend previous research and suggest that the hub-and-spoke hypothesis and the graded semantic hub hypothesis provide a neurobiologically constrained model of semantics that can account for abstract verb representation and processing.

A human neuronal model of sporadic Alzheimer's disease induced by FBXO2 downregulation shows A β aggregation, tau hyperphosphorylation and functional network impairment
Sporadic Alzheimer's disease (sAD) arises from a complex interplay between genetic and environmental factors that remains poorly understood, making it challenging to develop accurate cell models. To address this problem, by hypothesing that the early disease sAD states can be characterised by transcriptomic fingerprints, we assessed the effect on A{beta} aggregation in human neuroblastoma cells a set of genes obtained by analysing snRNA-seq data from post-mortem AD patients. We then validated the most effective genes in human iPSC-derived cortical neurons, and selected FBXO2, a gene encoding a subunit of the ubiquitin protein ligase complex SCF, for further analysis. We found that early downregulation of FBXO2 in human iPSC-derived cortical neurons resulted in A{beta} aggregation, tau hyperphosphorylation, and structural and functional neuronal network impairment. Based on these results, we report a neuronal sAD model (FBXO2 KD sAD) that recapitulates a set of molecular hallmarks of sAD. We suggest that this strategy can be expanded towards the generation of panels of preclinical stem cell-derived models that recapitulate the molecular complexity of the broad spectrum of AD patients.

Romantic Partners with Matching Relationship Satisfaction Showed Greater Interpersonal Neural Synchrony When Co-viewing Emotive Videos: An Exploratory fNIRS Hyperscanning Study
Emotion attunement refers to emotional co-regulation in an interpersonal relationship. Attunement can manifest as synchrony at the neurophysiological level, where partners exhibit similar brain responses to each other, known as interpersonal neural synchrony. However, in adult romantic relationships, the level of satisfaction that partners experience in a relationship may differ from each other, thus the extent of emotion attunement may differ according to the perceived relationship quality. Thus far, no study has examined how difference in relationship satisfaction between partners influence interpersonal neural synchrony. This exploratory study on 17 heterosexual Singaporean Chinese non-married couples investigated whether relationship satisfaction difference in romantic partners influenced the extent of interpersonal neural synchrony within a couple when sharing an emotive experience. Each couple wore an fNIRS cap, to measure brain activity in their prefrontal cortex (PFC), while co-viewing seven videos intended to evoke positive, negative or neutral emotions. We found preliminary evidence that differences in self-reported relationship satisfaction between romantic partners modulated interpersonal neural synchrony in the frontal right cluster of the PFC involved in social decision-making. This finding suggested that couples in which partners reported closer matching of relationship satisfaction displayed greater interpersonal neural synchrony, possibly due to more similar social cognitive processes when viewing emotive videos together. Further studies are recommended to replicate the findings with larger and more diverse samples.

Beats of the Brain: Mapping Neural Activation During Candombe Engagement
This research delves into the complex connection between traditional music in Uruguay, specifically candombe, and its cognitive advantages. Relying on real-life studies, we explore the impact of involvement with candombe music on diverse cognitive abilities such as cognitive flexibility, emotional regulation, and social cognition. Our results show that playing music, especially drumming, activates cer- tain brain pathways related to cognitive function and emotional regulation. The sense of community and distinct rhythmic patterns found in candombe not only boost individual cognitive skills but also foster social bonding, ultimately leading to better mental well-being and strength. This study highlights how cultural her- itage influences cognitive functions, showing that candombe is crucial for mental well-being in addition to being a significant cultural symbol. In summary, our research supports incorporating traditional Uruguayan music in educational and therapeutic environments, offering a new framework for cognitive and emotional growth. This research focuses on how Uruguay's diverse musical traditions can be used to enhance cognitive abilities and mental health, offering possibilities for application in different cultural settings globally.

The size-weight illusion and beyond: a new model of perceived weight
In the size-weight illusion (SWI), the smaller of two same-weight, same apparent material objects is perceived as heavier. The SWI has proved difficult to explain via traditional Bayesian models, which predict the opposite effect: expected weight from size (smaller = lighter) should be integrated with felt weight, such that the smaller object should be perceptually lighter. Other authors have proposed that weight and density are combined according to Bayesian principles, or that Bayesian models incorporating efficient coding can predict the SWI via 'likelihood repulsion'. These models, however, have been evaluated only under the narrow conditions of typical SWI stimuli. Here we establish a general model of perceived weight for pairs of objects that differ in weight and / or density and / or size by varying amounts. In a visuo-haptic task, participants (N = 30) grasped and lifted pairs of cubes, and reported their perceived heaviness. We report that the SWI occurs even at very small density differences, repudiating the idea that the illusion requires a significant conflict between expected and felt weight. Across all object pairs, perceived weight was well explained by a model (R2 = .98) that includes a positive influence of both objects' weights and the judged object's density, but a negative influence of the other object's density. Critically, the influence of both densities on perceived weight is strongly modulated by weight difference, being three times as large for zero / small weight differences than large differences. Thus, it is only under the unusual conditions of typical SWI studies that we confuse weight with density to a substantial extent. Unlike existing models, that are inconsistent with our more comprehensive dataset, our model provides a quantitative, accurate and generalised account of weight perception for pairs of objects across various weight and size conditions.

Lower-Limb Muscle Synergies in Musician's Dystonia: A Case Study of a Drummer
Musician's dystonia (MD) is a movement disorder characterized by involuntary muscle contractions specifically triggered by playing an instrument. This condition often leads to a loss of fine motor control, threatening the careers of affected musicians. While MD is commonly associated with the hands, it can also affect the lower limbs, particularly in drummers. Understanding the muscle coordination involved in MD is crucial for comprehending its neurological mechanisms, yet the muscle coordination of lower-limb dystonia has not been thoroughly explored. This study aimed to investigate the differences in lower-limb muscle synergies in a drummer with MD, utilizing Non-negative Matrix Factorization (NMF) to analyze coordinated muscle activity patterns during drumming tasks. A 36-year-old male professional drummer with lower-limb MD was instructed to play a drum set in time with a metronome set at 80 beats per minute. The task involved striking the bass drum pedal in time with the downbeat. Electromyographic (EMG) data were collected from ten muscles in the right lower limb. The data were analyzed using NMF to extract muscle synergies and compare the number of synergies, spatial modules, and temporal modules between the data with and without dystonia symptoms. The number of muscle synergies did not differ significantly between the data with and without symptoms. Notably, changes were observed in both the spatial and temporal modules of muscle synergies. Spatial modules revealed the appearance of dystonia-specific muscle synergy, which is considered related to compensatory movement. Temporal modules showed significant earlier overactivation in timing, which is considered the direct manifestation of dystonia symptoms. These findings indicate that lower-limb dystonia in drummers affects the spatial and temporal profiles of muscle synergies. This study underscores the importance of considering both spatial and temporal modules of muscle synergy in understanding and treating lower-limb dystonia in drummers. Further research is needed to validate these findings and apply muscle synergy analysis for the clinical assessment of lower-limb dystonia in drummers.

Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study
In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry.

The speed limits for tau pathology progression in Alzheimer's disease
Objective: To examine interactive effects of modifiable factors, genetic determinants and load-dependent pathology effects on tau pathology progression. Methods: Data of 162 amyloid-positive individuals were included, for whom longitudinal [18F]AV-1451-PET scans, baseline information on global amyloid load, ApoE4 status, body-mass-index (BMI), hypertension, education, neuropsychiatric symptom severity and demographic information were available in ADNI. All [18F]AV-1451 PETs were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects) and subsequently thresholded (z-score > 1.96) and converted to volume-maps. Based on these volume-maps, tau-changes over time were assessed in terms of 1) tau-speed (i.e. newly affected volume at follow-up), and 2) tau-level-rise (i.e. tau increase in previously affected volume). These two measures were entered as dependent variables in separate linear mixed effects models including four baseline risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), baseline amyloid, tau-volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the four modifiable factors on either tau-speed or tau-level-rise, respectively. Results: Faster tau-speed was linked to higher BMI, female sex, ApoE4-status, and baseline tau-volume. The effect of baseline tau-volume on tau-speed was driven by greater global amyloid burden. In terms of tau-level-rise, we observed that lower hypertension and BMI were linked to a slower increase in tau burden. A load-dependent effect of baseline amyloid and tau burden was found. Higher amyloid and BMI as well as lower education and higher tau burden were linked to greater tau-level-rise. Conclusion: Education, BMI and hypertension differentially influence tau speed and level rise by its interaction with initial pathological burden. Timely modification of these factors may overall slow tau's progression.

Visual experience-dependent auditory and visual plasticity in the mouse visual cortex
A lack of early visual experience causes pronounced auditory and visual cross-modal changes. However, the visual cortical region-specific cross-modal organization down to the single neuron level remains unknown. Here we used two-photon calcium imaging in awake mice that were reared in darkness from birth to map auditory and visual responsiveness of single neurons. We targeted neurons in the primary visual cortex (V1) and higher visual cortical areas (HVAs) that resemble the ventral and dorsal stream regions. We found that lateral dorsal stream areas showed a pronounced increase in auditory response strength, even after accounting for tone-induced whisker movement. Strikingly, this was accompanied by a decreased visual drive, measured in number of recruited neurons and response strength, although these visual effects were more widespread across cortical regions. Together, these results provide a comprehensive functional map of auditory and visual cross-modal changes after a lack of early visual experience across the mouse visual cortex. Moreover, our results suggest that a lack of visual drive of dorsal stream regions might provide an opportunity for remaining senses to take over.

Is criticality a unified set-point of brain function?
Brains face selective pressure to optimize computation, broadly defined. This optimization is achieved by myriad mechanisms and processes that influence the brain's computational state. These include development, plasticity, homeostasis, and more. Despite enormous variability over time and between individuals, do these diverse mechanisms converge on the same set-point? Is there a universal computational optimum around which the healthy brain tunes itself? The criticality hypothesis posits such a unified computational set-point. Criticality is a special dynamical brain state, defined by internally-generated multi-scale, marginally-stable dynamics which maximize many features of information processing. The first experimental support for this hypothesis emerged two decades ago, and evidence has accumulated at an accelerating pace, despite a contentious history. Here, we lay out the logic of criticality as a general computational end-point and systematically review experimental evidence for the hypothesis. We perform a meta-analysis of 143 datasets from manuscripts published between 2003 and 2024. To our surprise, we find that a long-standing controversy in the field is the product of a simple methodological choice that has no bearing on underlying dynamics. Our results suggest that a new generation of research can leverage the concept of criticality---as a unifying principle of brain function--to accelerate our understanding of behavior, cognition, and disease.

Biases in volumetric versus surface analyses in population receptive field mapping
Population receptive field (pRF) mapping is a quantitative fMRI analysis method that links visual field positions with specific locations in the visual cortex. A common preprocessing step in pRF analyses involves projecting volumetric fMRI data onto the cortical surface, often leading to upsampling of the data. This process may introduce biases in the resulting pRF parameters. To investigate this, we present CON-pRF, a fully containerized pipeline for pRF mapping analysis that is designed to maximize reproducibility in pRF mapping studies. Using this pipeline, we compared pRF maps generated from original volumetric with those from upsampled surface data. Our results show substantial increases in pRF coverage in the central visual field of upsampled data sets. These effects were consistent across early visual cortex areas V1-3. Further analysis indicates that this bias is primarily driven by the non-linear relationship between cortical distance and visual field eccentricity, known as cortical magnification. Our results demonstrate that reproducible analysis pipelines enable the detection of potential biases introduced by varying processing steps, particularly when comparing across differently processed datasets.

Ongoing activation of visual cortex and superior colliculus in the rd10 mouse model of retinitis pigmentosa
Efforts in vision restoration have been focused on a condition called Retinitis Pigmentosa, where photoreceptors in the retina degenerate while the rest of the visual pathway remain mostly intact. Retinal implants that replace the phototransduction process by stimulating retinal ganglion cells have shown promising but limited results in patients so far. Apart from technical limitations, cross-modal plasticity of visual areas might contribute to this problem. We therefore investigated if the primary visual cortex (V1) of the rd10 mouse model for retinal degeneration became more sensitive to auditory or tactile sensory inputs, potentially hindering retinal stimulation. After reaching complete blindness confirmed by the lack of optomotor responses, activity in visual cortex and superior colliculus (SC) was recorded using Neuropixels probes. While we could not find any significant differences in tactile or auditory responses compared to wildtype mice, the local field potential revealed distinct oscillatory events (0.5 to 6 Hz) in V1 and SC resembling previously observed aberrant activity in the retina of rd10 mice. Further absence of cross-modal plasticity was confirmed by a lacking increase in zif268 expression in V1 after tactile stimulation. We therefore propose that aberrant retinal activity is transmitted to higher visual areas where it prevents cross-modal changes.

Idiosyncratic choice bias and feedback-induced bias differ in their long-term dynamics
A well-known observation in repeated-choice experiments is that a tendency to prefer one response over the others emerges if the feedback consistently favors that response. Choice bias, a tendency to prefer one response over the others, however, is not restricted to biased-feedback settings and is also observed when the feedback is unbiased. In fact, participant-specific choice bias, known as idiosyncratic choice bias (ICB), is common even in symmetrical experimental settings in which feedback is completely absent. Here we ask whether feedback-induced bias and ICB share a common mechanism. Specifically, we ask whether ICBs reflect idiosyncrasies in choice-feedback associations prior to the measurement of the ICB. To address this question, we compare the long-term dynamics of ICBs with feedback-induced biases. We show that while feedback effectively induced choice preferences, its effect is transient and diminished within several weeks. By contrast, we show that ICBs remained stable for at least 22 months. These results indicate that different mechanisms underlie the idiosyncratic and feedback-induced biases.

Neural population dynamics during sleep in a songbird vocal circuit resemble sharp wave ripple activity
During vocal learning, juvenile songbirds use auditory feedback and trial-and-error motor learning to transition from acoustically simple, highly variable songs to complex and stereotypical adult songs. Similar to motor skill learning in mammals, vocal learning in songbirds requires a set of interconnected brain areas that make up an analogous basal ganglia-thalamocortical circuit known as the anterior forebrain pathway (AFP). Although neural activity in the AFP has been extensively investigated during awake singing, very little is known about its neural activity patterns during offline sleep periods. In this work, we used chronically implanted Neuropixels probes to investigate neural activity in the AFP during offline periods of natural sleep. We found that neurons in the pallial region LMAN (lateral magnocellular nucleus of the nidopallium) transitioned from sparse synchronous firing to asynchronous firing during sleep, which corresponded to slow wave sleep (SWS) and rapid eye movement (REM) sleep, respectively. SWS periods were associated with increased spiking variability for LMAN neurons, but not for neurons in the striatal region Area X (proper name). Coinciding with the increased spiking variability, we observed that populations of LMAN neurons were co-activated at specific time points during sleep in bursting events that were characterized by a negative deflection in the local field potential (LFP) and a transient increase in gamma power. Overall, the LMAN population bursting events were highly reminiscent of sharp-wave ripple (SWR) activity observed in rodent hippocampus. Contrary to our expectations, we did not observe strong cross-area field coherence between LMAN and Area X, although individual LMAN-Area X LFP pairs did show coherence > 0.5. These results provide the first description of cross-area dynamics within the AFP during sleep. Furthermore, the observation of SWR-like events during sleep in LMAN suggests that large-scale population events have diverse functions across vertebrates.

FaPDA: Facial paralysis detection algorithm applied in mice
Facial paralysis is characterized by an injury to the facial nerve, causing the loss of the functions of the structures that it innervates and changes in the central nervous system in the motor cortex. Therefore, it is important to use experimental models to further the neurophysiological study. Currently, the models have some limitations for the study of facial paralysis. Therefore, the development of an algorithm capable of automatically detecting facial paralysis and overcoming the existing limitations is proposed. C57/BL6 mice were used, which produced irreversible facial paralysis with permanent effects and reversible facial paralysis, where the effects of the paralysis disappear within the first 15 days after the nerve injury. Video recordings were made of the faces of paralyzed mice to develop the algorithm for detecting facial paralysis applied to mice, which allows us to detect the presence of reversible and irreversible facial paralysis automatically. At the same time, the algorithm was used to track facial movement during oral stimulation with sucrose and extracellular electrophysiological recordings in the anterolateral motor cortex. In the basal state, mice can make facial expressions associated with a pleasurable state, and the algorithm detects this movement; at the same time, the movement correlates with the activation in the cortical area. In the presence of facial paralysis, the algorithm can not detect movement. Therefore, it concludes that the condition exists, and the neuronal activity in the cortex is affected with respect to the evolution of facial paralysis. Therefore, the facial paralysis detection algorithm applied to mice allows deduce the presence of experimental facial paralysis, in the presence of oral stimulation or without it, at the same time that cortical electrophysiological recordings can be made for the neurophysiological study of facial paralysis.

Four SpsP neurons are an integrating sleep regulation hub in Drosophila
Sleep is an essential and conserved behavior, yet the mechanisms underlying sleep regulation remain largely unknown. To address the neural mechanisms of sleep drive, here we carry out whole brain calcium-modulated photoactivatable ratiometric integrator (CaMPARI) imaging of Drosophila and show that the activity of the protocerebral bridge (PB), a part of the central complex, correlates with sleep drive. Through a neural activation screen followed by anatomical and functional connectivity assays, we further narrow down the key player of sleep regulation in the PB to a three-layer circuit composed of 4 SpsP neurons and their upstream and downstream synaptic partners: the 4 SpsP neurons act as an integrating hub by responding to ellipsoid body (EB) signals from EPG neurons, and by sending signals back to the EB through PEcG neurons. Moreover, sleep deprivation enriches the presynaptic active zones of SpsP neurons and strengthens the connections of the EPG-SpsP-PEcG circuit, indicating plasticity gating in the circuit in response to sleep drive change. As the SpsP neurons also receive input from the sensorimotor brain region and given their known role in navigation, these neurons potentially further integrate sleep drive with other sensorimotor cues. The data taken together indicate that the four SpsP neurons and their sleep regulatory circuit play an important and dynamic role in sleep regulation.

Motor decision-making under uncertainty and time pressure
Purposeful movement often requires selection of a particular action from a range of alternatives, but how does the brain represent potential actions so that they can be compared for selection, and how are motor commands generated if movement is initiated before the final goal is identified? According to one hypothesis, the brain averages partially prepared motor plans to generate movement when there is goal uncertainty. This is consistent with the idea that motor decision making unfolds through competition between internal representations of alternative actions. An alternative hypothesis holds that only one movement, which is optimised for task performance, is prepared for execution at any time. Under this conception, decisions about the best motor goal given current information are completed upstream from neural circuits that perform motor planning. To distinguish between these hypotheses, we modified Alhussein and Smith (2021) experiment in which participants had to start reaching toward targets associated with opposite curl force-fields prior to knowing the correct target to reach. Crucially, we forced the participants to initiate movement immediately after target presentation (i.e. mean reaction times [~]250ms) so that they had limited opportunity to deliberate between the available alternatives. We found that the reaching dynamics reflected only those learnt for the selected reach direction, rather than a combination of those for the alternative targets presented, irrespective of the time available to initiate movement. The data are consistent with the conclusion that reaching dynamics were specified downstream of action selection under the target uncertainty conditions of this study.

NEW & NOTEWORTHYHere we found no evidence of "motor averaging" of reach dynamics for multiple potential actions when people had to respond as quickly as possible to uncertain target location cues. People exerted forces appropriate for the specific reach direction they selected irrespective of movement initiation time, suggesting that reaching dynamics were specified downstream of action selection.

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization
Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson's disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico (p<0.0056, N=1,000) and in vivo (p=0.0036, N=20). This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

An Efficient Direct Conversion Strategy to Generate Functional Astrocytes from Human Adult Fibroblasts
Direct reprogramming approaches offer an attractive alternative to stem-cell-derived models, allowing the retention of epigenetic information and age-associated cellular phenotypes, and providing an expedited method to generate target cell types. Several groups have previously generated multiple neuronal subtypes, neural progenitor cells, oligodendrocytes, and other cell types directly from fibroblasts. However, while some groups have had success at the efficient conversion of embryonic fibroblasts to astrocytes, they have not yet achieved similar conversion efficiency for adult human fibroblasts. To generate astrocytes for the study of adult-stage disorders, we developed an improved direct conversion strategy employing a combination of small molecules to activate specific pathways that induce trans-differentiation of human adult fibroblasts to astrocytes. We demonstrate that this method produces mature GFAP+/S100{beta}+ cells at high efficiency (40-45%), comparable to previous studies utilizing embryonic fibroblasts. Further, Fibroblast-derived induced Astrocytes (FdiAs) are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication, and glutamate uptake; and exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates a close correlation to human brain astrocytes and iPSC-derived astrocyte models. Fibroblast-derived induced astrocytes provide a useful tool in studying the adult brain and complement existing in vitro models of induced neurons (iNs), providing an additional platform to study adult-stage brain disorders.

Multisensory approach in Mental Imagery: ALE meta-analyses comparing Motor, Visual and Auditory Imagery
Mental Imagery is a topic of longstanding and widespread scientific interest. Individual studies have typically focused on a single modality (e.g. Motor, Visual, Auditory) of Mental Imagery. Relatively little work has considered directly comparing and contrasting the brain networks associated with these different modalities of Imagery. The present study integrates data from 439 neuroimaging experiments to identify both modality-specific and shared neural networks involved in Mental Imagery. Comparing the networks involved in Motor, Visual, and Auditory Imagery identified a pattern whereby each form of Imagery preferentially recruited "higher level" associative brain regions involved in the associated "real" experience. Results also indicate significant overlap in a left-lateralized network including the pre-supplementary motor area, ventral premotor cortex and inferior parietal lobule. This pattern of results supports the existence of a "core" network that supports the attentional, spatial, and decision-making demands of Mental Imagery. Together these results offer new insights into the brain networks underlying human imagination.

Histamine interferes with the early visual processing in mice
Sensory processing is dynamically modulated by an animal's behavior and internal states. Growing evidence suggests that such modulation starts from early stages, even at the retina, but the underlying mechanisms remain elusive. Combining pharmacological and chemogenetic tools with single-unit extracellular recordings in awake head-fixed mice, here we identified that the visual responses of retinal ganglion cells and the lateral geniculate nucleus were both made weaker and slower by histaminergic projections from the tuberomammillary nucleus of the posterior hypothalamus. The observed changes in the visual responses were, however, not directly linked with histaminergic modulation of pupil dynamics or locomotion behavior. Instead, our computational modelling analysis suggests neuronal circuit effects, such as gain modulation via the H1 receptors in the retina. As nocturnal animals, facilitation of visual processing at low histamine level will be ethologically beneficial for mice to respond faster to visual threats when animals are less active during daytime.

Elucidating the Selection Mechanisms in Context-Dependent Computation through Low-Rank Neural Network Modeling
Humans and animals exhibit a remarkable ability to selectively filter out irrelevant information based on context. However, the neural mechanisms underlying this context-dependent selection process remain elusive. Recently, the issue of discriminating between two prevalent selection mechanisms-- input modulation versus selection vector modulation--with neural activity data has been highlighted as one of the major challenges in the study of individual variability underlying context-dependent decision-making (CDM). Here, we investigated these selection mechanisms through low-rank neural network modeling of the CDM task. We first showed that only input modulation was allowed in rank-one neural networks and additional dimensions of network connectivity were required to endow neural networks with selection vector modulation. Through rigorous information flow analysis, we gained a mechanistic understanding of why additional dimensions are required for selection vector modulation and how additional dimensions specifically contribute to selection vector modulation. This new understanding then led to the identification of novel neural dynamical signatures for selection vector modulation at both single neuron and population levels readily testable in experiments. Together, our results provide a rigorous theoretical framework linking network connectivity, neural dynamics and selection mechanisms, paving the way towards elucidating the circuit mechanisms when studying individual variability in context-dependent computation.

Does transcutaneous vagus nerve stimulation alter pupil dilation? A living Bayesian meta-analysis
Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising technique to modulate autonomic functions, and pupil dilation has been recognized as a promising biomarker for tVNS-induced monoaminergic release. Nevertheless, studies on the effectiveness of various tVNS protocols have produced heterogeneous results on pupil dilatation to date. Here, we synthesize the existing evidence and compare conventional continuous and pulsed stimulation protocols using Bayesian meta-analysis. To maintain a living version, we developed a Shiny App with the possibility to incorporate newly published studies in the future. Based on a systematic review, we included 18 studies (N = 771) applying either continuous or pulsed stimulation protocols. Across studies, we found anecdotal evidence for the alternative hypothesis that tVNS increases pupil size (g = 0.14, 95% CI = [0.001, 0.29], BF01 = 2.5). Separating studies according to continuous vs. pulsed protocols revealed that results were driven by studies using pulsed taVNS (strong evidence for the alternative hypothesis: g = 0.34, 95% CI = [0.15, 0.53], BF10 = 14.15) while continuous tVNS provided strong evidence for the null hypothesis (g = 0.01, CI = [-0.15, 0.16], BF01= 20.7). In conclusion, our meta-analysis highlights differential effects of continuous and pulsed tVNS protocols on pupil dilation. These findings underscore the relevance of tVNS protocols in optimizing its use for specific applications that may require modulation of tonic vs. phasic monoaminergic responses.

Generation of motor program diversity and variability through inhibitory circuit motifs in the Drosophila larval locomotor system
How do neural networks generate and regulate diversity and variability in motor outputs with finite cellular components? Here we examine this problem by exploring the role that inhibitory neuron motifs play in generating mixtures of motor programs in the segmentally organised Drosophila larval locomotor system. We developed a computational model that is constrained by experimental calcium imaging data. The model comprises single-compartment cells with a single voltage-gated calcium current, which are interconnected by graded excitatory and inhibitory synapses. Local excitatory and inhibitory neurons form conditional oscillators in each hemisegment. Surrounding architecture reflects key aspects of inter- and intrasegmental connectivity motifs identified in the literature. The model generates metachronal waves of activity that recapitulate key features of fictive forwards and backwards locomotion, as well as bilaterally asymmetric activity in anterior regions that represents fictive head sweeps. The statistics of inputs to competing command-like motifs, coupled with inhibitory motifs that detect activity across multiple segments generate network states that promote diversity in motor outputs, while at the same time preventing maladaptive overlap in motor programs. Overall, the model generates testable predictions for connectomics and physiological studies while providing a platform for uncovering how inhibitory circuit motifs underpin generation of diversity and variability in motor systems.

The mitochondrial unfolded protein response promotes senescence in human microglia by increasing S-adenosylmethionine availability for polyamine synthesis.
Mitochondria have developed a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress conditions. Research in simple organisms has demonstrated that UPRmt activation in glial cells promotes proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this knowledge gap, we profiled the cell type-specific roles of the UPRmt using human induced pluripotent stem cell-derived neuronal and glial cultures and brain organoids. We found that UPRmt activation induces metabolic rewiring in human microglia, resulting in a senescence phenotype mediated by S-adenosylmethionine availability for polyamine synthesis. Additionally, UPRmt disrupted microglial intercellular communication, leading to microglia-mediated dysfunction of phagocytic pathways and increased inflammatory signaling. Using microglia-brain-assembloids, we observed distinct contributions by microglia to brain senescence and neurodegenerative disease processes driven by mitochondrial stress responses. These findings underscore the profound impact of defects in mitochondrial proteostasis on intercellular networks during brain aging and disease.

A gut-brain-gut interoceptive circuit loop gates sugar ingestion in Drosophila
The communication between the brain and digestive tract is critical for optimising nutrient preference and food intake, yet the underlying neural mechanisms remain poorly understood1-7. Here, we show that a gut-brain-gut circuit loop gates sugar ingestion in flies. We discovered that brain neurons regulating food ingestion, IN18, receive excitatory input from enteric sensory neurons, which innervate the oesophagus and express the sugar receptor Gr43a. These enteric sensory neurons monitor the sugar content of food within the oesophagus during ingestion and send positive feedback signals to IN1s, stimulating the consumption of high-sugar foods. Connectome analyses reveal that IN1s form a core ingestion circuit. This interoceptive circuit receives synaptic input from enteric afferents and provides synaptic output to enteric motor neurons, which modulate the activity of muscles at the entry segments of the crop, a stomach-like food storage organ. While IN1s are persistently activated upon ingestion of sugar-rich foods, enteric motor neurons are continuously inhibited, causing the crop muscles to relax and enabling flies to consume large volumes of sugar. Our findings reveal a key interoceptive mechanism that underlies the rapid sensory monitoring and motor control of sugar ingestion within the digestive tract, optimising the diet of flies across varying metabolic states.

Pharmacological blockade of glutamatergic input to the lateral habenula modulates consumption of palatable diet components in male Wistar rats
The lateral habenula (LHb), a small epithalamic nucleus, modifies downstream midbrain dopamine neuron output to regulate negative state and aversion. Furthermore, specific glutamatergic input, from, among others, lateral hypothalamus and central amygdala to LHb modulates consumption of (palatable) diet components. However, it is currently unclear if blockade of all glutamatergic input to the LHb is sufficient to alter eating behavior. Here, we used a pharmacological approach to inhibit all glutamatergic input to the LHb by bilateral infusion of either an AMPA/kainate receptor antagonist (CNQX) or an NMDA receptor antagonist (AP5) in the LHb of male Wistars rats. We then measured consumption of various palatable diets a control diet, a free-choice high-fat diet (fcHFD), a free-choice high-sugar diet (fcHSD), and a free-choice high-fat high-sugar diet (fcHFHSD)] at various timepoints up to 24h following infusion. Rats consumed their respective diets for 14 days before infusion of vehicle, CNQX or AP5, performed in counter-balanced random order. Infusion of CNQX or AP5 did not acutely (i.e. 1, 3, or 6h following infusion) affect consumption of a fcHFHSD component. Infusion of AP5 decreased fat intake at later time points (i.e. 10 or 24h following infusion) in fcHFHSD- and fcHFD-fed, but not fcHSD-fed, rats. Combined infusion of CNQX and AP5 decreased sucrose water consumption at 24h following infusion in fcHFHSD-fed rats. Collectively, these observations indicate that blocking glutamatergic transmission in the LHb does not have a major impact on acute consumption of a palatable free-choice diet components. Nonetheless, more subtle long-term effects were observed, suggesting a modulatory role of LHb in eating behavior in the current experimental set-up.

Adolescent development of anxiety-related behavior and shifts in behavioral responsiveness to estradiol in female mice
Early pubertal onset during adolescence is consistently linked with increased risk of anxiety and depression in girls. Although estradiol tends to have anxiolytic effects in adulthood, whether sensitivity to estradiols anxiolytic actions increases during adolescence is not clear. Using a rodent model, the current study tested the hypothesis that a shift in sensitivity to the anxiolytic effects of estradiol occurs during adolescence. To test this hypothesis, prepubertal and adult C57BL/6 female mice were ovariectomized, implanted with vehicle- or estradiol-filled silastic capsules, and behavioral tested one week later in the open field and elevated zero maze. Our hypothesis predicted that estradiol would decrease anxiety-related behavior to a greater extent in adults than in adolescent females, however, our results did not support this hypothesis. In the open field, estradiol implants significantly decreased anxiety-like behavior in adolescent females (relative to vehicle) and had little to no effect on the behavior of adults. These data suggest that adolescence is associated with a downward shift in sensitivity to the anxiolytic effects of estradiol on behavior in the open field. In contrast, although estradiol treatment did not influence anxiety-like responses in the elevated zero maze in early adolescent or adult females, adolescent females displayed significantly higher levels of anxiety-like behavior than adults. These findings demonstrate that substantial changes in anxiety-related behavior occur during adolescence, including a context-dependent shift in behavioral responsiveness to estradiol.