bioRxiv Subject Collection: Neuroscience's Journal

Collective Learning in Living Neural Networks Facilitated by Contextual Background Photostimulation
This study explores collective learning in living neural networks, focusing on group-to-group Hebbian learning, i.e., strengthening and weakening of links dependent on the precise timing of their activities. While neuronal plasticity is now well understood for single pairs of neurons, recent research has demonstrated that groups of tens of neurons are required to encode information in mammalian brains. Thus, it is critical to understand how mechanisms of plasticity, in particular spike-timing-dependent plasticity (STDP) operate at the group scale. We find that neuronal groups can reach significant plasticity after only 45 stimuli when a proper tradeoff between pulse duration and photostimulation effectiveness is chosen. Background stimulation, which enhances the reliability of response for the targeted neuronal groups, is necessary for rapid network-level Hebbian learning. By demonstrating enhanced learning in the presence of background activity, this study underscores the highly cooperative character of neurons and the importance of investigating learning, information flow, and memory formation at the network scale.

Functional organizational principle evaluated by microstimulation in the cortical facial motor areas
Facial gestures are crucial for social interactions among all primates. Since these actions are performed in the absence of direct visual feedback, their effectiveness relies on their stereotypical, almost reflexive patterns. One efficient mechanism for controlling ethological actions could involve motor cortical action maps (Graziano et al., 2002; 2016). Here, we studied whether stereotypical socio-communicative facial expressions are organized into discrete cortical zones by applying long-duration, supra-threshold microstimulation to fMRI-identified cortical areas of the facial motor system. Our findings revealed that these stimulation parameters produced complex facial responses by engaging multiple facial regions but did not elicit social-communicative facial behavior. The effects of long-duration stimulation appeared to be an amplified (both spatially and temporally) version of the responses seen with short-duration stimulation. The stimulation-evoked neural activity extended across the facial motor system, suggesting that these cortical regions function as part of a large-scale network designed to generate coherent, context-specific, and socially relevant motor outputs.

Production of clinical grade patient iPSC-derived 3D retinal organoids containing transplantable photoreceptor cells
Neurodegenerative conditions that affect the retina are currently the leading cause of incurable blindness in the developed world. Although gene and drug therapies are being developed to slow disease progression in some cases, restorative cell replacement approaches are needed for patients with significant vision impairment due to retinal degeneration. While a variety of different cell types have been evaluated in the context of retinal cell replacement, induced pluripotent stem cells (iPSCs), which can be generated and delivered as an autologous therapeutic, are in many ways the most attractive donor cell source currently available. Like embryonic stem cells, iPSCs must be differentiated into the target therapeutic cell type prior to transplantation. For instance, for patients with retinitis pigmentosa who have primary photoreceptor cell disease, photoreceptor cell derivation and enrichment are required prior to transplantation. Although other effective retinal differentiation protocols exist, they are often not fully compatible with clinical manufacturing. In this study, we report development of a xeno-free 3D retinal differentiation protocol based on the most robust adherent/non-adherent 3D differentiation strategies published to date. In addition, we demonstrate that while iPSC reprogramming efficiency is enhanced under reduced oxygen tension (i.e., 5%), efficient embryoid body and subsequent retinal organoid production require standard oxygen levels (i.e., 21%). Finally, we show that photoreceptor precursor cells obtained from 3D retinal organoids derived using the developed protocol under current good manufacturing practices (cGMP) survive in the subretinal space of dystrophic Pde6b-null rats for 1-month post-transplantation and form new synaptic connections with host bipolar neurons.

Accumulation of virtual tokens towards a jackpot reward enhances performance and value encoding in dorsal anterior cingulate cortex
Normatively, our decisions ought to be made relative to our total wealth, but in practice, we make our decisions relative to variable, decision-time-specific set points. This predilection introduces a major behavior bias that is known as reference-point dependence in Prospect Theory, and that has close links to mental accounting. Here we examined neural activity in the dorsal anterior cingulate cortex (dACC) of macaques performing a token-based risky choice task, in which the acquisition of 6 tokens (accumulated over several trials) resulted in a jackpot reward. We find that subjects make faster and more accurate choices as the jackpot reward becomes more likely to be achieved, suboptimal behavior that can readily be explained by reference dependence. This biased behavior systematically covaries with the neural encoding of corresponding offer values. Moreover, we found significant enhancement in speed, accuracy and neural encoding strength for easier levels of difficulty in detecting the offer with the best expected value. These results suggest a neural basis of reference dependence biases in shaping decision-making behavior and highlight the critical role of value representations in dACC in driving those biases.

Modulation statistics of natural soundscapes
Modulation statistics of "natural soundscapes" were estimated by calculating the modulation power spectrum (MPS) of a database of acoustic samples recorded in nine pristine terrestrial habitats for four moments of the day and two contrasting periods differing in precipitation level. Following Singh and Theunissen (2003), a set of statistics estimating low-pass quality, starriness, separability, asymmetry, modulation depth and 1/ft temporal-modulation power-law relationships were calculated from the MPS of the samples and related to geographical, meteorological factors and diel variations. MPS were found to be generally low-pass in shape in the modulation domain, with most of their modulation power restricted to low temporal (<10-20 Hz) and spectral modulations (<0.5-1 cycles/kHz). Modulation statistics distinguished between habitats irrespective of moment of the day and precipitation period, with a greater role of Modulation depth and Starriness. Separability and Starriness were found to be related to the global biodiversity decrease from tropical to polar regions, suggesting that the lack of joint high spectral and fast temporal modulations, and MPS complexity are important features characterising "biophony", the collective sound produced by animals in a given habitat. These findings may help guide research on monitoring auditory behaviors and underlying mechanisms expected to exploit regularities of natural scenes.

Noise decorrelation optimizes SNR of GABA-edited MRS data: A comparison of RF coil combination methods
Introduction: Determining the best radiofrequency (RF) coil combination method is crucial for maximizing the signal-to-noise ratio (SNR) to detect low concentration metabolites (e.g., {gamma}-aminobutyric acid (GABA)) in magnetic resonance spectroscopy (MRS). We hypothesized that algorithms accounting for noise correlations between coil elements would optimize SNR, given that phased-array coils provide better SNR than surface coils and allow accelerated acquisitions, and methods accounting for noise correlations outperform those assuming no correlations. Methods: We examined six coil combination methods, the latter half accounting for noise correlations: 1) equal weighting; 2) signal weighting; 3) S/N2 weighting; 4) noise-decorrelated combination (nd-comb); 5) whitened singular value decomposition (WSVD); 6) generalized least squares (GLS). We utilized MEGA-PRESS data from 119 participants (mean age: 26.4 {+/-} 1 SD 4.2 years; males/females: 54/65) acquired on 3T GE and Siemens MRI scanners at 11 research sites, obtained from the Big GABA study. We measured the SNR of GABA and N-acetylaspartate (NAA). We also calculated the intersubject coefficients of variation of GABA. Results: There were significant differences in SNR between coil combination methods for both GABA+ and NAA. More specifically, the noise decorrelation methods produced higher GABA+ and NAA SNR than the other approaches, where nd-comb, WSVD, and GLS produced, on average, ~37% and ~34% more SNR than equal weighting, respectively. GLS produced the highest SNR for GABA+ and NAA. The coefficients of variation for GABA+ were generally slightly smaller for the noise decorrelation methods. Conclusion: Noise-decorrelation methods produced higher SNR than other methods, especially GLS, which should be investigated in advanced editing protocols.

The Olfactory Epithelium: A Critical Gateway for Pathological Tau Propagation and a Target for Mitigating Tauopathy in the Central Nervous System
Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g. EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE's middle stratum and in the OB's olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human post-mortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to ageing or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

Zinc Finger Repressors mediate widespread PRNP lowering in the nonhuman primate brain and profoundly extend survival in prion disease mice
Prion disease is a rapidly progressing and invariably fatal neurodegenerative disorder with no approved treatment. The disease is caused by the self-templated misfolding of the prion protein (PrP) into toxic species, ultimately leading to neurodegeneration and death. We evaluated a novel epigenetic regulation approach using Zinc Finger Repressors (ZFRs) to ablate PrP expression at the transcriptional level. When delivered using adeno-associated virus (AAV), ZFRs potently and specifically reduced prion mRNA expression by >95% in vitro and to near undetectable levels within single neurons in vivo. In wildtype mice, ZFRs stably lowered neuronal PrP expression throughout the central nervous system for at least 17 months. In mice inoculated with misfolded PrP, AAV-ZFRs given at either early or late disease stages profoundly extended lifespan, significantly reduced PrP in the brain, and improved an array of molecular, histological, biomarker, and behavioral readouts. Finally, we delivered a ZFR targeting the human prion gene (PRNP) to cynomolgus monkeys using a novel blood-brain-barrier penetrant AAV capsid. Extensive bulk and single-cell assessments revealed widespread ZFR expression and PRNP repression in all 35 brain regions assessed, providing the first demonstration of epigenetic regulation across the nonhuman primate neuraxis following a single intravenous (IV) dose. These results highlight the potential of a one-time IV administered ZFR treatment for prion disease and other neurological disorders.

Macropinocytosis of aggregated amyloid-beta and tau requires Arf6 and the RhoGTPases Rac1, Cdc42 and RhoA.
The neuron-to-neuron transfer of amyloid-beta (A{beta}) and tau aggregates have been proposed to underlie the propagation of protein aggregation in Alzheimers disease (AD) and contributing to progressive neurodegeneration. Several studies have provided evidence that aggregates of A{beta} and tau are taken up into neuronal cells and neurons from the extracellular environment, where they contribute to the propagation of A{beta} and tau aggregation in AD through seeding their aggregation. As a result, attention has been placed on determining the cellular mechanisms that contribute to this uptake, with the hopes that targeting these mechanisms could halt the progression of AD by preventing aggregate transfer. Previous studies have demonstrated the uptake of A{beta} and tau aggregates through the endocytic process called macropinocytosis. The activity of several GTPases has been demonstrated to regulate macropinocytosis, including Arf6 and the RhoGTPases Rac1, Cdc42 and RhoA. Here, we examined the uptake of A{beta}42 oligomers and tau fibrils by macropinocytosis in neurons and the role of Arf6, Rac1, Cdc42 and RhoA activity in the macropinocytosis of these aggregates. In this study, we demonstrated that extracellular A{beta}42 oligomers and tau fibrils are taken up by iPSC-derived neurons and delivered directly to LAMP1-labeled lysosomes through macropinocytosis. This was demonstrated by reduced uptake in response to treatment with the macropinocytosis inhibitor EIPA, but not in response to the clathrin inhibitor Pitstop2. The uptake of these aggregates by macropinocytosis was significantly reduced by the inhibition of the GTPases Arf6, Rac1, Cdc42 and RhoA. Further, we also demonstrated that accumulation of extracellular A{beta}42 oligomers and tau fibrils results in an accumulation of cytoplasmic tau within aggregate-containing lysosomes. Together these results provide evidence that the GTPases Arf6, Rac1, Cdc42 and RhoA play a role in the neuronal uptake of A{beta} and tau aggregates by macropinocytosis and identifies new molecular targets to explore preventing the neuron-to-neuron transfer of these aggregates in AD.

Intranasal Human NSC-derived EVs Therapy in Late Middle Age Can Restrain the Activation of NLRP3 Inflammasome and cGAS-STING Signaling in the Aged Hippocampus
Age-related cognitive impairments are linked to detrimental alterations in the hippocampus, which include increased oxidative stress and chronic neuroinflammation known as inflammaging. Inflammaging comprises the activation of the nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain-containing 3 (NLRP3) inflammasomes, and the cyclic GMP-AMP synthase, and the stimulator of interferon genes (cGAS-STING) pathway that triggers type 1 interferon (IFN-1) signaling. Recent studies have shown that extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) contain therapeutic miRNAs and proteins capable of alleviating oxidative stress and neuroinflammation. This study examined the effects of male and female C57BL6/J mice receiving two doses of intranasal (IN) hiPSC-NSC-EVs (12 x 109 EVs/dose, aged-EVs group) or vehicle (aged-Veh group) in late middle age (i.e., at 18 months) on the extent of oxidative stress and chronic neuroinflammation in the hippocampus at 20.5 months of age. Compared to the Aged-Veh group, the hippocampus in the aged-EVs group displayed diminished astrocyte hypertrophy and microglial clusters. Furthermore, the concentrations of oxidative stress markers were reduced, associated with elevated levels of the nuclear factor erythroid 2-related factor 2 and superoxide dismutase and enhanced expression of genes encoding proteins that maintain mitochondrial respiratory chain integrity. Moreover, the hippocampus in the aged-EVs group displayed reduced concentrations of mediators and end products of NLRP3 inflammasome and the downstream p38/mitogen-activated protein kinase activation, and proteins involved in the activation of cGAS-STING-IFN-1 signaling, and the consequent Janus kinase and signal transducer and activator of transcription signaling pathway that leads to the transcription of interferon-stimulated genes. These antioxidant and antiinflammatory molecular changes in the aged-EVs group also improved ability to form recognition and location memories. The results provide the first evidence that IN administrations of hiPSC-NSC-EVs in late middle age can effectively reduce oxidative stress and major neuroinflammatory signaling cascades in the aged hippocampus, leading to better cognitive function in old age.

Macropinocytosis of amyloid precursor protein requires the adaptor protein Fe65 and the recruitment and activity of Arf6 and the RhoGTPases Rac1, Cdc42 and RhoA.
Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the buildup of the highly toxic peptide amyloid-beta (A{beta}). Previously, we demonstrated that A{beta} is generated from the cleavage of amyloid precursor protein (APP) after internalization to lysosomes via macropinocytosis. However, the regulation of APP micropinocytosis has remained uncharacterized. Evidence suggests that APP may function as a cell surface receptor which could contribute to this regulation. Arf6 and the RhoGTPases Rac1, Cdc42 and RhoA are known to regulate macropinocytosis in response to signaling of other receptors. An adaptor protein called Fe65, which can associate with both amyloid precursor protein and Arf6, could function as the link between APP and these known regulatory elements. Thus, we hypothesized that the binding and/or crosslinking of APP recruits Fe65, which then recruits and activates Arf6, which in turn activates Rac1, Cdc42 and RhoA, resulting in APP macropinocytosis. Rapid and transient recruitment of Fe65 and Arft6 was observed to APP 30 seconds following binding/crosslinking. Rac1, Cdc42 and RhoA all examined demonstrated more sustained recruitment to crosslinked APP. Prevention of Fe65 binding by APP mutation and Arf6 inhibition by NAV-2729 prevented the recruitment of all proteins. Together, these observations are the first to demonstrate that a network of regulatory proteins is recruited to bound/crosslinked APP which regulates its macropinocytosis. Targeting these regulatory proteins could be explored to modulate the membrane to lysosomal trafficking of APP and reducing the production of A{beta} in AD.

Tactile Illusion Reveals Central Neural Basis for Touch Pleasantness
Although the general outlines of pleasant touch perception and C low threshold mechanoreceptors (C-LTMRs) have been sketched out, the current extent of knowledge still pales in comparison to our understanding of other neural pathways and somatosensory modalities, e.g., pain and nociceptive C-fibres. This project explored the peripheral and central mechanisms in affective touch, through comparing gentle stroking with apparent motion - an illusory perception of movement produced by successively presented touches on the skin. We examined whether previously established velocity tuning of true lateral motion is also observed in apparent motion, when the local information provided to peripheral nerve afferents is held constant. If similar patterns were observed, then central modulation may govern the velocity dependence of the perception of pleasant touch. To investigate this relationship, pleasantness-ratings were collected across an array of velocities (1 - 300mm/s; N=23). Linear and quadratic regression analyses were performed on group- and individual-level. For both conditions, the addition of a quadratic term improved the overall model fit, reaching significance (p < 0.001). The quadratic term coefficients were negative for both conditions, displaying an inverted-U shape. Additionally, a multilevel mixed-effects model revealed that motion-condition did not alter the relationship between stimulus velocity and pleasantness, neither for the linear nor the quadratic velocity-term. In conclusion, similar patterns in velocity-dependent pleasantness were seen in both apparent motion and the control condition, brushing-like motion. These findings suggest that the velocity tuning of pleasantness in apparent motion cannot be attributed to velocity tuning of individual C-LTMRs.

Manifold Transform by Recurrent Cortical Circuit EnhancesRobust Encoding of Familiar Stimuli
A ubiquitous phenomenon observed along the ventral stream of the primate hierarchical visual system is the suppression of neural responses to familiar stimuli at the population level. The observation of the suppression of the neural response in the early visual cortex (V1 and V2) to familiar stimuli of size that are multiple times larger in size than the receptive fields of individual neurons reflects the plausible development of recurrent circuits for encoding these global stimuli. In this work, we investigated the neural mechanisms of familiarity suppression and showed that an excitatory recurrent neural circuit, consisting of neurons with small and local receptive fields, can develop to encode specific global familiar stimuli robustly as a result of familiarity training. This Hebbian learning based model attributes the observed familiarity suppression effect to the sparsification of the population neural code for the familiar stimuli due to the formation of image-specific local excitatory circuits and competitive normalization among neurons, leading to the paradoxical neural response suppression to the familiar stimuli at the population level. We explored the computational implications of the proposed circuit by relating it to the sparse manifold transform. The recurrent circuit, by linking spatially co-occurring visual features together, compresses the dimensions of irrelevant variations of a familiar image in the neural response manifold relative to the dimensions for discriminating different familiar stimuli. The computation can be considered as a globally non-linear but locally linear manifold transform that orthogonalizes the slow modes of network dynamics relative to the subspace of irrelevant stimulus variations, resulting in increased robustness of the global stimulus representation against noises and other irrelevant perturbations. These results provide testable predictions for neurophysiological experiments.

A core driver of somatic markers: Interoception controls the transition of decision making
A multitude of brain regions exhibit synchronized activity in conjunction with cardiorespiratory and gastric processes. This study demonstrates the mu- tual influence of interoception and perceptual decision-making processes, with a particular focus on the phenomenon of human binocular rivalry. Combining this finding with computational modeling and mathematical analysis, we show that a common interoceptive input to competing neurons can control the transition prob- ability of fixed decisions. The Somatic Marker Hypothesis (SMH) proposes that interoception is essential for adaptive coordination of the decision process to reach a rational decision. Our results revealed a fundamental mechanism underlying the SMH.

The impact of intrinsic connectome dynamics on perception is context-dependent
The functional relevance of time-averaged (static) functional connectome patterns is well recognized. However, the real-time relationship between ongoing connectome dynamics and behavioral outcomes is not well understood. It is particularly unclear whether behavior is linked to connectivity dynamics mainly among a common set of connections regardless of the task (suggesting fluctuations in task-common processes like general arousal), or if it varies with different connections depending on the task (indicating fluctuations in context-dependent processes). To investigate this, we compared fMRI data of healthy participants across three cognitive tasks (total N=35): deciding between faces or a vase in the ambiguous Rubin figure, detecting near-random motion in a dot kinematogram, and detecting a near-threshold auditory tone. By using long inter-stimulus intervals (>20s), we examined how pre-stimulus connectome states influenced the perception of upcoming ambiguous stimuli on a trial-by-trial basis across these tasks. Using Support Vector Machine (SVM) models, we demonstrated that pre-stimulus connectome states can predict the perception of upcoming ambiguous or threshold stimuli. At the connection level, we found that distinct sets of task-specific connections enabled these predictions for each task. No single connection was associated with perceptual outcomes across multiple tasks. Predictive connections in all tasks spanned both the task-relevant sensory modality network and high-order cognitive control networks. Only when averaged to the level of intrinsic connectivity networks did perceptually predictive connectivity show some similarity among pairs of tasks. Our findings highlight the functional significance of ongoing connectome states for moment-to-moment behavior, demonstrating that this relationship is largely context-dependent.

TLR4+ Dermal fibroblasts induce acute and transitional pain states
The prominence of non-neuronal cells driving pain states has gained attention in recent years. Fibroblasts, a major stromal cell, perform essential functions during inflammation, tissue remodeling, and wound healing; however, recent studies suggest that fibroblasts may play a role in pain. Toll-like receptor 4 (TLR4) is an essential component of the innate immune system and activation of the receptor promotes pain. This study utilized a novel mouse model with dermal fibroblast specific expression of TLR4 on a TLR4-null background, which allows us to understand the sufficiency of skin fibroblast activation in pain development. Here we demonstrate that dermal fibroblast activation induces both acute inflammatory pain and hyperalgesic priming in both male and female mice. In vivo, activated dermal fibroblasts change cellular morphology in mice and humans. In vitro we observed pro-inflammatory cytokine production and activation of calcium signaling pathways. These data demonstrate that dermal fibroblast activation can cause acute pain and drive mechanisms involved in the transition to chronic pain.

FACED 2.0 enables large-scale voltage and calcium imaging in vivo
Monitoring neuronal activity at large scale and high spatiotemporal resolution is crucial for understanding information processing within the brain. We optimized a kilohertz-frame-rate two-photon fluorescence microscope with all-optical megahertz line-scan rate to achieve ultrafast imaging across large areas and volumes at subcellular resolution. Applying this technique to voltage and calcium imaging in vivo, we demonstrated simultaneous recording of voltage activity over 200 neurons and calcium activity over 14,000 neurons.

Infrequent strong connections constrain connectomic predictions of neuronal function
How does circuit wiring constrain neural computation? Recent work has leveraged connectomic datasets to predict the function of cells and circuits in the brains of many species. However, many of these hypotheses have not been compared with physiological measurements, obscuring the limits of connectome-based functional predictions. To explore these limits, we characterized the visual responses of 91 cell types in the fruit fly and quantitatively compared them to connectomic predictions. We show that these predictions are accurate for some response properties, such as orientation tuning, but are surprisingly poor for other properties, such as receptive field size. Importantly, strong synaptic inputs are more functionally homogeneous than expected by chance, and exert an outsized influence on postsynaptic responses, providing a powerful modeling constraint. Finally, we show that physiology is a stronger predictor of wiring than wiring is of physiology, revising our understanding of the structure-function relationship in the brain.

Females versus males exhibit greater brain activation in sensorimotor regions during motor imagery after stroke
Motor imagery (MI; the mental rehearsal of movement) activates sensorimotor regions, providing the basis for its effectiveness as an intervention for motor recovery after stroke. Yet, the impact of biological sex on MI-related brain activation after stroke is unexplored. Here, we investigated sex-related differences in MI-related brain activation after stroke and explored associations between questionnaire-based MI ability and MI-related brain activation. Thirty-four individuals with chronic stroke performed MI of a complex, upper-limb movement using their paretic arm/hand. Brain activation was captured using functional magnetic resonance imaging (fMRI). Individual differences in MI ability were also assessed prior to the scan using an established MI questionnaire. MI-related brain activation was observed across sensorimotor regions. Yet, group-level contrasts revealed greater activation in sensorimotor regions for females vs. males, while greater activation in the cerebellar and parietal regions was noted in males vs. females. Females also recruited greater ipsilesional regions vs. males. Questionnaire-based MI ability was associated with brain activation localized to occipital regions. Our findings suggest that females and males may respond differently to MI-based tasks. Further, we did not find a relationship between questionnaire-based data and activity in sensorimotor regions. This finding suggests that multiple measures of MI may be needed to assess its impact. Overall, this work informs the use of MI after stroke.

RoSe-BaL: A neuroanatomically plausible model of routine action sequencing
The performance of routine action sequences constitutes a significant proportion of human behaviour, and has received much attention in the cognitive psychology literature. However, a neuroanatomically plausible explanation of the cognitive processes underlying this routine sequential behaviour has hitherto remained elusive. This is despite wide acceptance that an established hierarchy of interconnected basal-ganglia thalamocortical (BGTC) loops appear to be heavily involved in organising and executing context-sensitive routine action. Here, we build on existing computational models of action selection in the basal ganglia to develop the 'Routine-Sequencing Basal-ganglia Loops' (RoSe-BaL) model of multiple basal-ganglia thalamocortical loops occupying associative and motor territories of the brain. We demonstrate this model in the sequential routine tasks of tea- and coffee-making. This model incorporates a novel hypothesis of the nature of the organisation of cognitive information in associative territories of the BGTC hierarchy, which we term the 'BG subset-selection hypothesis'. Erroneous behaviour made by the model under conditions of disruption shows similar trends to those observed in previous studies of action slips and action disorganisation syndrome. This finding provides support for the previously untested hypothesis that damaged temporal order knowledge and action schemas underlie many of the errors typically performed by humans. The neuroanatomical grounding of the model naturally reconciles two influential competing computational models of routine behaviour. Finally, we propose a novel interpretation of the widespread competitive queueing account, which we term 'suitability queueing'. This is shown to be consistent with existing cognitive, neurophysiological and neuroanatomical findings.

Advancing image-based meta-analysis for fMRI: A framework for leveraging NeuroVault data
Image-based meta-analysis (IBMA) is a powerful method for synthesizing results from various fMRI studies. However, challenges related to data accessibility and the lack of available tools and methods have limited its widespread use. This study examined the current state of the NeuroVault repository and developed a comprehensive framework for selecting and analyzing neuroimaging statistical maps within it. By systematically assessing the quality of NeuroVault's data and implementing novel selection and meta-analysis techniques, we demonstrated the repository's potential for IBMA. We created a multi-stage selection framework that includes preliminary, heuristic, and manual image selection methods. We conducted meta-analyses for three distinct domains: working memory, motor, and emotion processing. The results from the three manual IBMA approaches closely resembled reference maps from the Human Connectome Project. Importantly, we found that while manual selection provides the most precise results, heuristic methods can serve as robust alternatives, especially for domains that include a heterogeneous set of fMRI tasks and contrasts, such as emotion processing. Additionally, we evaluated five different meta-analytic estimator methods to assess their effectiveness in handling spurious images. For domains characterized by heterogeneous tasks, employing a robust estimator (e.g., median) is essential. This study is the first to present a systematic approach for implementing IBMA using the NeuroVault repository. We introduce an accessible and reproducible methodology that allows researchers to make the most of NeuroVault's extensive neuroimaging resources, potentially fostering greater interest in data sharing and future meta-analyses utilizing NeuroVault data.

A chemical screen identifies p38 MAPK inhibition as a candidate neuroprotective strategy for combinatorial SMA therapy
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. The identification of effectors and modifiers of pathogenic events downstream of SMN deficiency is key to understanding disease mechanisms and broadening the range of targets for developing SMA therapies that can complement SMN upregulation. Here, we report a cell-based phenotypic screen for chemical modifiers of SMN biology that identified inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) as suppressors of proliferation defects induced by SMN deficiency in mouse fibroblasts. We further show that SMN deficiency induces p38 MAPK activation and that pharmacological inhibition of this pathway improves motor function in SMA mice through SMN-independent neuroprotective effects. Using a highly optimized p38 MAPK inhibitor (MW150) and a specific paradigm of combinatorial treatment in SMA mice, we observed synergistic enhancement of the phenotypic benefit induced by either MW150 or an SMN-inducing drug alone. By promoting survival of motor neurons, pharmacological inhibition of p38 MAPK synergizes with SMN induction and enables enhanced synaptic rewiring of motor neurons within sensory-motor spinal circuits, resulting in increased motor function, weight gain, and survival of SMA mice. Together, our studies identify the p38 MAPK pathway as a therapeutic target and MW150 as a candidate pharmacological approach for SMN-independent neuroprotection with clinical relevance for combination therapy in SMA.

High Incidence of Estrous Cycle Irregularities in Heterogeneous Stock (HS) Rats is Associated with Severe Cocaine Addiction-like Behaviors
Hormonal fluctuations throughout the estrous cycle have been hypothesized to influence drug-related behaviors. Preclinical models show that some cocaine-related behaviors are influenced by the estrous cycle. However, the extent to which the estrous cycle modulates cocaine self-administration in outbred heterogeneous stock (HS) rats, a population that captures human genetic diversity, is unknown. This study aimed to examine the relationship between estrous phases and cocaine self-administration behavior in HS rats using a model of extended access to cocaine self-administration. We focused on the escalation of intake, breaking point, and resistance to foot shock. Using vaginal swabbing and lavage techniques, we first characterized the relationship between estrous phase and cocaine intake. We then comprehensively evaluated estrous cycling patterns in young adult and adult HS rats, comparing them with Wistar rats. Contrary to our hypothesis, estrous phase showed no association with cocaine self-administration in HS rats. HS rats exhibited irregular estrous cycling with variability to the phase length, even in the absence of drug exposure, a phenomenon not observed in the Wistar strain. Irregular estrous cycle was associated with high cocaine-related behaviors. This study provides the first evidence that some female HS rats exhibit irregular estrous cycling. Moreover, rats with severe addiction-like behaviors had more instances of irregular cycling. These results demonstrate that, in HS rats, the estrous phase per se has no major influence on cocaine self-administration, but that the severity of addiction-like behaviors are associated with more irregularity of the estrus cycle. As HS rats gain popularity in behavioral and genome-wide studies, understanding these cycle disruptions is crucial as they may reveal genetic links into female vulnerability to drugs.

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation
Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a-deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of A{beta} and A{beta} fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

Heterocellular and homocellular electrically coupled networks of the thalamus and cortex revealed by focal photomapping
Electrical synapses are present widely across the mammalian brain and are crucial components of active neural circuitry and connectomes. Identification of electrically coupled networks in living tissue has been limited by technical demands of multiplexed recordings, and no dyes, fluorescent reporters, or genetic labels are currently able to fill the gap. Here, we introduce a novel method of identifying and measuring electrical synapses: opto-{delta}L combines focal photostimulation of soma-targeted opsins and a novel method for computing the strength of electrical synapses, based on spike timing, to rapidly measure and map electrically coupled networks in vitro. We measured electrical synapses and characterized coupled networks in mature thalamic reticular nucleus (TRN) and in cortex. We used opto-{delta}L to show that TRN neurons form functional networks that extend as far as 100 m, and that TRN neurons synapse promiscuously, coupling both matching and disparate genetic subtypes of neurons. Future applications of opto-{delta}L will allow identification and characterization of coupled networks across the brain and enable circuit and systems-level interrogations of the identity and roles of electrical synapses in circuitry, behavior, and cognition.

Independent Continuous Tracking of Multiple Agents in the Human Hippocampus
The pursuit of fleeing prey is a core element of many species behavioral repertoires. It poses the difficult problem of continuous tracking of multiple agents, including both self and others. To understand how this tracking is implemented neurally, we examined responses of hippocampal neurons while humans performed a joystick-controlled continuous prey-pursuit task involving two simultaneously fleeing prey (and, in some cases, a predator) in a virtual open field. We found neural maps encoding the positions of all the agents. All maps were multiplexed in single neurons and were disambiguated by the use of the population coding principle of semi-orthogonal subspaces, which can facilitate cross-agent generalization. Some neurons, more common in the posterior hippocampus, had narrow tuning functions reminiscent of place cells, lower firing rates, and high information per spike; others, which were found in both anterior and posterior hippocampus, had broad tuning functions, higher firing rates, and less information per spike. Semi-orthogonalization was selectively associated with the broadly tuned neurons. These results suggest an answer to the problem of navigational individuation, that is, how mapping codes can distinguish different agents, and establish the neuronavigational foundations of pursuit.

A dynamic spatiotemporal normalization model for continuous vision
Perception and neural activity are profoundly shaped by the spatial and temporal context of sensory input, which has been modeled by divisive normalization over space or time. However, theoretical work has largely treated normalization separately within these dimensions and has not explained how future stimuli can suppress past ones. Here we introduce a computational model with a unified spatiotemporal receptive field structure that implements normalization across both space and time and ask whether this model captures the bidirectional effects of temporal context on neural responses and behavior. We found that biphasic temporal receptive fields emerged from this normalization computation, consistent with empirical observations. The model also reproduced several neural response properties, including nonlinear response dynamics, subadditivity, response adaptation, backwards masking, and bidirectional contrast-dependent suppression. Thus, the model captured a wide range of neural and behavioral effects, suggesting that a unified spatiotemporal normalization computation could underlie dynamic stimulus processing and perception.

Octopamine regulates neural circuits in the mushroom body and central complex, influencing sleep and context-dependent arousal.
Sleep is a complex and ubiquitous phenomenon in the animal kingdom, yet the mechanisms, modes, and effects of sleep on the brain and body remain highly variable and not fully understood. While sleep and wakefulness are often measured as two binary states at the behavioral level, animals exhibit a wide range of arousal states during wakefulness. Behaviors such as feeding, courting, escaping predators, or avoiding unfavorable environments are critical for survival and often compete with sleep. Biogenic amines, including dopamine, norepinephrine, and serotonin, are known to regulate sleep and arousal behaviors across species, offering valuable insights into how these states are co-regulated. In this study, we leverage the small number, discrete organization, and well-defined connectivity patterns of neuromodulatory neurons in the fly brain to investigate how specific octopamine (OA) neurons regulate sleep and context-dependent arousal. We focus on a pair of OA neurons, VPM3, which project extensively to the mushroom body (MB) and central complex (CX). Our findings reveal that VPM3 neurons are sexually monomorphic and that their activity is essential for sleep suppression and male courtship behavior. Furthermore, we demonstrate that the male-specific form of the fruitless gene in these neurons plays a critical role in sleep regulation and that their activity is influenced by sleep history. Using connectome data and highly specific genetic tools, we identify upstream inputs to VPM3 neurons from the CX and elucidate the downstream pathways mediated by the MB, as well as the role of specific OA receptors. These detailed investigations highlight the multifaceted role of octopamine in sleep suppression and context-specific arousal, providing a crucial link between identified sleep microcircuits in the mushroom body and central complex.

PIA SSN: Parallel Image Acquisition and Spatial Similarity Network for Tandem Mass Spectrometry Imaging
Unambiguous molecular annotation in mass spectrometry imaging is essential for understanding complex biochemical processes. Here, we present Parallel Image Acquisition (PIA), for simultaneous imaging with high mass resolution and tandem mass spectrometry, and Spatial Similarity Network (SSN), to annotate isobars and isomers and reveal molecular colocalization. With PIA SSN we uncover phospholipid isomers and isobars in mouse brain tissue and derive cholesterol oxidation metabolites linked to multiple sclerosis.

Isolated Configuration: Holistic Processing Beyond the Realm of Faces
Holistic processing has traditionally been regarded as unique to faces, attributed to the spatial layout across facial features and their variability across individuals. However, whether such processing can occur in stimuli other than faces has remained an open and contentious question. Here, we show that novel non-face stimuli, which are designed to be differentiated strictly by configural properties, can drive holistic processing effects, while similar non-configural stimuli do not generate these effects. Using novel, abstract stimuli that isolate configural information, we systematically examined four effects typically associated with holistic face perception: the inversion, part-whole, composite, and misalignment effects. We observed all four effects with these stimuli, suggesting that this special form of visual processing extends beyond the realm of faces, and primarily requires that stimuli contain configural information for accurate classification. These effects manifested with minimal training, demonstrating that the visual system can rapidly integrate spatial relationships. Furthermore, convolutional neural networks, trained to categorize these stimuli, also show these effects, and like humans, these effects are only observed with the configural stimuli, and not with the non-configural stimuli. Our results challenge the traditional view of holistic processing as face-specific, and propose that configural processing itself serves as a primary driver of holistic perception and may be a fundamental visual process of its own.

Adolescent onset of volitional ethanol intake normalizes sex differences observed with adult-onset ethanol intake and negative affective behaviors during protracted forced abstinence
Rationale: Negative affect during ethanol abstinence can lead to relapse and dependence. Voluntary ethanol drinking models are crucial for examining negative affect following chronic ethanol access, but female rodents often drink more ethanol than males, complicating comparisons between sexes. Since chronic adolescent ethanol use poses a substantial risk for later alcohol use disorder, we hypothesize that adolescence is a critical window for consolidating drinking behavior before major hormonal changes affect ethanol consumption. Objectives: This study compared sex differences in voluntary ethanol consumption and negative affective behavior in mice that initiated ethanol consumption during early adolescence (~PND30) or early adulthood (>PND49). Methods: Male and female C57BL/6J mice underwent the Chronic Drinking Forced Abstinence (CDFA) paradigm, with the Ethanol group given two-bottle choice access to ethanol and water, and the Water group given two water bottles. Ethanol intake and preference were measured over six weeks. Two weeks following ethanol removal, mice underwent behavioral testing for negative affective-like behavior. Results: Adult-onset female mice consumed significantly more ethanol and displayed higher ethanol preference compared to adult-onset male mice. In contrast, adolescent-onset male and female mice consumed similar ethanol levels and displayed similar preference. We observed increased immobility during the forced swim test in adult-onset ethanol females, but not males, during protracted abstinence. However, both sexes of adolescent-onset ethanol mice displayed increased immobility during forced abstinence. Conclusions: These findings highlight adolescence as a critical period during which both sexes voluntarily consume ethanol and are equally vulnerable to the behavioral disturbances associated with ethanol abstinence.

Calcium-Based Synaptic and Structural Plasticity Link Pathological Activity to Synaptic Reorganization in Parkinson's Disease
Altered motor symptoms of Parkinson's disease (PD) are associated with dopaminergic neuronal loss. Widespread synaptic reorganization and neural activity changes, including exaggerated beta oscillations and bursting, follow dopamine depletion (DD) of the basal ganglia (BG). Our computational model examines DD-induced neural activity changes and synaptic reorganization. It encompasses the BG sub-circuit comprising the subthalamic nucleus and globus pallidus externus. Calcium-dependent synaptic and structural plasticity mechanisms were incorporated, allowing neural activity to alter network topology. We show how elevated iMSN firing rates can induce synaptic connectivity changes consistent with PD animal models. We suggest synaptic reorganization following DD results from a series of homeostatic calcium-based synaptic changes triggered by elevated iMSN activity. Structural plasticity counteracts DD-induced neural activity changes and opposes exaggerated beta oscillations, whereas synaptic plasticity alone amplifies beta oscillations. Our results suggest that synaptic and structural plasticity have qualitatively different contributions to DD-induced synaptic reorganization in the BG.

Sparse memory ensembles set brain-wide network states to sustain learned associations
The ability to recall spatial memories and adapt behavior to changing conditions is essential for efficient navigation of environments. These processes are thought to rely on sparse populations of neurons, embedded within distributed brain networks. However, how the activity of these neurons impacts large-scale network connectivity to sustain behavior remains poorly understood. To address this, we tagged neurons active during peak performance in an appetitive spatial memory T-maze task in male and female TetTag-hM3Dq transgenic mice and chemogenetically reactivated these ensembles during functional magnetic imaging (fMRI) of brain activity. Reactivation of these ensembles triggered widespread network reorganization, optimizing the brain's modular specialization while maintaining integration across the network via key hubs and gateways. We identified two distinct clusters dominated by the ventral and dorsal hippocampus, respectively, that exhibit distinct connectivity with cortical and subcortical areas. Control mice showed effective extinction learning (EL) in the T-maze when the reward incentive was absent. Reactivating the tagged memory ensembles during EL significantly prevented this process. These findings reveal the brain-wide network hubs that support effective spatial memory acquisition, but also indicate that decay of this network connectivity is likely to be an essential facet of effective EL of spatial experience.

Formation of Task Representations and Replay in Mouse Medial Prefrontal Cortex
The medial prefrontal cortex (mPFC) is thought to support cognitive flexibility by forming and maintaining generalized representations of abstract tasks. The formation of these representations as well as their relation to preexisting representations of contextual or spatial information is incompletely understood. In this study, we analyzed longitudinal 1-photon calcium recordings in mice performing an olfaction-guided spatial memory task over an eight-week period that included habituation, training, and sleep epochs. Our results reveal that, while a minority of neurons initially conveyed significant information about the behavior of the animal, the bulk of task-related activity only emerged after the animals reached proficient performance. Although goal arm information is robustly represented at both the single-cell and network levels both during learning and in task proficient mice, it undergoes significant remapping throughout the learning process. Additionally, we identified the establishment of recurring sequences during learning and their replay at reward locations, with no evidence of them existing during odor sampling phase, during sleep or before training. These findings suggest that the mPFC predominantly establishes generalized task representations de novo during learning, relying only minimally on preexisting spatial representations and that sub-second neural sequences in the mPFC are more likely involved in evaluating behavioral outcomes rather than planning future actions.

A rapid arousal brake on hunger neurons and its release in narcolepsy
Human sleep-wake disorders are often accompanied by eating disorders; the reasons for this apparent interplay between hunger and arousal remain unclear. Pupil-linked arousal fluctuates second-by-second, closely correlating with dynamics of hypocretin/orexin (H/O) neurons, whose malfunctions are linked to multiple pathologies. It is currently thought that H/O neurons activate hunger-causing agouti-related peptide (AGRP) neurons, thus creating concurrent arousal and hunger. Here, we directly measure pupil-linked arousal dynamics and concurrent AGRP neuron activity and find that, instead, pupil dilations correlate with reductions in AGRP neuron activity. Direct H/O neuron stimulation reproduced this inhibitory effect, while H/O neuron ablation attenuated it. Furthermore, in a mouse model of human type 1 (i.e. O/H deficient) narcolepsy, which involves unexplained overeating, we detected abnormal AGRP neuron hyperactivation during specific brain states, including the symptomatic shut-downs of arousal (cataplexy). Finally, we show that intact H/O neurons are required for normal food value perception by AGRP neurons, and for eating and AGRP neuron suppression by unexpected non-food stimuli. By demonstrating a rapid inhibitory H/O->AGRP influence and multiple pathophysiological consequences of its loss, these findings reveal a rapid functional link between arousal and hunger that is impaired by a neural defect associated with human disorders.

Tonic pain revalues associative memories of phasic pain
Tonic pain is proposed to adapt protective behaviours during recovery from injury. A key untested prediction of this homeostatic model is that it appropriately reshapes internal representations of phasic pain. We investigated whether lateralised tonic pain modulates phasic pain-predictive cues on that side. Using a virtual-reality Pavlovian revaluation paradigm, we assessed physiological and neural conditioned responses with EEG in theta, alpha, and beta frequency bands. Pain-predictive cues elicited neural enhanced alpha and beta suppression and increased pupil diameter during conditioning acquisition. Critically, tonic pain revalued phasic conditioned responses during extinction, with reduced midfrontal theta synchronisation when the laterality of tonic pain was congruent with predicted phasic pain. Greater tonic pain unpleasantness also enhanced posterior beta suppression for congruent cues. These findings provide evidence for an internal representation of cue-pain associations that is topographically modulated by tonic pain, suggesting that tonic pain actively reconfigures pain predictions, enabling anticipatory protective behaviours.

Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons
Administration of {Delta}9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the {beta}-arrestin 1/Akt/GSK3{beta} signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3{beta}-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.

Deviant functional connectivity patterns in the EEG and their potential use for dyslexia screening
Developmental dyslexia (DD) is a common learning disorder with potential neural origins. While EEG-based brain activation measures combined with machine learning have shown promise for DD screening, these approaches often lack validation on independent participants, which is a crucial step for practical application. This study developed an EEG-based screening approach and investigated the neural correlates of DD in Chinese children. EEG signals were recorded from 130 children (82 with DD, 48 typically developing) aged betweeen 7 and 11 during resting-state and working memory tasks. The EEG data were preprocessed into clean segments to compute functional connectivity (FC) matrices across four frequency bands (delta, theta, alpha, beta). The segments were split into two independent samples, ensuring independence at the participant level: Sample 1, used for training and five-fold cross validation of the convolutional neural networks, and Sample 2, used for cross-sample validation with the trained model. The beta-band FC index in the eyes-open condition achieved the highest within-sample classification accuracy (98%) and cross-sample accuracy (70%, p < .001). Discriminative FC patterns revealed that children with DD exhibited reduced temporal-parietal and central connectivity but increased frontal-central connectivity, likely reflecting compensatory mechanisms. Within the DD group, stronger FCs showed significant negative correlations with Chinese word reading accuracy and fluency. These findings suggest that EEG-based FC measures can effectively distinguish DD and reveal neural markers associated with impaired reading performance. This approach shows promise for noninvasive screening and deeper insight into the neural basis of DD, particularly in non-alphabetic language systems.

Neural Synchrony Links Sensorimotor Cortices in a Network for Facial Motor Control
Primate societies rely on the production and interpretation of social signals, in particular those displayed by the face. Facial movements are controlled, according to the dominant neuropsychological schema, by two separate circuits, one originating in medial frontal cortex controlling emotional expressions, and a second one originating in lateral motor and premotor areas controlling voluntary facial movements. Despite this functional dichotomy, cortical anatomy suggests that medial and lateral areas are directly connected and may thus operate as a single network. Here we test these contrasting hypotheses through structural and functional magnetic resonance imaging (fMRI) guided electrical stimulation and simultaneous multi-channel recordings from key face motor areas in the macaque monkey brain. These areas include medial face motor area M3 (located in the anterior cingulate cortex); two lateral face-related motor areas: M1 (primary motor) and PMv (ventrolateral premotor); and S1 (primary somatosensory cortex). Cortical responses evoked by intracortical stimulation revealed that medial and lateral areas can exert significant functional impact on each other. Simultaneous recordings of local field potentials in all face motor areas further confirm that during facial expressions, medial and lateral face motor areas significantly interact, primarily in the alpha and beta frequency ranges. These functional interactions varied across different types of facial movements. Thus, contrary to the dominant neuropsychological dogma, control of facial movements is not mediated through independent (medial/lateral) functional streams, but results from an extensive interacting sensorimotor network.

Transformations of the spatial activity manifold convey aversive information in CA3
Hippocampal circuits form cognitive maps representing spatial position and integrating contextual information, including affective cues, within episodic memory representations. We investigated how spatial and affective information combine in the population activity of CA3 axons by imaging intermediate-to-dorsal and dorsal-to-dorsal projections in mice navigating a linear track before, during, and after exposure to an aversive air puff stimulus. Our analyses reveal that both axonal populations maintain a robust, time-invariant spatial coding manifold across recordings, independent of affective context. Alterations to this common manifold encode the presence of the aversive stimulus without disrupting the spatial representation. Both axonal pathways encoded affective information with similar efficacy. This population-level encoding was distributed similarly across place and non-place cells. Our findings demonstrate that hippocampal CA3 axons integrate spatial and affective information within a common representational geometry while preserving the ability to extract each information type separately.

Global brain maintenance predicts well-preserved cognitive function: A pooled analysis of three longitudinal population-based Swedish cohorts
Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is lacking. We pooled data from three population-based Swedish cohorts (Betula, N = 196; SNAC-K, N = 472; H70, N = 688; aged 60-93 years at baseline, follow-up duration up to 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles (adjusted for total intracranial volume), and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., 'aged') versus high (i.e., 'youth-like') brain integrity based on ventricular volume estimates available for a younger reference sample in one of the cohorts (Betula, 25-55 years, N = 60). Subgroup differences in cognition at baseline and over the follow-up were assessed with ANCOVAs and linear mixed effects models. Logistic regressions were used to examine lifestyle predictors of brain maintenance. Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition (p < .001) and less cognitive decline longitudinally (p < .001). Moreover, lower cardiovascular disease (CVD) risk and the absence of diabetes predicted brain maintenance at baseline (CVD risk, OR = 0.80, 95% CI [0.68, 0.93]; diabetes, OR = 0.39, 95% CI [0.26, 0.59]) and over the follow-up (CVD risk, OR = 0.79, 95% CI [0.64, 0.96]; diabetes, OR = 0.53, 95% CI [0.29, 0.94]). These findings underscore brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

Assigning Targetable Molecular Pathways to Transdiagnostic Subgroups Across Autism and Related Neurodevelopmental Disorders
Significant genetic, behavioural and neuroanatomic heterogeneity is common in autism spectrum- and related- neurodevelopmental disorders (NDDs). This heterogeneity constrains the development of effective therapies for diverse patients in precision medicine paradigms. This has led to the search for subgroups of individuals having common etiologic factors/biology (e.g., genetic pathways), thus creating potential uniformity in prognosis and/or treatment response. Despite NDDs having a strong genetic component, only ~15-20% of individuals will present with a specific rare genetic variant considered clinically pathogenic, and therefore, subtyping efforts tend to focus on using clinical, cognitive, and/or brain imaging phenotypes to group individuals. Here we delineated mechanisms via mouse to human translational neuroscience. Using MRI derived structural neuroanatomy and a spatial transcriptomic comparison, we linked subgroups of 135 NDD relevant mouse models (3,515 individual mice) separately to two human databases, with 1,234 and 1,015 human individuals with NDDs, composed of autism, attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), other related NDDs, and typically developing controls. Subgroups were significantly linked by consistent neuroanatomy across all three datasets, mouse and human, indicating that direct cross-species subgrouping and translation is consistent and reproducible. Ultimately, four specific neuroanatomical clusters were found and linked to precise molecular mechanisms: two showing a chromatin/transcription motif, with one of those showing specific links to G-protein coupled receptors (GPCR) and Notch signalling, and another two being mainly synaptic in origin, with one off those showing specific connections to axon guidance and Wnt signaling. Assigning molecular pathways, and thus genetic information, from the mouse to individual participants provides an insight into undetected and/or related genetic variants that could be working in combination or interacting with an environmental influence. Moreover, the subgroups found are transdiagnostic, including participants with autism, ADHD, and OCD, which indicates that NDDs as a whole can be subdivided into consistent neuroanatomical clusters with cohesive underlying biological mechanisms. This work allows us to bridge the gap between preclinical models and human disorders, linking previously idiopathic human patients to pertinent genetics, molecular mechanisms, and pathways.

Dynamic Causal Tractography Analysis of Auditory Descriptive Naming:An Intracranial Study of 106 Patients
Humans understand and respond to spoken questions through coordinated activity across distributed cortical networks. However, the causal roles of connectivity engagements alternating across multiple white matter bundles remain understudied at the whole-brain scale. Using intracranial high-gamma activity recorded from 7,792 non-epileptic electrode sites in 106 epilepsy patients who underwent direct cortical stimulation mapping, we constructed an atlas visualizing the millisecond-scale dynamics of functional connectivity during a naming task in response to auditory questions. This atlas, the Dynamic Causal Tractography Atlas, identified functional connectivity patterns at specific time windows most strongly associated with stimulation-induced language- and speech-related manifestations (p-value range: 2.5 x 10-5 to 6.6 x 10-14; rho range: +0.54 to +0.82). The atlas revealed that no single intra-hemispheric fasciculus was consistently engaged in all naming stages; instead, each fasciculus supported specific stages, with multiple distinct major fasciculi simultaneously contributing to each stage. Additionally, this atlas identified the specific linguistic stages and fasciculi where handedness effects became evident. Our findings clarify the dynamics and causal roles of alternating, coordinated neural activity through specific fasciculi during auditory descriptive naming, advancing current neurobiological models of speech network organization. Additionally, we have made our white matter streamline template and intracranial EEG data available as open-source material, enabling investigators to construct personalized dynamic tractography atlases.

Intermittent movement control emerges from information-based planning
Dominant models of reactive motion control in humans, based on optimal feedback control, predict smooth trajectories that reflect averaged behaviors. However, the observation of individual movements suggests that mammalian motor control is inherently discrete, with movement corrections occurring at a rate that depends on task demands and sensory information quality. To address these limitations, we introduce the Information Predictive Control (IPC) framework that integrates model predictive control with information theory, which triggers movement corrections only when unexpected deviations occur and corrections are likely to succeed. By quantifying "surprise" relative to anticipated internal and external states, IPC produces successful movements while robustly responding to sensorimotor noise, task constraints, and target variability. Simulations demonstrate IPC's ability to reproduce human-like responses to novel force fields during reaching, continuous target tracking, and adaptive planning under noise, while dynamically adjusting the planning horizon in complex, unpredictable environments.

Mechanisms of Tone-in-Noise Encoding in the Inferior Colliculus
Extracellular single-unit responses to tone-in-noise (TIN) stimuli were recorded in the inferior colliculus (IC) of awake female Dutch-belted rabbits. Stimuli consisted of wideband and narrowband tone-in-noise (TIN) with on-and off-characteristic frequency tones. Neural responses to wideband TIN showed a pattern of rates that increased when the tone matched CF and decreased (with respect to noise-alone responses) when the tone was above or below CF. This result differed from narrowband TIN IC responses that depended on envelope fluctuations in the stimulus, consistent with neural-fluctuation sensitivity. The WB-TIN responses could be fit with a difference-of-gaussians model that had narrow excitation and broad inhibition; responses to TIN could not be predicted by response-maps or spectrotemporal receptive fields. Responses to diotic and contralateral presentations of WB-TIN did not differ due to presentation ear. A single-CF computational model of the IC could not predict responses to wideband TIN. However, adding local off-CF inhibitory inputs to an on-CF IC model improved accuracy. These results suggest that broad inhibition could explain encoding of wideband TIN at suprathreshold signal-to-noise ratios, whereas neural fluctuation sensitivity is more important for narrowband sounds.

Neuronal activity and amyloid-beta cause tau seeding in the entorhinal cortex in Alzheimer's disease
The entorhinal cortex is the earliest site of tau pathology in both Alzheimer's disease and primary age-related tauopathy, yet the mechanisms underlying this selective vulnerability remain poorly understood. Here, we use a computational model integrating neuronal activity and amyloid-beta deposition with interneuronal tau transport to predict regional susceptibility to tau seeding. Using fluorodeoxyglucose PET as a measure of neuronal activity, we show that brain-wide activity patterns drive tau accumulation in the medial temporal lobe, independent of amyloid status. Incorporating amyloid PET, we further show that amyloid-beta selectively amplifies tau seeding in the entorhinal cortex, aligning with its early involvement in Alzheimer's disease. These predictions are supported by cross-subject correlation analysis, which reveals a significant association between model-derived seeding concentrations and empirical tau deposition. Our findings suggest that neuronal activity patterns shape the early landscape of tau pathology, while amyloid-beta deposition creates a unique vulnerability in the entorhinal cortex, potentially triggering the pathological cascade that defines Alzheimer's disease.

Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency
Tau is a pathogenic protein in Alzheimer's (AD) and other neurodegenerative diseases. The misfolding of tau into beta-sheet rich elongated filaments is thought to be a key event in disease pathogenesis, followed by subsequent templated recruitment of monomeric tau into this pathogenic form. Cryo-electron microscopy has revealed that specific tau conformations characterize different diseases. In this study, we explored how tau filament core structure and post-translational modifications in its disordered fuzzy coat influence its seeding capacity in primary neurons and mice. We show that the structure of the seeds affects seeding capacity, but that the AD tau core structure alone is insufficient to capture the full seeding capacity of AD tau. Proteolytic cleavage of AD tau which removes the fuzzy coat causes a loss in seeding capacity, as does removal of phosphorylation from the fuzzy coat by phosphatase treatment. Re-phosphorylation of phosphatase-treated AD tau by kinase treatment partially restores seeding activity. Finally, we find that filaments of recombinant tau with twelve phospho-mimetic residues (PAD12 tau) with the AD fold are able to recapitulate the seeding capacity of AD tau. Combined, these results suggest that the structure of the ordered core, together with phosphorylation in the fuzzy coat, confers the seeding capacity of tau filaments.

Prediction of individual melodic contour processing in sensory association cortices from resting state functional connectivity
Recent studies suggest that it is possible to predict an individual brain's spatial activation pattern in response to a paradigm from their functional connectivity at rest (rsFC). However, it is unclear whether this prediction works across the brain. We here aim to understand whether individual task activation can be best predicted in local regions that are highly specialised to the task at hand or whether there are domain-independent regions in the brain that carry most information about the individual. To answer this question, we used fMRI data from participants (nonmusicians, N=52) at rest and during an auditory oddball paradigm while watching a silent movie. We then predicted individual differences in brain responses to melodic deviants from their rsFC both across the whole brain (global parcellation in 22 regions) and within the auditory cortices (local parcellation in 22 regions). Predictability was consistently higher in specific brain areas. These areas are centred around sensory association cortices: In the local (auditory cortex) parcellation, the best predicted area is the right superior temporal gyrus (STG), an auditory association area. The right STG is a critical region in melodic contour processing, a capacity that is central to the paradigm at hand. Interestingly, the best predicted network in the global parcellation is the bilateral visual association cortex. Sensory association cortices may carry more information specific to an individual regardless of the particular paradigm. Our results indicate that individual differences can be predicted in paradigm-relevant areas or general areas with higher inter-individual variability.

Engineering Cortical Networks: An Open Platform for Controlled Human Circuit Formation and Synaptic Analysis In vitro
Neuronal circuits are complex networks formed by specific neuron connections across brain regions. Understanding their development is key to studying circuit-related dysfunctions in brain diseases. Human-induced pluripotent stem cell (iPSC) models aid in this research but lack precise architecture, limiting insights into neuronal interactions and activity-dependent processes. Microfluidic technologies offer structural control but are restricted by closed systems that hinder 3D integration, scalability, and cell retrieval. To address these limitations, we developed an open cortical network platform integrating iPSC-derived cortical neurons with bioengineering techniques. Using a polydimethylsiloxane (PDMS)-based microgroove topography and a cell plating guide, we created neuronal nodes for controlled circuit assembly. This design enables large-scale functional cortical circuits without physical barriers, allowing optogenetic control of neural activity and flexible network modifications, including cellular composition, neurite directionality, and synapse formation. The open design facilitates neuronal material accessibility, supporting multi-level analyses such as proteomics. This platform serves as a powerful tool for investigating neuronal network development and function, offering new opportunities to study both normal and pathological states, including molecular changes linked to connectivity loss in brain diseases.

Visual adaptation stronger at horizontal than vertical meridian: Linking performance with V1 cortical surface area
Visual adaptation, a mechanism that conserves bioenergetic resources by reducing energy expenditure on repetitive stimuli, leads to decreased sensitivity for similar features (e.g., orientation and spatial frequency). In human adults, visual performance declines with eccentricity and varies around polar angle for many visual dimensions and tasks: Performance is superior along the horizontal than the vertical meridian (horizontal-vertical anisotropy, HVA), and along the lower than the upper vertical meridian (vertical meridian asymmetry, VMA)(Carrasco et al., 2001). However, it remains unknown whether visual adaptation differs around polar angle. In this study, we investigated adaptation effects at the fovea and perifovea across the four cardinal locations, for horizontal and vertical adaptor and target orientations, with stimulus size adjusted as per a cortical magnification factor (Rovamo & Virsu, 1979). We measured contrast thresholds at each location separately for adaptation and non-adaptation conditions. Results confirmed the expected HVA and VMA effects in non-adapted conditions and showed they are stronger for horizontal than vertical orientations. They also revealed that, for both orientations, adaptation effects are stronger along the horizontal than the vertical meridian, which in turn is stronger than at the fovea. Furthermore, for both orientations, individual's adaptation effects at the perifoveal locations positively correlated with their cortical surface area of V1. The association of a stronger adaptation effect with larger V1 surface area suggests a more pronounced conservation of bioenergetic resources along the horizontal than the vertical meridian. Visual adaptation alleviates the HVA in contrast sensitivity, promoting a more homogeneous perception around the visual field.

Attractor-based models for sequences and pattern generation in neural circuits
Neural circuits in the brain perform a variety of essential functions, including input classification, pattern completion, and the generation of rhythms and oscillations that support functions such as breathing and locomotion. There is also substantial evidence that the brain encodes memories and processes information via sequences of neural activity. Traditionally, rhythmic activity and pattern generation have been modeled using coupled oscillators, whereas input classification and pattern completion have been modeled using attractor neural networks. Here, we present a theoretical model that demonstrates how attractor-based networks can also generate diverse rhythmic patterns, such as those of central pattern generators (CPGs). Additionally, we propose a mechanism for transitioning between patterns. Specifically, we construct a network that can step through a sequence of five different quadruped gaits. It is composed of two dynamically different networks: a ``counter'' network that can count the number of external inputs it receives, encoded via a sequence of fixed points; and a locomotion network that encodes five different quadruped gaits as limit cycles. A sequence of locomotive gaits is obtained by connecting the sequence of fixed points in the counter network with the dynamic attractors of the locomotion network. To accomplish this, we introduce a new architecture for layering networks that produces ``fusion'' attractors, minimizing interference between the attractors of individual layers. All of this is accomplished within a unified framework of attractor-based models using threshold-linear networks.