bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholinergic dynamics in the septo-hippocampal system provide phasic multiplexed signals for spatial novelty and correlate with behavioral states
Authors: Moghadam Fatemeh Farokhi , Guzman Blanca E. Gutierrez , Zheng Xihui , Parsa Mina , Hozyen Lojy M. , Dannenberg Holger 
Published: January 2025

ABSTRACTIn the hippocampal formation, cholinergic modulation from the medial septum/diagonal band of Broca (MSDB) is known to correlate with the speed of an animal’s movements at sub-second timescales and also supports spatial memory formation. Yet, the extent to which sub-second cholinergic dynamics, if at all, align with transient behavioral and cognitive states supporting the encoding of novel spatial information remains unknown. In this study, we used fiber photometry to record the temporal dynamics in the population activity of septo-hippocampal cholinergic neurons at sub-second resolution during a hippocampus-dependent object location memory task using ChAT-Cre mice. Using a general linear model, we quantified the extent to which cholinergic dynamics were explained by changes in movement speed, behavioral states such as locomotion, grooming, and rearing, and hippocampus-dependent cognitive states such as recognizing a novel location of a familiar object. The data show that cholinergic dynamics contain a multiplexed code of fast and slow signals i) coding for the logarithm of movement speed at sub-second timescales, ii) providing a phasic spatial novelty signal during the brief periods of exploring a novel object location, and iii) coding for environmental novelty at a seconds-long timescale. Furthermore, behavioral event-related phasic cholinergic activity around the onset and offset of the behavior demonstrates that fast cholinergic transients help facilitate a switch in cognitive and behavioral state before and during the onset of behavior. These findings enhance understanding of the mechanisms by which cholinergic modulation contributes to the coding of movement speed and encoding of novel spatial information.
Working memory shapes neural geometry in human EEG over learning
Authors: Wójcik Michał J. , Li Amy , Wasmuht Dante , Stroud Jake P. , Stokes Mark G. , Myers Nicholas E. , Hunt Laurence T. 
Published: January 2025

AbstractWorking memory has been traditionally studied as a passive storage for information. However, recent advances have suggested that working memory is prospective rather than retrospective, meaning that its content undergoes transformations that will support future behaviour. One perspective that underscores this notion conceptualises memory processes as a computational resource that can be used to reduce the complexity of computation at decision time. Here, we explore this perspective by examining whether the process of maintenance shapes neural geometry and leads to low-dimensional representations during storage and later decision time. We recorded EEG in 25 human participants who learnt to solve a XOR task. We hypothesised that separating task features by a working memory delay would result in participants temporally decomposing the XOR computation, by prospectively processing one of the task features early in trial time. In line with our predictions, participants transformed the first feature from a sensory to an abstract format and maintained this pre-processed information throughout the delay. This process was related to the low-dimensional representation required at decision time early in learning, a representation that has recently been shown to support later cross-generalisation. These results demonstrate that low-dimensional representations, elsewhere associated with slow learning, might also provide a mechanism for maintenance processes in working memory.
Exploiting Endogenous Cas9-Based Genome Editing ofLacticaseibacillus rhamnosusGG (LGG) for Precision Food Fermentation and Live Biotherapeutics
Authors: Xie Zifan , Jin Yong-Su , Miller Michael J. 
Published: January 2025

AbstractLacticaseibacillus rhamnosusGG (LGG) is one of the most studied probiotic strains and is widely used in both food and therapeutic industries. With its safe and health-beneficial properties, LGG is an ideal candidate for genome modification to enhance its functionalities for food, industrial and pharmaceutical applications. However, precise and efficient genome engineering tools for LGG are unavailable. In this study, we developed a novel genome engineering tool for LGG based on its endogenous type II-A CRISPR-Cas9 system. By employing a validated protospacer adjacent motif (PAM), a customized single guide RNA (sgRNA) expression cassette and a homologous repair template, we successfully reprogrammed the native CRISPR-Cas9 system for targeted genome modifications. Using this method, we successfully constructed a fucose-negative LGG incapable of growing on L-fucose and a lactose-positive LGG. The lactose-positive LGG exhibited significantly improved growth in milk compared to its parental strain LGG, which is unable to ferment lactose, attributed to its ability to metabolize lactose efficiently. Moreover, this strain showed robust growth during yogurt fermentation and maintained viability during cold storage for at least three weeks. These findings highlight the potential of the lactose-positive LGG as an improved culture for dairy industry and a functional probiotic for food and therapeutic applications.ImportanceA precise and efficient genome editing tool is essential for unlocking the full potential ofLacticaseibacillus rhamnosusGG (LGG), the most extensively studied probiotic strain. This study established the first high-efficiency genome editing platform for LGG by harnessing the endogenous type II-A CRISPR-Cas9 system. Using this tool, we achieved targeted gene modifications, without introducing scars, heterologous DNA, or antibiotic resistance genes. The engineered lactose-positive LGG strain demonstrated improved growth in lactose-containing dairy products and robust performance during yogurt fermentation, highlighting its industrial and therapeutic value. This platform not only advances the development of enhanced probiotic strains but also establishes LGG as a versatile vehicle for synthetic biology and biotechnological applications.
Population-level encoding of somatosensation in mouse sensorimotor cortex
Authors: Park Seungbin , Lipton Megan H. , Dadarlat Maria C. 
Published: January 2025

1AbstractDexterous limb movements rely on somatosensation (touch and proprioception), which provides the sense of the body’s posture, movement, and interaction with objects. The heterogeneous responses of single neurons in sensorimotor cortex to somatosensation have led to disparate views of the computa-tional role of this brain area in somatosensory processing. Here, we use population-level analyses of neural activity recorded during active and passive limb movements to assess the structure and sum-marize the properties of neural encoding in sensorimotor cortex. We used 2-photon imaging to record the activity of thousands of neurons in these brain areas from eight anesthetized mice during passive deflections of each limb. We additionally analyzed neural responses to passive limb movements in eight awake mice, sourced from an open dataset [1], and neural responses to spontaneous limb movements in eight mice, collected during a previous study [2]. To conduct the population-level analyses, we found the principal components of the time-varying neural population activity matrix in each set of experi-ments. Across all three datasets and behavioral conditions, a small fraction of principal components explained a large fraction of variance in the neural responses. These low-dimensional representations of single and multi-limb movements were well conserved across animals, including orthogonal represen-tations of ipsilateral and contralateral limbs. This organization of somatosensory information mirrors the well-known structure of neural encoding of motor commands. Furthermore, while the activity of in-dividual neurons and small populations best encoded intrinsic variables, larger populations of neurons additionally encode extrinsic variables — a representational structure that is commonly associated with higher-level brain areas. Together, these analyses demonstrate that population-level encoding of somatosensory information in mouse sensorimotor cortex is structured to facilitate sensorimotor integration across the brain.
Paraspeckle Protein NONO Regulates Active Chromatin by Allosterically Stimulating NSD1
Authors: Hsu Chen-I , Mei Shenglin , Demmerle Justin , Ruttenberg Sarah , Sahn Mahnue , Yu Jia-Ray 
Published: January 2025

SUMMARYNSD1 is a key lysine methyltransferase for di-methylation of lysine 36 of histone H3 (H3K36me2) essential for the establishment of active chromatin domains. While the loss of NSD1 catalytic activity halts embryonic development and a gain of that drives oncogenesis in leukemia and glioma, the regulatory mechanisms that control NSD1 activity in these processes remain poorly understood. Here, we uncover that NSD1 requires allosteric activation through the aromatic pocket of its PWWP2 domain. Surprisingly, we identify that NSD1-PWWP2 binds to a non-canonical target, nuclear paraspeckle protein NONO, and this protein-protein interaction allosterically stimulates the catalytic activity of NSD1. Mouse embryonic stem cells (mESC) engineered with mutations in the aromatic pocket of NSD1-PWWP2 cannot differentiate into neural progenitor cells (NPC), and genetic depletion of NONO partially phenocopied this defect at cellular and transcriptional levels, potentially explaining the neurodevelopmental disorder phenotypes in NSD1- or NONO-deficient patients. Our work revealed a novel mechanism driving active chromatin domain formation and has critical implications in the interplay between nuclear paraspeckles and active chromatin, and a vulnerability of NSD1 for therapeutic interventions.GRAPHIC ABSTRACTHIGHLIGHTSThe catalytic activity of NSD1 requires the aromatic pocket of its PWWP2 domainThe aromatic pocket of NSD1-PWWP2 binds to a non-canonical target, paraspeckle protein NONO, which allosterically stimulates NSD1Disruption of the assemblies of paraspeckles dampens global H3K36me2 levelsNONO deficiency partially phenocopies the defects of neural differentiation in NSD1-knockout embryonic stem cells
Novel antimicrobial activity of photoactive compounds originally synthesized for industrial applications
Authors: Ezquerra-Aznárez José Manuel , Alonso-Román Raquel , Lucía Ainhoa , Andreu Raquel , Franco Santiago , Aínsa José A. , Ramón-García Santiago 
Published: January 2025

AbstractThe emergence of antimicrobial resistance threatens advances achieved by medicine in the last century. This situation has been aggravated by the suboptimal outcome of screening campaigns to provide novel antibiotics. In this study, we took an alternative approach to discover new chemical scaffolds with antimicrobial activity. We screened a collection of photoactive compounds originally synthesized for industrial purposes and found that 4H-pyran-4-ylidenes are active against Gram-positive bacteria. Compounds belonging to this family displayed dose-dependent bactericidal activity against wild-typeStaphylococcus aureusand Methicillin ResistantS. aureus(MRSA). Importantly, they were not cytotoxic to hepatic cell lines at the concentrations at which antimicrobial activity was observed. Resistance to 4H-pyran-4-ylidenes inS. aureuswas achieved via mutations in thernylocus, likely via changes in mRNA levels of genes critical for their activity. Overall, we demonstrate that chemical libraries not originally intended for drug discovery can be a fruitful source of chemical diversity for the development of novel antimicrobials.
The patient-specific mouse model withFoxg1frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome
Authors: Jeon Shin , Park Jaein , Moon Ji Hwan , Shin Dongjun , Li Liwen , O’Shea Holly , Hwang Seon Ung , Lee Hyo-Jong , Brimble Elise , Lee Jae W. , Clark Stewart , Lee Soo-Kyung 
Published: January 2025

AbstractsSingle allelic mutations in the forebrain-specific transcription factor geneFOXG1lead to FOXG1 syndrome (FS). To decipher the disease mechanisms of FS, which vary depending on FOXG1 mutation types, patient-specific animal models are critical. Here, we report the first patient-specific FS mouse model,Q84Pfsheterozygous (Q84Pfs-Het) mice, which emulates one of the most predominant FS variants. Remarkably, Q84Pfs-Het mice recapitulate various human FS phenotypes across cellular, brain structural, and behavioral levels, such as microcephaly, corpus callosum agenesis, movement disorders, repetitive behaviors, and anxiety. Q84Pfs-Het cortex showed dysregulations of genes controlling cell proliferation, neuronal projection and migration, synaptic assembly, and synaptic vesicle transport. Interestingly, the FS-causingQ84Pfsallele produced the N-terminal fragment of FOXG1, denoted as Q84Pfs protein, in Q84Pfs-Het mouse brains. Q84Pfs fragment forms intracellular speckles, interacts with FOXG1 full-length protein, and triggers the sequestration of FOXG1 to distinct subcellular domains. Q84Pfs protein also promotes the radial glial cell identity and suppresses neuronal migration in the cortex. Together, our study uncovered the role of the FOXG1 fragment derived from FS-causingFOXG1variants and identified the genes involved in FS-like cellular and behavioral phenotypes, providing essential insights into the pathophysiology of FS.
Chronic social instability stress differentially affects the behavior and the transcriptome of the anterodorsal bed nucleus of the stria terminalis between male and female mice
Authors: Degroat Thomas J. , Paladino Sarah E. , Denney Katherine , Moran Kevin M. , Samuels Benjamin A. , Roepke Troy A. 
Published: January 2025

AbstractStress can be broken down into systemic and processive stressors with processive stressors requiring higher limbic processing. These are also often called social stressors as they require an understanding of social dynamics as opposed to physical based stressors. This differing of processing necessitates we study both phenomena. Additionally, sex is an important aspect of stress research as men and women show differing responses to stress and mood disorder development. To study this, we used a chronic social instability stress (CSIS) paradigm to stress male and female mice. This paradigm is approximately 7-weeks long and involves changing the cage mates of a mouse every 3 days so stable social dynamics cannot form. Afterwards, one cohort was used for avoidance behavior testing using the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. A second cohort was used for bulk RNA-Sequencing of the anterodorsal bed nucleus of the stria terminalis which is a limbic structure known to be related to chronic stress signaling. In the behavior assays, CSIS caused the females to be less avoidant, while the males became more avoidant. Additionally, we found that a low estrogen state in the females caused them to be less avoidant than in a high estrogen state. In the transcriptome, we found major differences between the males and females with the males expressing more genes related to transcription whereas the females expressed more genes related to synaptic transmission. We also found that the transcriptome in the males is more sensitive to the stress than the females. In summary, we have found how social stress is differentially regulated between males and females and how this may be related to the development of stress-related behavioral changes.
A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists
Authors: Yacawych Warren T. , Wang Yi , Zhou Guoxiang , Hassan Shad , Kernodle Stace , Sass Frederike , DeVaux Martin , Wu Iris , Rupp Alan , Tomlinson Abigail J. , Lin Zitian , Secher Anna , Raun Kirsten , Pers Tune , Seeley Randy J. , Myers Martin , Qiu Weiwei 
Published: January 2025

AbstractGLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and that mediate the physiologic control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstemGlp1rneurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Hence, we defined roles for AP and NTSGlp1r-expressing neurons (APGlp1rand NTSGlp1rneurons, respectively) in the physiologic control of body weight, the GLP1RA-dependent suppression of food intake, and the GLP1RA-mediated stimulation of aversive responses. While silencing non-aversive NTSGlp1rneurons interfered with the physiologic restraint of feeding and body weight, restoring NTSGlp1rneuronGlp1rexpression on an otherwiseGlp1r-null background failed to enable long-term body weight suppression by GLP1RAs. In contrast, selectiveGlp1rexpression in APGlp1rneurons restored both aversive responses and long-term body weight suppression by GLP1RAs. Thus, while non-aversive NTSGlp1rneurons control physiologic feeding, aversive APGlp1rneurons mediate both the anorectic and weight loss effects of GLP1RAs, dictating the functional inseparability of these pharmacologic GLP1RA responses at a circuit level.
Scg2 drives reorganization of the corticospinal circuit with spinal premotor interneurons to recover motor function after stroke
Authors: Sato Tokiharu , Nakamura Yuka , Hoshina Kana , Inoue Ken-ichi , Takada Masahiko , Yano Masato , Matsuzawa Hitoshi , Ueno Masaki 
Published: January 2025

AbstractBrain injuries such as stroke damage neural circuitry and lead to functional deficits. Spared motor pathways are often reorganized and contribute to functional recovery; however, the connectivity and molecular mechanisms that drive the reorganization are largely unknown. Here, we demonstrate structural and functional connectivity reformed by spared corticospinal axons after stroke and determine a key secretory protein that drives the reorganization. We first found that corticospinal axons innervate specific areas of the denervated cervical cord after stroke. Anatomical and photometric analyses reveal that the axons reconnect to premotor V2a interneurons. Kinematic analyses of forelimb movements and chemogenetic silencing reveal their contribution to motor recovery. Translated mRNA expression analyses of V2a interneurons and astrocytes in the denervated cervical cord reveal diverse transcripts upregulated in the rewiring process. In particular, a secretory protein Scg2 is upregulated by injury-induced purinergic ATP signals and rehabilitative training-induced neural activity and possesses an ability to promote axon growth via cAMP and S6 signaling. Scg2 overexpression in the denervated cervical cord enhances axon rewiring, while the Scg2 knockdown attenuates it. The present data reveal the neural substrate and molecular mechanism essential to induce reorganization and recovery of the motor system, providing fundamental therapeutic targets for CNS injuries.
Sensory Appendage Protein triggers alarm to pyrethroid in Indian malarial vector Anopheles culicifacies
Authors: Saini Vaishali , Rohilla Pooja , Srivastava Vartika , Tandon Gitanjali , Yadav Pooja , Sankhala Nirmala , Singh Tanvi , Sharma Gunjan , Tyagi Suchi , De Tanwee Das , Dixit Rajnikant 
Published: January 2025

AbstractSensory appendage proteins (SAPs) serve as molecular arms of odorant-binding protein family members and mediate chemical communication from the external to the internal environment of the insect body. We recently reported that SAP members might have an important role in blood-feeding and/or insecticide resistance-associated behavioral physiologies, but the mechanism remains unclear. Here we show howSAPcontributes (i) to the host attraction during navigation for blood-feeding, and (ii) triggers an alertviaintegrated actions of eyes and peripheral sensory organs to circumvent the toxic effect of insecticide in the susceptible strain ofAn. culicifacies. Among the six identified SAP members,AcSAP1andAcSAP2are abundantly expressed in the olfactory and legs, and their expression is significantly modulated at night in naïve adult female mosquitoes. We noticed thatAcSAP1silencing significantly impairs the host-attraction properties of the mosquitoes. Its strong binding affinity to the synthetic pyrethroid prompted us to evaluate theAcSAP1response to insecticide exposure. Confocal microscopy and molecular profiling data reveal a heightened modulation in the expression ofAcSAP1in eyes, and other peripheral sensory organs including the olfactory (****p<0.00001), legs (**p < 0.004), wings (***p < 0.0004). These findings collectively suggest a crucial role ofAcSAP1in facilitating mosquito navigation, and/or insecticide avoidance. Unraveling the basis of SAP interactions with peripheral sensory systems could pave the way for the development of novel vector control tools.
Proximity labeling of the Tau repeat domain enriches RNA-binding proteins that are altered in Alzheimer’s disease and related tauopathies
Authors: Shapley Sarah M. , Shantaraman Anantharaman , Kearney Masin A. , Dammer Eric B. , Duong Duc M. , Bowen Christine A. , Bagchi Pritha , Guo Qi , Rangaraju Srikant , Seyfried Nicholas T. 
Published: January 2025

AbstractIn Alzheimer’s disease (AD) and other tauopathies, tau dissociates from microtubules and forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions of tau have been identified from postmortem brain tissue, these studies are limited by their inability to capture transient interactions. To investigate the interactome of aggregate-prone fragments of tau, we applied anin vitroproximity labeling technique using split TurboID biotin ligase (sTurbo) fused with the tau microtubule repeat domain (TauRD), a core region implicated in tau aggregation. We characterized sTurbo TauRD co-expression, robust enzyme activity and nuclear and cytoplasmic localization in a human cell line. Following enrichment of biotinylated proteins and mass spectrometry, we identified over 700 TauRD interactors. Gene ontology analysis of enriched TauRD interactors highlighted processes often dysregulated in tauopathies, including spliceosome complexes, RNA-binding proteins (RBPs), and nuclear speckles. The disease relevance of these interactors was supported by integrating recombinant TauRD interactome data with human AD tau interactome datasets and protein co-expression networks from individuals with AD and related tauopathies. This revealed an overlap with the TauRD interactome and several modules enriched with RBPs and increased in AD and Progressive Supranuclear Palsy (PSP). These findings emphasize the importance of nuclear pathways in tau pathology, such as RNA splicing and nuclear-cytoplasmic transport and establish the sTurbo TauRD system as a valuable tool for exploring the tau interactome.