bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ventral CA2 region of the hippocampus and its differential contributions to social memory and social aggression
Authors: Boyle Lara M. , Sheng Wanhui , Leroy Felix , Sahai Rhea , Irfan Sarah , Lee Heon-Jin , Villegas Andres , Young W.Scott , Siegelbaum Steven A. 
Published: June 2024

AbstractAlthough it is well-known that the hippocampus mediates declarative memory (the repository of information of people, places, things and events) and influences behavior, the differential contributions of the dorsal and ventral hippocampus to specific forms of memory and behavior remain largely unknown. Studies to date show that the dorsal hippocampal CA1 region is important for cognitive and spatial tasks whereas the ventral CA1 region is associated with affective or emotional processing. Whether other regions and forms of hippocampal-dependent memory and behavior show a similar distinction remains unclear. Here we examine how social memory and related social behaviors are encoded across the dorso-ventral axis of the hippocampus. Although recent studies show that the dorsal hippocampal CA2 region is required for social memory and acts to promote social aggression, the behavioral role of ventral CA2 remains unknown. Indeed, whether a defined CA2 region extends throughout ventral hippocampus is controversial. Here, we report that a molecularly, anatomically and electrophysiologically defined CA2 region extends to the extreme ventral pole of hippocampus, with both similarities and important differences in its projection patterns and synaptic impact compared to dorsal CA2. Of particular importance, we find that ventral CA2 is not required for social memory but is critical for promoting social aggression. These results support the view that the ventral region of hippocampus is more generally tuned for emotionally-related behaviors compared to the cognitively-tuned dorsal hippocampus.
Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced hyperphagia
Authors: Li Li , Hernandez Ciria C. , Gimenez Luis E. , Xu Baijie , Dahir Naima S. , Swati  , Birnbaum Shari G. , Cone Roger D. , Liu Chen 
Published: June 2024

SUMMARYMost antipsychotic drugs (APDs) induce hyperphagia and weight gain. However, the neural mechanisms are poorly understood, partly due to challenges replicating their metabolic effects in rodents. Here, we report a new mouse model that recapitulates overeating induced by clozapine, a widely prescribed APD. Our study shows that clozapine boosts food intake by inhibiting melanocortin 4 receptor (MC4R) expressing neurons in the paraventricular nucleus of the hypothalamus. Interestingly, neither clozapine nor risperidone, another commonly used APD, affects receptor-ligand binding or the canonical Gαs signaling of MC4R. Instead, they inhibit neuronal activity by enhancing the coupling between MC4R and Kir7.1, leading to the open state of the inwardly rectifying potassium channel. Deletion ofKir7.1inMc4r-Creneurons prevents clozapine-induced weight gain, while treatment with a selective Kir7.1 blocker mitigates overeating in clozapine-fed mice. Our findings unveil a molecular pathway underlying the effect of APDs on feeding behavior and suggest its potential as a therapeutic target.
Mixed representations of choice direction and outcome by GABA/glutamate cotransmitting neurons in the entopeduncular nucleus
Authors: Locantore Julianna R. , Liu Yijun , White Jesse , Wallace Janet Berrios , Beron Celia C. , Kraft Emily , Sabatini Bernardo L. , Wallace Michael L. 
Published: June 2024

AbstractThe basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EPSst+) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior. We find that EPSst+neurons are strongly engaged during this task and show bidirectional changes in activity during the choice and outcome periods of a trial. We then tested the effects of either permanently blocking cotransmission or modifying the GABA/glutamate ratio on behavior in well-trained animals. Neither manipulation produced detectable changes in behavior despite significant changes in synaptic transmission in the LHb, demonstrating that the outputs of these neurons are not required for on-going action-outcome updating in a probabilistic switching task.
Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States
Authors: Peisley Alys , Hernandez Ciria C. , Dahir Naima S. , Koepping Laura , Raczkowski Ashleigh , Su Min , Ghamari-Langroudi Masoud , Ji Xinrui , Gimenez Luis E. , Cone Roger D. 
Published: June 2024

ABSTRACTHereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.1 may be regulated by a GPCR, the melanocortin-4 receptor, in certain hypothalamic neurons. We present the first structures of human Kir7.1 and describe the conformational bias displayed by two pathogenic mutations, R162Q and E276A, to provide an explanation for the basis of disease and illuminate the gating pathway. We also demonstrate the structural basis for the blockade of the channel by a small molecule ML418 and demonstrate that channel blockade in vivo activates MC4R neurons in the paraventricular nucleus of the hypothalamus (PVH), inhibiting food intake and inducing weight loss. Preliminary purification, and structural and pharmacological characterization of an in tandem construct of MC4R and Kir7.1 suggests that the fusion protein forms a homotetrameric channel that retains regulation by liganded MC4R molecules.
Fiber-based Probes for Electrophysiology, Photometry, Optical and Electrical Stimulation, Drug Delivery, and Fast-Scan Cyclic Voltammetry In Vivo
Authors: Driscoll Nicolette , Antonini Marc-Joseph , Cannon Taylor M. , Maretich Pema , Olaitan Greatness , Phi Van Valerie Doan , Nagao Keisuke , Sahasrabudhe Atharva , Vargas Emmanuel , Hunt Sydney , Hummel Melissa , Mupparaju Sanju , Jasanoff Alan , Venton Jill , Anikeeva Polina 
Published: June 2024

AbstractRecording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and imaging of fluorescent indicators. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by simultaneously interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.
Fast and Accurate EEG/MEG BEM-Based Forward Problem Solution for High-Resolution Head Models
Authors: Wartman William A. , Ponasso Guillermo Nuñez , Qi Zhen , Haueisen Jens , Maess Burkhard , Knösche Thomas R. , Weise Konstantin , Noetscher Gregory M. , Raij Tommi , Makaroff Sergey N. 
Published: June 2024

AbstractA BEM (boundary element method) based approach is developed to accurately solve an EEG/MEG forward problem for a modern high-resolution head model in approximately 60 seconds using a common workstation. The method utilizes a charge-based BEM with fast multipole acceleration (BEM-FMM) and a “smart” mesh pre-refinement (calledb-refinement) close to the singular source(s). No costly matrix-filling or direct solution steps typical for the standard BEM are required; the method generates on-skin voltages as well as MEG magnetic fields for high-resolution head models in approximately 60 seconds after initial model assembly. The method is verified both theoretically and experimentally.
Ultrasound system for precise neuromodulation of human deep brain circuits
Authors: Martin Eleanor , Roberts Morgan , Grigoras Ioana F , Wright Olivia , Nandi Tulika , Rieger Sebastian W , Campbell Jon , den Boer Tim , Cox Ben T , Stagg Charlotte J , Treeby Bradley E 
Published: June 2024

AbstractTranscranial ultrasound stimulation (TUS) has emerged as a promising technique for non-invasive neuromodulation, but current systems lack the precision to target deep brain structures effectively. Here, we introduce an advanced TUS system that achieves unprecedented precision in deep brain neuromodulation. The system features a 256-element, helmet-shaped transducer array operating at 555 kHz, coupled with a stereotactic positioning system, individualised treatment planning, and real-time monitoring using functional MRI. In a series of experiments, we demonstrate the system’s ability to selectively modulate the activity of the lateral geniculate nucleus (LGN) and its functionally connected regions in the visual cortex. Participants exhibited significantly increased visual cortex activity during concurrent TUS and visual stimulation, with high reproducibility across individuals. Moreover, a theta-burst TUS protocol induced robust neuromodulatory effects, with decreased visual cortex activity observed for at least 40 minutes post-stimulation. These neuromodulatory effects were specific to the targeted LGN, as confirmed by control experiments. Our findings highlight the potential of this advanced TUS system to non-invasively modulate deep brain circuits with high precision and specificity, offering new avenues for studying brain function and developing targeted therapies for neurological and psychiatric disorders. The unprecedented spatial resolution and prolonged neuromodulatory effects demonstrate the transformative potential of this technology for both research and clinical applications, paving the way for a new era of non-invasive deep brain neuromodulation.
A replicable and generalizable neuroimaging-based indicator of pain sensitivity across individuals
Authors: Zhang Li-Bo , Lu Xue-Jing , Zhang Hui-Juan , Wei Zhao-Xing , Kong Ya-Zhuo , Tu Yi-Heng , Iannetti Gian Domenico , Hu Li 
Published: June 2024

AbstractDeveloping neural indicators of pain sensitivity is crucial for revealing the neural basis of individual differences in pain and advancing individualized pain treatment. To identify reliable neural indicators of pain sensitivity, we leveraged six large and diverse functional magnetic resonance imaging (fMRI) datasets (total N=1046). We found replicable and generalizable correlations between nociceptive-evoked fMRI responses and pain sensitivity for laser heat, contact heat, and mechanical pains. These fMRI responses correlated more strongly with pain sensitivity than with tactile, auditory, and visual sensitivity. Moreover, we developed a machine learning model that accurately predicted not only pain sensitivity but also pain reduction from different interventions in healthy individuals. Notably, these findings were influenced considerably by sample sizes, requiring >200 for univariate correlation analysis and >150 for multivariate machine learning modelling. Altogether, we demonstrate the validity of decoding pain sensitivity from fMRI responses, thus facilitating interpretations of subjective pain reports and promoting more mechanistically informed investigation of pain physiology.
Microphthalmia and disrupted retinal development due to aLacZknock-in/knock-out allele at theVsx2locus
Authors: Napoli Francesca R. , Li Xiaodong , Hurtado Alan A. , Levine Edward M. 
Published: June 2024

AbstractVisual System Homeobox 2 (Vsx2) is a transcription factor expressed in the developing retina that regulates tissue identity, growth, and fate determination. Several mutations in theVsx2gene exist in mice, including a spontaneous nonsense mutation and two targeted missense mutations originally identified in humans. Here, we expand the genetic repertoire to include aLacZreporter allele (Vsx2LacZ) designed to express beta-Galactosidase (b-GAL) and simultaneously disruptVsx2function (knock-in/knock-out). The retinal expression pattern of b-GAL is concordant with VSX2, and the mutant allele is recessive.Vsx2LacZhomozygous mice have congenital bilateral microphthalmia accompanied by defects in retinal development including ectopic expression of non-retinal genes, reduced proliferation, delayed neurogenesis, aberrant tissue morphology, and an absence of bipolar interneurons - all hallmarks ofVsx2loss-of-function. Unexpectedly, the mutant VSX2 protein is stably expressed, and there are subtle differences in eye size and early retinal neurogenesis when compared to the null mutant,ocular retardation J. The perdurance of the mutant VSX2 protein combined with subtle deviations from the null phenotype leaves open the possibility thatVsx2LacZallele is not a complete knock-out. TheVsx2LacZallele exhibits loss-of-function characteristics and adds to the genetic toolkit for understandingVsx2function.
Leveraging protein language and structural models for early prediction of antibodies with fast clearance
Authors: Mazrooei Parisa , O’Neil Daniel , Izadi Saeed , Chen Bingyuan , Ramanujan Saroja 
Published: June 2024

AbstractMonoclonal antibodies (mAbs) with long systemic persistence are widely used as therapeutics. However, antibodies with atypically fast clearance require more dosing, limiting their clinical usefulness. Deep learning can facilitate using sequence-based modeling to predict potential pharmacokinetic (PK) liabilities before antibody generation. Assembling a dataset of 103 mAbs with measured nonspecific clearance in cynomolgus monkeys (cyno), and using transfer learning from large protein language models, we developed multiple machine learning models to predict mAb clearance as fast/slow clearing. Focusing on minimizing misclassification of potentially promising molecules as fast clearing, our results show that using physicochemical properties yielded up to 73.1+/-1.1% classification accuracy on hold-out test data (precision 65.2+/-2.3%). Using only sequence-based features from deep learning protein language models yielded a comparable performance of 71+/-1.4% (precision 65.5+/-2.5%). Combining structural and deep learning derived features yielded a similar accuracy of 73.9+/-1.1%, and slightly improved precision (68.3+/-2.4%). Features important for classifying fast/slow clearance point to charge, moment, and surface area properties at pH 7.4 as well as deep learning derived features. These results suggest that the protein language models provide comparable information and predictive performance of clearance as physicochemical features. This work provides a foundation for in silico prediction of protein pharmacokinetics to inform antibody candidate generation and early deprioritization of designs with high risk of fast clearance. More generally, it illustrates the value of transfer learning-based application of protein language models to address characteristics of importance for protein therapeutics.
Identification of molecular determinants of gene-specific bursting patterns by high-throughput imaging screens
Authors: Sood Varun , Holewinski Ronald , Andresson Thorkell , Larson Daniel R. , Misteli Tom 
Published: June 2024

SummaryStochastic transcriptional bursting is a universal property of active genes. While different genes exhibit distinct bursting patterns, the molecular mechanisms for gene-specific stochastic bursting are largely unknown. We have developed and applied a high-throughput-imaging based screening strategy to identify cellular factors and molecular mechanisms that determine the bursting behavior of human genes. Focusing on epigenetic regulators, we find that protein acetylation is a strong acute modulator of burst frequency, burst size and heterogeneity of bursting. Acetylation globally affects the Off-time of genes but has gene-specific effects on the On-time. Yet, these effects are not strongly linked to promoter acetylation, which do not correlate with bursting properties, and forced promoter acetylation has variable effects on bursting. Instead, we demonstrate acetylation of the Integrator complex as a key determinant of gene bursting. Specifically, we find that elevated Integrator acetylation decreases bursting frequency. Taken together our results suggest a prominent role of non-histone proteins in determining gene bursting properties, and they identify histone-independent acetylation of a transcription cofactor as an allosteric modulator of bursting via a far-downstream bursting checkpoint.
Engineered Cortical Microcircuits for Investigations of Neuroplasticity
Authors: Winter-Hjelm Nicolai , Sikorski Pawel , Sandvig Axel , Sandvig Ioanna 
Published: June 2024

AbstractRecent advances in neural engineering have opened new ways to investigate the impact of topology on neural network function. Leveraging microfluidic technologies, it is possible to establish modular circuit motifs that promote both segregation and integration of information processing in the engineered neural networks, similar to those observedin vivo. However, the impact of the underlying topologies on network dynamics and response to pathological perturbation remains largely unresolved. In this work, we demonstrate the utilization of microfluidic platforms with 12 interconnected nodes to structure modular, cortical engineered neural networks. By implementing geometrical constraints inspired by a Tesla valve within the connecting microtunnels, we additionally exert control over the direction of axonal outgrowth between the nodes. Interfacing these platforms with nanoporous microelectrode arrays reveals that the resulting laminar cortical networks exhibit pronounced segregated and integrated functional dynamics across layers, mirroring key elements of the feedforward, hierarchical information processing observed in the neocortex. The multi-nodal configuration also facilitates selective perturbation of individual nodes within the networks. To illustrate this, we induced hypoxia, a key factor in the pathogenesis of various neurological disorders, in well-connected nodes within the networks. Our findings demonstrate that such perturbations induce ablation of information flow across the hypoxic node, while enabling the study of plasticity and information processing adaptations in neighboring nodes and neural communication pathways. In summary, our presented model system recapitulates fundamental attributes of the microcircuit organization of neocortical neural networks, rendering it highly pertinent for preclinical neuroscience research. This model system holds promise for yielding new insights into the development, topological organization, and neuroplasticity mechanisms of the neocortex across the micro- and mesoscale level, in both healthy and pathological conditions.
“Shedding light on plant proteolysis: genetically encoded fluorescent sensors as tools for profiling protease activities.”
Authors: Fernández-Fernández Álvaro Daniel , Tack Simon , Van Durme Matthias , Nolf Jonah , Nowack Moritz K. , Staal Jens , Stael Simon , Van Breusegem Frank 
Published: June 2024

AbstractProteolysis, a ubiquitous process in living organisms, is driven by proteases that regulate numerous signaling pathways through the hydrolysis of peptide bonds in protein substrates. Understanding the temporal and spatial dynamics of proteolysis and the activation of proteases is crucial for elucidating their roles in biological pathways. Here, we introduce a suite of genetically encoded FRET reporters designed to detect various proteolytic activities in plants. These sensors effectively reportedin plantathe specific activity of both Tobacco Etch Virus protease and caspase-3. Furthermore, we developed sensors for detecting plant metacaspase activity, validated through bothin vitroandin plantaexperiments. These experiments revealed the spatial dynamics of proteolysis triggered by metacaspase activation following wounding and programmed cell death in roots. The implementation of these tools in plant biology research opens new avenues for investigating proteolytic mechanisms, significantly enhancing the potential for in-depth studies. Our work demonstrates the feasibility of using these sensors to detect diverse protease activitiesin vivowith high spatiotemporal resolution. These plant proteolytic biosensors hence represent a valuable toolbox for understanding protease functions within their natural context, paving the way for future advancements in plant biology research.
DET1 dynamics underlie co-operative ubiquitination by CRL4DET1-COP1 complexes
Authors: Burgess Abigail E , Loughran Tarren A , Turk Liam S , Dunlop Jess L , Jamieson Sam A , Curry Jack R , Filipcik Pavel , Brown Simon HJ , Mace Peter D 
Published: June 2024

AbstractUbiquitin ligases regulate core cellular processes through diverse mechanisms. The ubiquitin ligase COP1 is conserved from plants to humans and is particularly important for targeting developmental transcription factors for ubiquitination. COP1 can function independently, but can also be recruited to Cullin-4 ubiquitin ligase complexes via the DET1 adaptor protein. However, the mechanism of action of complexes containing COP1 and DET1 is not well understood. Here we report the cryo-electron microscopy structure of human DET1, bound to proteins that enable Cullin-4 recruitment (DDB1-DDA1) and an additional ubiquitin ligase enzyme (Ube2e2). We observe that DDA1 stabilises a closed conformation of DET1, binding adjacent to a unique Ube2e2 binding-insert in DET1. Moreover, we demonstrate that closure of DET1 underlies COP1 recruitment, which binds in an antiparallel dimeric state. Disrupting either the Ube2e2-binding insertion of DET1, or distinct recruitment sites on COP1, abolish DET1–COP1 binding and DET1-mediated modulation of COP1 levels. The multifaceted architecture provides an efficient platform for ubiquitination of substrates, or COP1 itself, by Cullin-4DET1and offers multiple opportunities for physiological regulation.