bioRxiv Subject Collection: Neuroscience's Journal

Ultradeep N-glycoproteome Atlas of Mouse Reveals Spatiotemporal Signatures of Brain Aging and Neurodegenerative Diseases
The current depth of site-specific N-glycoproteomics is insufficient to fully characterize glycosylation events in biological samples. Herein, we achieved an ultradeep and precision analysis of the N-glycoproteome of mouse tissues by integrating multiple workflows. The largest N-glycoproteomic dataset to date was established on mice, which contained 91,972 precursor glycopeptides, 62,216 glycoforms, 8,939 glycosites and 4,563 glycoproteins. The database consisted of 6.8 million glyco-spectra (containing oxonium ions), among which 160,928 were high-quality spectra with confident N-glycopeptide identifications. The large-scale and high-quality dataset enhanced the performance of current artificial intelligence models for glycopeptide tandem spectrum prediction. Using this ultradeep dataset, we observed tissue specific microheterogeneity and functional implications of protein glycosylation in mice. Furthermore, the region-resolved brain N-glycoproteomes for Alzheimer's Diseases, Parkinson Disease and aging mice revealed the spatiotemporal signatures and distinct pathological functions of the N-glycoproteins. A comprehensive database resource of experimental N-glycoproteomic data from this study and previous literatures were further established. This N-glycoproteome atlas serves as a promising tool for revealing the role of protein glycosylation in biological systems.

A Drd1-cre mouse line with nucleus accumbens gene dysregulation exhibits blunted fentanyl seeking
The synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands of overdose deaths every year. Despite this, the neurobiological effects of fentanyl use remain largely understudied. The nucleus accumbens (NAc) is a central locus promoting persistent drug use and relapse, largely dependent on activity of dopamine D1 receptors. NAc D1 receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular and physiological adaptations that contribute to negative affect during fentanyl abstinence, but whether these neuroadaptations also promote fentanyl relapse is unclear. Here, we obtained Drd1-cre120Mxu mice to investigate D1-dependent mechanisms of fentanyl relapse. We serendipitously discovered this mouse line is resistant to fentanyl seeking, despite similar intravenous fentanyl self-administration, and greater fentanyl-induced locomotion, compared to wildtype counterparts. In drug naive mice, we found Drd1-cre120Mxu mice have elevated D1 receptor expression in NAc, alongside increased expression of MSN marker genes Chrm4 and Penk. We show Drd1-cre120Mxu mice have increased sensitivity to the D1 receptor agonist SKF-38393, and exhibit divergent expression of MSN markers, opioid receptors, glutamate receptor subunits, and TrkB after fentanyl self-administration that may underly blunted fentanyl seeking. Finally, we show fentanyl-related behavior is unaltered by chemogenetic manipulation of D1-MSNs in Drd1-cre120Mxu mice. Conversely, chemogenetic stimulation of putative D1-MSNs in wildtype mice recapitulated the blunted fentanyl seeking of Drd1-cre120Mxu mice, supporting a role for aberrant D1-MSN signaling in this behavior. Together, our data uncover alterations in NAc gene expression and function with implications for susceptibility and resistance to developing fentanyl use disorder.

Investigating Facial Expression Processing during Fast Periodic Visual Stimulation using Highly Variable Stimuli
Facial expression recognition is a fundamental aspect of human social interaction, enabling effective communication and emotional understanding. Fast Periodic Visual Stimulation (FPVS) paradigms have recently emerged as a powerful approach for studying facial expression processing. However, previous studies often utilized identical base stimuli, making it difficult to disentangle neural responses to low-level perceptual differences from those reflecting conceptual discrimination of emotion. By introducing variability in our stimuli, we aimed to overcome these limitations and investigate neural responses to facial expressions of anger, fear, happiness, and sadness. Using EEG, robust oddball responses were observed across participants at both individual and group levels, demonstrating the paradigm's sensitivity even with brief recordings and limited post-processing. Significant neural responses were detected across key regions of interest, with the right occipito-temporal region showing the strongest activity, consistent with its role in high-level facial expression processing. This study highlights the effectiveness of the FPVS paradigm for examining emotional processing using naturalistic stimuli and provides a framework for future research into neural mechanisms underlying facial emotion recognition in diverse and pathological populations.

Histone Lysine Crotonylation Regulates Long-Term Memory Storage
Histone post-translational modifications (PTMs), particularly lysine acetylation (Kac), are critical epigenetic regulators of gene transcription underlying long-term memory consolidation. Beyond Kac, several other non-acetyl acylations have been identified, but their role in memory consolidation remains unknown. Here, we demonstrate histone lysine crotonylation (Kcr) as a key molecular switch of hippocampal memory storage. Spatial memory training induces distinct spatiotemporal patterns of Kcr induction in the dorsal hippocampus of mice. Through genetic and pharmacological manipulations, we show that reducing hippocampal Kcr levels impairs long-term memory, while increasing Kcr enhances memory. Utilizing single-nuclei multiomics, we delineate that Kcr enhancement during memory consolidation activates transcription of genes involved in neurotransmission and synaptic function within hippocampal excitatory neurons. Cell-cell communication analysis further inferred that Kcr enhancement strengthens glutamatergic signaling within principal hippocampal neurons. Our findings establish Kcr as a novel epigenetic mechanism governing memory consolidation and provide a foundation for therapeutic strategies targeting memory-related disorders.

Cell type transcriptomics reveal shared genetic mechanisms in Alzheimer's and Parkinson's disease
Historically, Alzheimer's disease (AD) and Parkinson's disease (PD) have been investigated as two distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single gene-centric genetic studies, including GWAS and differential gene expression analyses, have struggled to unravel the molecular links between AD and PD. To address this, we tailor a pattern-learning framework to analyze synchronous gene co-expression at sub-cell-type resolution. Utilizing recently published single-nucleus AD (70,634 nuclei) and PD (340,902 nuclei) datasets from postmortem human brains, we systematically extract and juxtapose disease-critical gene modules. Our findings reveal extensive molecular similarities between AD and PD gene cliques. In neurons, disrupted cytoskeletal dynamics and mitochondrial stress highlight convergence in key processes; glial modules share roles in T-cell activation, myelin synthesis, and synapse pruning. This multi-module sub-cell-type approach offers insights into the molecular basis of shared neuropathology in AD and PD.

Prior expectations guide multisensory integration during face-to-face communication
Face-to-face communication relies on the seamless integration of multisensory signals, including voice, gaze, and head movements, to convey meaning effectively. This poses a fundamental computational challenge: optimally binding signals sharing the same communicative intention (e.g. looking at the addressee while speaking) and segregating unrelated signals (e.g. looking away while coughing), all within the rapid turn-taking dynamics of conversation. Critically, the computational mechanisms underlying this extraordinary feat remain largely unknown. Here, we cast face-to-face communication as a Bayesian Causal Inference problem to formally test whether prior expectations arbitrate between the integration and segregation of vocal and bodily signals. Moreover, we asked whether there is a stronger prior tendency to integrate audiovisual signals that show the same communicative intention, thus carrying a crossmodal pragmatic correspondence. In a spatial localization task, participants watched audiovisual clips of a speaker where the audio (voice) and the video (bodily cues) were sampled either from congruent positions or at increasing spatial disparities. Crucially, we manipulated the pragmatic correspondence of the signals: in a communicative condition, the speaker addressed the participant with their head, gaze and speech; in a non-communicative condition, the speaker kept the head down and produced a meaningless vocalization. We measured audiovisual integration through the ventriloquist effect, which quantifies how much the perceived audio position is misplaced towards the video position. Bayesian Causal Inference outperformed competing models in explaining participants' behaviour, demonstrating that prior expectations guide multisensory integration during face-to-face communication. Remarkably, participants showed a stronger prior tendency to integrate vocal and bodily information when signals conveyed congruent communicative intent, suggesting that pragmatic correspondences enhance multisensory integration. Collectively, our findings provide novel and compelling evidence that face-to-face communication is shaped by deeply ingrained expectations about how multisensory signals should be structured and interpreted.

Neurochemical markers of uncertainty processing in humans
How individuals process and respond to uncertainty has important implications for cognition and mental health. Here we use computational phenotyping to examine individualised 'uncertainty fingerprints' in relation to neurometabolites and trait anxiety in humans. We introduce a novel categorical state-transition extension of the Hierarchical Gaussian Filter (HGF) to capture implicit learning in a four-choice probabilistic sensorimotor reversal learning task by tracking beliefs about stimulus transitions. Using 7-Tesla Magnetic Resonance Spectroscopy, we measured baseline neurotransmitter levels in the primary motor cortex (M1). Model-based results revealed dynamic belief updating in response to environmental changes. We further found region-specific relationships between M1 glutamate+ glutamine levels and prediction errors and volatility beliefs, revealing an important neural marker of probabilistic reversal learning in humans. High trait anxiety was associated with faster post-reversal responses. By integrating computational modelling with neurochemical assessments, this study provides novel insights into the neurocomputations that drive individual differences in processing uncertainty.

On the typical development of the central sulcus in infancy: a longitudinal evaluation of its morphology and link to behaviour
Introduction: The progressive folding of the cortex is an important feature of neurodevelopment starting early during gestation. The central sulcus (CS) is one of the first to fold. Since it represents the anatomical boundary between primary somatosensory and motor functional regions, its developing morphology may inform on the acquisition of sensorimotor skills. We aimed to identify potential asynchronous morphological changes along the CS during infancy, with the hypothesis that this may reflect the gradual emergence of body usage. Method: Based on 3T anatomical magnetic resonance imaging (MRI) and dedicated post-processing, we characterized the evolution in CS depth and curvature in 33 typical infants (aged 1 and 3 months, 22 with longitudinal data) in relation to 23 young adults as a reference. Four regions of interest (ROIs) along the CS, supposed to correspond to different parts of the body and one centred on the hand knob (HK), were reproducibly examined and compared across groups. We also explored the relationship between the age-related changes in morphological features and the global motor scaled scores evaluated at 3 months of age with the Bayley Scales of Infant and Toddler Development. Results: While all ROIs showed significant increases in CS depth and curvature between 3-month-olds and adults, the results were more variable between 1 and 3 months of age depending on cross-sectional and longitudinal analyses. The central-medial and central-lateral regions showed the most consistent increase in depth. Besides, motor development at 3 months of age was not significantly related to CS morphological changes, but a positive trend was observed for depth changes in the (HK-related) central-medial ROI. Conclusion: The rapid evolution of CS folding during infancy may reflect the intense but asynchronous maturation of the brain sensorimotor system, with the differential growth of cortical areas related to body parts and underlying white matter connections. Although it will have to be replicated on larger groups and at other ages, this longitudinal and multimodal study highlights the potential of characterizing CS features as key markers of early sensorimotor development, both at the cerebral and behavioural levels. Combining anatomical and functional neuroimaging could provide deeper insights into the relationship between CS morphology and somatotopic organization in typical infants, but also in infants at risk of developing motor disorders.

Decoding memory dysfunction in hippocampal amnesia
The hippocampus reconstructs past experiences by integrating sensory, perceptual, and conceptual information across a cortico-hippocampal autobiographical memory network (AMN). Here, in 18 human participants with amnesia, we decoded the effects of bilateral focal hippocampal damage on distinct autobiographical representations using representational dissimilarity matrices (RDMs). Hippocampal pathology resulted in: (1) impaired generalised episodic memory retrieval RDM model fit in the left angular gyrus; and, (2) reduced distinct episodic memory RDM model fit and trial-by-trial voxel-representational stability in the right angular gyrus, right orbitofrontal cortex, and right inferior frontal gyrus. RDM model fits and mnemonic stability were predicted by total CA23 volumes. Trial-by-trial retrieval stability within the right orbitofrontal cortex and right inferior frontal gyrus predicted autobiographical memory performance, providing the first direct neural correlate between hippocampal dysfunction, altered mnemonic representations, and amnesia. The results demonstrate that hippocampal-mediated amnesia results from impaired mnemonic representational distinctiveness and stability within the AMN.

The neural basis of creative thought: An activation likelihood estimation meta-analysis involving over 17,000 participants
Humans can create impressive art, make major scientific breakthroughs, and generate creative solutions that solve everyday life problems. But how are these creative activities supported by the brain? This question is of great scientific interest but remains unanswered. New hypotheses, grounded in converging evidence from cognitive neuroscience, are needed to guide breakthroughs in understanding the neural basis of creative thought. It has long been suggested that creativity is a distinct mental function. However, converging clinical-cognitive neuroscience evidence is starting to suggest that creative thought is not functionally distinct but, instead, might arise from general purpose cognitive mechanisms supporting semantic cognition, controlled episodic memory retrieval, and executive mechanisms (i.e., Cognitive Cornerstones Hypothesis; Chan et al., 2023). Results from this large-scale activation likelihood estimation (ALE) meta-analysis, based on 787 experiments with 10,357 foci from 17,228 healthy adult participants, showed that the brain regions implicated in creativity tasks heavily overlap with the brain regions implicated in the cognitive cornerstones of creative thought (i.e., pre-existing knowledge and executive mechanisms). These striking results suggest that innovative insights will arise from considering the roles of these fundamental cognitive functions and their interactions in supporting creative thought.

Altered auditory feature discrimination in a rat model of Fragile X Syndrome
Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is the leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 KO rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 knockout (KO) rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of sound bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiology recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. These findings suggest that cortical hyperexcitability may account for a range of auditory behavioral phenotypes in FXS, providing a potential locus for development of novel biomarkers and treatment strategies that could extend to other forms of ASD.

Human newborns form musical predictions based on rhythmic but not melodic structure
The ability to anticipate rhythmic and melodic structures in music is considered a fundamental human trait, present across all cultures and predating linguistic comprehension in human development. Yet, it remains unclear the extent to which this ability is already developed at birth. Here, we used temporal response functions to assess rhythmic and melodic neural encoding in newborns (N = 49) exposed to classical monophonic musical pieces (real condition) and control stimuli with shuffled tones and inter-onset intervals (shuffled condition). We computationally quantified context-based rhythmic and melodic expectations and dissociated these high-level processes from low-level acoustic tracking, such as local changes in timing and pitch. We observed encoding of probabilistic rhythmic expectations only in response to real but not shuffled music. This proves newborns' ability to rely on rhythmic statistical regularities to generate musical expectations. We found no evidence for the tracking of melodic information demonstrating a downweighing of this dimension compared to the rhythmic one. This study provides neurophysiological evidence that the capacity to track statistical regularities in music is present at birth and driven by rhythm. Melodic tracking, in contrast, may receive more weight through development with exposure to signals relevant to communication, such as speech and music.

A single-cell transcriptomic atlas of developing inhibitory neurons reveals expanding and contracting modes of diversification.
The cerebral cortex relies on vastly different types of inhibitory neurons to compute. How this diversity emerges during development remains an open question. The rarity of individual inhibitory neuron types often leads to their underrepresentation in single-cell RNA sequencing (scRNAseq) datasets, limiting insights into their developmental trajectories. To address this problem, we developed a computational pipeline to enrich and integrate rare cell types across multiple datasets. Applying this approach to somatostatin-expressing (SST+) inhibitory neurons - the most diverse inhibitory cell class in the cortex - we constructed the Dev-SST-Atlas, a comprehensive resource containing mouse transcriptomic data of over 51,000 SST+ neurons. We identify three principal groups - Martinotti cells (MCs), non-Martinotti cells (nMCs), and long-range projecting neurons (LRPs) - each following distinct diversification trajectories. MCs commit early, with distinct embryonic and neonatal clusters that map directly to adult counterparts. In contrast, nMCs diversify gradually, with each developmental cluster giving rise to multiple adult cell types. LRPs follow a unique 'contracting' mode. Initially, two clusters are present until postnatal day 5 (P5), but by P7, one type is eliminated through programmed cell death, leaving a single surviving population. This transient LRP type is also found in the fetal human cortex, revealing an evolutionarily conserved feature of cortical development. Together, these findings highlight three distinct modes of SST+ neuron diversification - invariant, expanding, and contracting - offering a new framework to understand how the large repertoire of inhibitory neurons emerges during development.

White-matter controllability at birth predicts social engagement and language outcomes in toddlerhood
Social engagement and language are connected through early development. Alterations in their development can have a prolonged impact on children's lives. However, the role of white matter at birth in this ongoing connection is less well-known. Here, we investigate how white matter at birth jointly supports social engagement and language outcomes in 642 infants. We use edge-centric network control theory to quantify edge controllability, or the ability of white-matter connections to drive transitions between diverse brain states, at 1 month. Next, we used connectome-based predictive modeling (CPM) to predict the Quantitative Checklist for Autism in Toddlers (Q-CHAT) for social engagement risks and the Bayley Scales of Infant and Toddler Development (BSID-III) for language skills at 18 months from edge controllability. We created the social engagement network (SEN) to predict Q-CHAT scores and the language network (LAN) to predict BSID-III scores significantly. The SEN and LAN were complex, spanning the whole brain. They also significantly overlapped in anatomy and generalized across measures. Controllability in the SEN at 1 month partially mediated associates between Q-CHAT and BSID-III language scores at 18 months. Further, controllability in the SEN significantly differed between term and preterm infants and predicted Q-CHAT scores in an external sample of preterm infants. Together, our results suggest that the intertwined nature of social engagement and language development is rooted in an infant's white-matter controllability.

Computational modelling reveals slower safety learning and threat extinction are associated with higher anxiety severity in remote fear conditioning
Anxiety disorders are are chronic, pervasive, and debilitating; characterised by a persistent or exaggerated response to distal or abstract threats. Impaired threat discrimination (distinguishing safe from threatening stimuli) and impaired threat extinction (learning a once threatening stimulus is now safe), are known risk factors in the development and persistence of anxiety disorders. These effects can be experimentally elicited through fear conditioning. First, repeated trials of paired aversive and neutral stimuli are delivered during a fear acquisition phase, followed by repeated trials with no aversive stimuli in a fear extinction phase. The effects are typically measured through comparison of end-phase data points, or simple descriptive or statistical models. Computational modelling, by contrast, can offer a hypothesis-driven, trial-by-trial mechanistic account of fear conditioning. This unmasks within subject task variance by estimating the rate of threat learning, safety learning, and threat extinction, examining individual differences in the cognitive mechanisms behind anxiety. A normative sample (n = 145) underwent a differential fear conditioning task on a bespoke smartphone app, in addition to completing an anxiety severity measure (GAD-7). Computational models fitted to task data estimated learning rates. Whilst the threat learning rate showed no association, the threat extinction and safety learning rates showed small negative associations with anxiety severity (r = -0.218, p = 0.008 & r = -0.214, p = 0.01 respectively). These findings are in keeping with prior studies using traditional analytical approaches, and indicate that anxious individuals are not quicker to develop fear of a stimulus, but take more time than their non-anxious counterparts to learn that a stimulus is safe. This study strengthens the evidence for impairments in fear extinction in those with anxiety, and the importance of learning rates as an index of anxiety severity, a previously hidden cognitive mechanism underlying anxiety persistence.

Syngap+/- CA1 pyramidal neurons exhibit upregulated translation of long mRNAs associated with LTP
In the Syngap+/- model of SYNGAP1-related intellectual disability (SRID), excessive neuronal protein synthesis is linked to deficits in synaptic plasticity. Here, we use Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) to identify mistranslating mRNAs in Syngap+/- CA1 pyramidal neurons that exhibit enhanced synaptic stability and impaired long-term potentiation (LTP). We find the translation environment is significantly altered in a manner that is distinct from the Fmr1-/y model of Fragile X Syndrome (FXS), another monogenic model of autism and intellectual disability (ID). The Syngap+/- translatome is enriched for regulators of DNA repair, and mimics changes induced with chemical LTP (cLTP) in WT. This includes a striking upregulation in the translation of mRNAs with a longer length (>2kb) coding sequence (CDS). In contrast, long CDS transcripts are downregulated with induction of Gp1 metabotropic glutamate receptor induced long-term depression (mGluR-LTD) in WT, and this profile is mimicked in the Fmr1-/y model. Together, our results show the Syngap+/- and Fmr1-/y models mimic the translation environments of LTP and LTD, respectively, consistent with the dysregulation of these plasticity states in each model. Moreover, we show that translation of >2kb mRNAs is a defining feature of LTP that is oppositely regulated during LTD, revealing a novel mRNA signature of plasticity.

Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis in vivo and in Cellular Models
Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimers disease. However, no study has validated its functional role in these diseases, explored the disease stage at which it is acting nor its mechanism of action. Here, we show that syntaxin-6 acts at early stages of prion disease in experimental mice by increasing disease transmission risk following inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Syntaxin-6 manipulation in cellular models profoundly alters the subcellular distribution and morphologies of disease-related PrP and modifies prion export. Furthermore, syntaxin-6 knockout in a transgenic tauopathy mouse model exerts protective effects on numerous physiological, behavioural and neuropathological outcome measures. Therefore, our studies firmly establish syntaxin-6 as a modifier of prion and tau pathogenesis, providing key insights into a fundamental mechanism of neurodegeneration.

Effects of Pesticide Exposure on Neuroinflammation and Microglial Gene Expression: Relevance to Mechanisms of Alzheimer's Disease Risk
BackgroundAlzheimers disease (AD) is characterized by the presence of amyloid-{beta} plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.

ObjectiveHere, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.

MethodsEffects of DDT on inflammation and disease-associated microglia were determined in primary mouse microglia and C57BL/6J mice.

ResultsPMG exposed to DDT (0.5-5.0 {micro}M) elicited a [~]2-3-fold increase in Il-1b mRNA levels, with similar concentration-dependent upregulation in Il-6, Nos2, and Tnfa. These effects were blocked by the sodium channel antagonist tetrodotoxin, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. Additionally, NOS2 protein levels increased by [~]1.5-2-fold, while TNFa was elevated by 2-4-fold. C57BL/6J male and female mice exposed to DDT (30 mg/kg) demonstrated significantly increased mRNA levels of Nos2, Il-1b, and Il-6 in the frontal cortex (1.5-2.3-fold), and Nos2, Il-1b, and Tnfa (1.5-1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes, Cx3cr1, P2ry12, and Tmem119, were downregulated, while stage 1 disease-associated microglia genes were upregulated both in vitro and in vivo. Notably, Apoe and Trem2 were only upregulated in the frontal cortex and hippocampus of females.

ConclusionThese data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.

Boosting Brainpower in Ageing: Task-Specific and Transfer Effects of tDCS-Enhanced Working Memory Training
Ageing is associated with neural alterations that impair cognitive abilities, particularly working memory (WM)--the capacity to temporarily store and manipulate information essential for daily functioning. Transcranial Direct Current Stimulation (tDCS) has shown promise in enhancing WM in older adults by modulating cortical excitability and promoting neuroplasticity. However, findings on the combined effects of tDCS and WM training remain inconsistent, particularly regarding transfer effects to non-trained WM tasks (near transfer) or other cognitive domains (far transfer). This study examined the behavioural and neural effects of tDCS on distinct WM phases (encoding, retention/manipulation, recall) in older adults. Over three weeks, participants underwent six sessions of adaptive WM training paired with tDCS targeting the left dorsolateral prefrontal cortex (DLPFC). Neural activity was assessed via EEG, focusing on theta and alpha bands. Participants were divided into tDCS and placebo groups and completed two WM tests, the Letter Span and Corsi Test, with retention and manipulation conditions. Results showed no additional behavioural or neural benefits of tDCS. However, both groups exhibited near-transfer effects that persisted one-month post-training. Neural changes varied by task: the Letter Span showed increased alpha power during manipulation, indicating enhanced maintenance of information during that phase, while the Corsi Test showed reduced left-hemisphere theta power during recall, reflecting reduced hemispheric asymmetry. Inter-individual variability likely contributed to inconsistencies and a lack of correlations between outcomes. These findings highlight the importance of personalised tDCS protocols and suggest adaptive WM training can yield enduring cognitive and neural benefits in older adults.

Effective connectivity between the medial temporal lobes and early visual cortex modulated by unrestricted viewing predicts memory retrieval and gaze reinstatement
Memory and gaze behavior are intricately linked, guiding one another to extract information and create mental representations of our environment for subsequent retrieval. Recent findings from functional neuroimaging and computational modeling suggest that reciprocal interactions between the extended hippocampal system and visuo-oculomotor regions are functionally relevant for building these mental representations during visual exploration. Yet, evidence for the directionality of information flow during encoding within this reciprocal architecture in humans is limited. In the current study, we used dynamic causal modeling (DCM) to give a non-invasive account for the directional influences between these systems when new memories are created. Here, we provide novel evidence demonstrating how unrestricted, naturalistic visual exploration induces changes in this connectivity. Subsequent memory retrieval performance was also predicted by the pattern of connectivity modulated by unrestricted visual exploration, identifying the mechanism underlying a rich history of previous work linking increased gaze behavior during encoding to later memory. Together, these findings suggest that gaze behavior shapes the ways in which brain dynamics within and between the hippocampal system and early visual cortex unfold during encoding in humans. Importantly, these directional interactions support the building of coherent, lasting mental representations.

CellFIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology
Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis and an imaging-based pooled genetic perturbation study to examine modifiers of Huntington's disease (HD). The computational analysis highlighted several genes in a subnetwork enriched for modifiers of neuronal development and morphology. To test the functional roles of these genes, we developed an experimental pipeline that allows pooled CRISPRi KD of 21 genes in human iPSC-derived neurons followed by optical analysis of genotypes, neuronal arborization, multiplexed pathway activity and morphological fingerprint readout. This approach recovered known genes involved in morphology and confirmed unexpected links from the network between several genetic modifiers of HD and morphology. Our approach overcomes challenges in pooled measurement of neuronal function and health and could be adapted for other phenotypes in HD and other neurological diseases.

Gender imbalance in citations most pronounced in high-impact neuroscience journals
In the past several years, neuroscience, like many other fields, has worked to address pervasive gender imbalances. Although tangible improvements have been made in academic publishing and conference participation, gender imbalances in citations among leading neuroscience journals persist and are increasing with time. Here, we expand upon prior work by providing a more comprehensive analysis of citation practices across fifty journals to improve our understanding of the dynamics of the field as a whole, particularly across different kinds of journals. We first confirm that reference lists tend to include more papers with men as first and last author than expected if gender were unrelated to citation practices. Further, we demonstrate that this effect is strongest in the most influential journals. We also find that the apparent closure of the gender gap is due to the interaction of three unique, nuanced patterns of citation: one that is characterized by relative overcitation of papers with men as both first and last author; one that is characterized by relative overcitation of women as the last author, and one that is characterized by relative undercitation of women as the first author. In addition, we find that these patterns of citation are not distributed evenly across the field: more prestigious journals tend to have articles with citation gaps favoring men, while less prestigious journals tend to overcite papers with women as last authors. We discuss potential drivers for these patterns and suggest some implications for the field moving forward.

Influence of sustained cognitive loading on finger circulatory and thermoperceptual responsiveness to localized cooling
Our aim was to examine whether finger vasomotor and thermoperceptual responses to local cooling would be modulated by sustained cognitive loading. To this end, finger temperature, circulatory (i.e., cutaneous vascular conductance, CVC) and perceptual responses were monitored, in twelve healthy men, during and after a 30-min hand immersion in 8{degrees}C water, performed either immediately after a 60-min continual execution of a cognitive task battery (cognitive[->]cold trial), or during the simultaneous performance of the cognitive task (cognitive+cold trial). Subjects responses were compared with those obtained in a control cold-provocation trial, wherein they watched an emotionally-neutral documentary. The cognitive task temporary enhanced the perceived levels of mental effort and fatigue in both intervention trials. In the cognitive[->]cold trial, the cold-induced reduction in finger CVC and increase in mean arterial pressure were blunted (P < 0.01), and the thermal discomfort was alleviated (P = 0.05). In the cognitive+cold trial, no intertrial differences were noted during the cold-water immersion phase (P [≥] 0.28), but the finger CVC was enhanced during the last part of the rewarming phase (P = 0.05). Present findings, therefore, demonstrate that (i) in moderately mentally-fatigued individuals, finger cold-induced vasoconstriction is transiently attenuated, and thermal discomfort is mitigated, and (ii) superimposition of cognitive loading on cold stress does not alter finger vasoreactivity or thermosensitivity during cooling, but facilitates finger reperfusion following cooling.

Modulations of thalamo-cortical coupling during voluntary movement in patients with essential tremor
The ventral intermediate nucleus of the thalamus (VIM) is the main thalamic hub for processing cerebellar inputs and the main deep brain stimulation target for the treatment of essential tremor (ET). As such, it presumably plays a critical role in motor control. So far, however, this structure has been rarely investigated in humans, and almost all of the existing studies focus on tremor. Here, we set out to study neural oscillations in the VIM and their coupling to cortical oscillations during voluntary movement. We investigated thalamo-cortical coupling by means of simultaneous recordings of thalamic local field potentials and magnetoencephalography in 10 ET patients with externalized deep brain stimulation electrodes. Brain activity was measured while patients were pressing a button repeatedly in response to a visual cue. In a whole-brain analysis of coherence between VIM and cortex, we contrasted activity around a pre-movement baseline and button pressing. Button pressing was associated with a bilateral decrease of thalamic power in the alpha (8-12 Hz) and beta (13-21 Hz) band and a contralateral power increase in the gamma (35-90 Hz) band. Moreover, changes in VIM-cortex coherence were observed. Alpha/low beta (8-20 Hz) coherence decreased before and during movement, and the effect localized to the supplementary motor area and premotor cortex. A rebound of high beta (21-35 Hz) coherence occurred in the same region, but was more focal than the suppression. Pre-movement levels of thalamo-cortex low-beta coherence correlated with reaction time. Our results demonstrate that voluntary movement is associated with modulations of behaviourally relevant thalamic coupling, primarily to premotor areas. We observed a clear distinction between low- and high-beta frequencies and our results suggest that the concept of antikinetic beta oscillations, originating from research on Parkinson's disease, is transferable to ET.