bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal Activation of the Gαq Protein EGL-30/GNAQ Late in Life Rejuvenates Cognition Across Species
Authors: Stevenson Morgan E. , Bieri Gregor , Kaletsky Rachel , Ange Jonathan St. , Remesal Laura , Pratt Karishma J. B. , Zhou Shiyi , Weng Yifei , Murphy Coleen T. , Villeda Saul A. 
Published: June 2023

AbstractCognitive decline is perhaps the most devastating aging loss. EGL-30/GNAQ and Gαq signaling pathways are highly conserved betweenC. elegansand mammals. We find that activation of EGL-30 in aged worms at least triples memory span, and we wondered if this highly conserved pathway could also improve memory in very old mice. MurineGnaqis enriched in hippocampal excitatory neurons and declines with age. Furthermore, GNAQ gain-of-function significantly improved memory in aged mice: GNAQ(gf)in hippocampal neurons of 24-month-old mice rescued age-related impairments in health metrics and long-term memory. Single-nucleus RNAseq revealed gene expression changes related to synaptic function, axon guidance, and learning and memory pathways. Several worm orthologs of mouse genes upregulated by GNAQ(gf) overexpression are required for EGL-30(gf)-dependent memory improvement. These results demonstrate that the molecular and genetic pathways betweenC. elegansand mammals are highly conserved, as activation of EGL-30/GNAQ, a pathway first identified in worms, rejuvenates cognitive function in two-year old mice (the equivalent of 70-80 yo humans). To our knowledge, this is the oldest age an intervention has successfully improved age-related cognitive decline.One-Sentence SummaryNeuronal activation of the Gαq protein EGL-30/GNAQ restores long-term memory at old age in worms and mice.
DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates
Authors: Mueller Sascha A.L. , Oler Jonathan A. , Roseboom Patrick H. , Aggarwal Nakul , Kenwood Margaux M. , Riedel Marissa K. , Elam Victoria R. , Olsen Miles E. , DiFilippo Alexandra H. , Christian Bradley T. , Hu Xing , Galvan Adriana , Boehm Matthew A. , Michaelides Michael , Kalin Ned H. 
Published: June 2023

AbstractAnxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.
Precision-engineered biomimetics: the human fallopian tube
Authors: Crawford Ashleigh J. , Forjaz André , Bhorkar Isha , Roy Triya , Schell David , Queiroga Vasco , Ren Kehan , Kramer Donald , Bons Joanna , Huang Wilson , Russo Gabriella C. , Lee Meng-Horng , Schilling Birgit , Wu Pei-Hsun , Shih Ie-Ming , Wang Tian-Li , Kiemen Ashley , Wirtz Denis 
Published: June 2023

AbstractThe fallopian tube has an essential role in several physiological and pathological processes from pregnancy to ovarian cancer. However, there are no biologically relevant models to study its pathophysiology. The state-of-the-art organoid model has been compared to two-dimensional tissue sections and molecularly assessed providing only cursory analyses of the model’s accuracy. We developed a novel multi-compartment organoid model of the human fallopian tube that was meticulously tuned to reflect the compartmentalization and heterogeneity of the tissue’s composition. We validated this organoid’s molecular expression patterns, cilia-driven transport function, and structural accuracy through a highly iterative platform wherein organoids are compared to a three-dimensional, single-cell resolution reference map of a healthy, transplantation-quality human fallopian tube. This organoid model was precision-engineered to match the human microanatomy.One sentence summaryTunable organoid modeling and CODA architectural quantification in tandem help design a tissue-validated organoid model.
Lineage motifs: developmental modules for control of cell type proportions
Authors: Tran Martin , Askary Amjad , Elowitz Michael B. 
Published: June 2023

SummaryIn multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells that produce specific sets of descendant cell types. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer progenitor states and understand how they establish overall cell type proportions. Here, we introduce Lineage Motif Analysis (LMA), a method that recursively identifies statistically overrepresented patterns of cell fates on lineage trees as potential signatures of committed progenitor states. Applying LMA to published datasets reveals spatial and temporal organization of cell fate commitment in zebrafish and rat retina and early mouse embryo development. Comparative analysis of vertebrate species suggests that lineage motifs facilitate adaptive evolutionary variation of retinal cell type proportions. LMA thus provides insight into complex developmental processes by decomposing them into simpler underlying modules.
Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2aK1422Emice
Authors: Echevarria-Cooper Dennis M. , Hawkins Nicole A. , Kearney Jennifer A. 
Published: June 2023

AbstractPathogenic variants inSCN2Aare associated with a range of neurodevelopmental disorders (NDD). Despite being largely monogenic,SCN2A-related NDD show considerable phenotypic variation and complex genotype-phenotype correlations. Genetic modifiers can contribute to variability in disease phenotypes associated with rare driver mutations. Accordingly, different genetic backgrounds across inbred rodent strains have been shown to influence disease-related phenotypes, including those associated withSCN2A-related NDD. Recently, we developed a mouse model of the variantSCN2A-p.K1422E that was maintained as an isogenic line on the C57BL/6J (B6) strain. Our initial characterization of NDD phenotypes in heterozygousScn2aK1422Emice revealed alterations in anxiety-related behavior and seizure susceptibility. To determine if background strain affects phenotype severity in theScn2aK1422Emouse model, phenotypes of mice on B6 and [DBA/2JxB6]F1 hybrid (F1D2) strains were compared.Convergent evidence from neurobehavioral assays demonstrated lower anxiety-like behavior inScn2aK1422Emice compared to wild-type and further suggested that this effect is more pronounced on the B6 background compared to the F1D2 background. Although there were no strain-dependent differences in occurrence of rare spontaneous seizures, response to the chemoconvulsant kainic acid revealed differences in seizure generalization and lethality risk, with variation based on strain and sex. Continued examination of strain-dependent effects in theScn2aK1422Emouse model could reveal genetic backgrounds with unique susceptibility profiles that would be relevant for future studies on specific traits and enable the identification of highly penetrant phenotypes and modifier genes that could provide clues about the primary pathogenic mechanism of the K1422E variant.
Activation of M1 cholinergic receptors in mouse somatosensory cortex enhances information processing and improves detection behaviour
Authors: Mishra Wricha , Kheradpezhouh Ehsan , Arabzadeh Ehsan 
Published: June 2023

AbstractAn important function of the brain is to form accurate representations of the world around us. To optimise sensory representations based on the demands of the environment, activity of cortical neurons is regulated by neuromodulators such as Acetylcholine (ACh). As such, ACh is implicated in cognitive functions including attention, arousal and sleep cycles. However, it is not clear how specific ACh receptors shape the baseline activity of cortical neurons and their evoked response to sensory stimuli. Here, we investigate the role of a densely expressed muscarinic ACh receptor 1 (M1) in information processing in the mouse primary somatosensory cortex (vS1) and in the animal’s sensitivity in detecting vibrotactile stimuli. We show that M1 activation significantly enhances the evoked response of vS1 neurons and the reversal of this enhancement by blocking M1. In addition, we demonstrate that M1 activation results in faster and more reliable neuronal responses, which is manifested by a significant reduction in response latencies and the trial-to-trial variability in neuronal activity. At the population level, M1 activation reduces the network synchrony and thus enhances the capacity of vS1 neurons in conveying sensory information. Consistent with the neuronal findings, we show that M1 activation significantly improves performances in a vibrotactile detection task. Overall, the M1-mediated enhancement in sensory efficiency reflects a multiplicative gain modulation at the neuronal level, resembling the changes observed during high attention states.
Recall tempo of Hebbian sequences depends on the interplay of Hebbian kernel with tutor signal timing
Authors: Farrell Matthew , Pehlevan Cengiz 
Published: June 2023

AbstractUnderstanding how neural circuits generate sequential activity is a longstanding challenge. While foundational theoretical models have shown how sequences can be stored as memories with Hebbian plasticity rules, these models considered only a narrow range of Hebbian rules. Here we introduce a model for arbitrary Hebbian plasticity rules, capturing the diversity of spike-timing-dependent synaptic plasticity seen in experiments, and show how the choice of these rules and of neural activity patterns influences sequence memory formation and retrieval. In particular, we derive a general theory that predicts the speed of sequence replay. This theory lays a foundation for explaining how cortical tutor signals might give rise to motor actions that eventually become “automatic”. Our theory also captures the impact of changing the speed of the tutor signal. Beyond shedding light on biological circuits, this theory has relevance in artificial intelligence by laying a foundation for frameworks whereby slow and computationally expensive deliberation can be stored as memories and eventually replaced by inexpensive recall.
DIETS: a simple and sensitive assay to measure and control the intake of complex solid foods, like high-fat diets, inDrosophila
Authors: Thakare Manikrao R. , Choudhary Prerana , Pydah Bhavna , Sunke Suhas , Yadav R Sai Prathap , Agrawal Pavan , Das Gaurav 
Published: June 2023

AbstractThe fruit flyDrosophila melanogaster offers a powerful model to study how diet affects the body and brain. However, existing methods for measuring their food intake often rely on dyes or tags mixed with food, which can be inaccurate due to how the flies absorb and eliminate them. Capillary-based assays like CAFE directly measure consumption, but only work with liquids and shorten fly lifespan. Additionally, capillary assays are incompatible with delivering viscous foods like high-fat diets. Even solidified high-fat diets tend to be sticky death traps for flies. Another longstanding challenge for fly researchers is that dietary restriction in flies involves diluting food, leading to compensatory feeding. To address these shortcomings, we have developed DIETS, a sensitive feeding assay that can be implemented even in low-resource settings. DIETS eliminates the need for labels and directly weighs the solid food consumed by small groups of flies over extended periods of hours to weeks. It allows us to deliver precise amounts of food to flies and implement accurate dietary restrictions. Importantly, DIETS is compatible with studying energy-dense high-fat diets. Using DIETS, we observed that, unlike a high-sugar diet, an isocaloric high-fat diet did not improve the flies’ ability to withstand starvation, even though they consumed more calories and had higher fat deposition.
Time for What? Dissociating Explicit Timing Tasks Through Electrophysiological Signatures
Authors: Bueno Fernanda D. , Nobre Anna C. , Cravo André M. 
Published: June 2023

AbstractEstimating durations between hundreds of milliseconds and seconds is essential for several daily tasks. Explicit timing tasks, which require participants to estimate durations to make a comparison (time for perception) or to reproduce them (time for action), are often used to investigate psychological and neural timing mechanisms. Recent studies have proposed that mechanisms may depend on specific task requirements. In this study, we conducted electroencephalogram (EEG) recordings on human participants as they estimated intervals in different task contexts to investigate the extent to which timing mechanisms depend on the nature of the task. We compared the neural processing of identical visual reference stimuli in two different tasks, in which stimulus durations were either perceptually compared or motorically reproduced in separate experimental blocks. Using multivariate pattern analyses, we could successfully decode the duration and the task of reference stimuli. We found evidence for both overlapping timing mechanisms across tasks as well as recruitment of task-dependent processes for comparing intervals for different purposes. Our findings suggest both core and specialised timing functions are recruited to support explicit timing tasks.
Cell type-specific contributions to a persistent aggressive internal state in femaleDrosophila
Authors: Chiu Hui , Robie Alice A. , Branson Kristin M. , Vippa Tanvi , Epstein Samantha , Rubin Gerald M. , Anderson David J. , Schretter Catherine E. 
Published: June 2023

AbstractPersistent internal states are important for maintaining survival-promoting behaviors, such as aggression. In femaleDrosophila melanogaster, we have previously shown that individually activating either aIPg or pC1d cell types can induce aggression. Here we investigate further the individual roles of these cholinergic, sexually dimorphic cell types, and the reciprocal connections between them, in generating a persistent aggressive internal state. We find that a brief 30-second optogenetic stimulation of aIPg neurons was sufficient to promote an aggressive internal state lasting at least 10 minutes, whereas similar stimulation of pC1d neurons did not. While we previously showed that stimulation of pC1e alone does not evoke aggression, persistent behavior could be promoted through simultaneous stimulation of pC1d and pC1e, suggesting an unexpected synergy of these cell types in establishing a persistent aggressive state. Neither aIPg nor pC1d show persistent neuronal activity themselves, implying that the persistent internal state is maintained by other mechanisms. Moreover, inactivation of pC1d did not significantly reduce aIPg-evoked persistent aggression arguing that the aggressive state did not depend on pC1d-aIPg recurrent connectivity. Our results suggest the need for alternative models to explain persistent female aggression.
Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids
Authors: Febbraro Fabia , Breum Andersen Helena Hørdum , Willnow Thomas E. 
Published: June 2023

ABSTRACTVacuolar protein sorting 10 protein (VPS10P) domain receptors are a unique class of intracellular sorting receptors that emerge as major risk factors associated with psychiatric and neurodegenerative diseases, including bipolar disorders, autism, schizophrenia, as well as Alzheimer’s disease and frontotemporal dementia. Yet, the lack of suitable experimental models to study receptor functions in the human brain has hampered elucidation of receptor actions in brain disease. Here, we have adapted protocols in human cerebral organoids to the detailed characterization of VPS10P domain receptor expression during development and in mature brain tissue, including single-cell RNA sequencing. Our studies uncovered spatial and temporal patterns of expression unique to individual receptor species in the human brain. WhileSORL1expression is abundant in stem cells andSORCS1peaks at onset of neurogenesis,SORT1andSORCS2show increasing expression with maturation of neuronal and non-neuronal cell types, arguing for distinct functions in development versus the adult brain. In neurons, subcellular localization also distinguishes between two types of receptors, either mainly localized to the cell soma (SORL1andSORT1) or also to neuronal projections (SORCS1andSORCS2), suggesting divergent functions in protein sorting between Golgi and the endo-lysosomal system or along axonal and dendritic tracks. Taken together, our findings provide an important resource concerning temporal, spatial, and subcellular patterns of VPS10P domain receptor expression in cerebral organoids for further elucidation of receptor (dys)functions causative of behavioral and cognitive defects of the human brain.
Midbrain encodes sound detection behavior without auditory cortex
Authors: Lee Tai-Ying , Weissenberger Yves , King Andrew J , Dahmen Johannes C 
Published: June 2023

AbstractHearing involves analyzing the physical attributes of sounds and integrating the results of this analysis with other sensory, cognitive and motor variables in order to guide adaptive behavior. The auditory cortex is considered crucial for the integration of acoustic and contextual information and is thought to share the resulting representations with subcortical auditory structures via its vast descending projections. By imaging cellular activity in the corticorecipient shell of the inferior colliculus of mice engaged in a sound detection task, we show that the majority of neurons encode information beyond the physical attributes of the stimulus and that the animals’ behavior can be decoded from the activity of those neurons with a high degree of accuracy. Surprisingly, this was also the case in mice in which auditory cortical input to the midbrain had been removed by bilateral cortical lesions. This illustrates that subcortical auditory structures have access to a wealth of non-acoustic information and can, independently of the auditory cortex, carry much richer neural representations than previously thought.
Peripheral direct current suppresses physiologically evoked nociceptive responses at the spinal cord in rodent models of pain
Authors: Su Tom F. , Hamilton Jack D. , Guo Yiru , Potas Jason R. , Shivdasani Mohit N. , Moalem-Taylor Gila , Fridman Gene Y. , Aplin Felix P. 
Published: June 2023

AbstractElectrical neuromodulation is an established non-pharmacological treatment for chronic pain. However, existing devices using pulsatile stimulation are not suitable for all types of chronic pain. Direct current stimulation is a recently developed technology which shows better selectivity for small-diameter fibres. We investigated if this selectivity could be applied to preferentially suppress nociceptive signalling. We applied direct current to the sciatic nerve of rats and compared its effects on spinal activity produced by physiological (non-electrical) stimuli delivered to the foot. Tests were performed across models of neuropathic and inflammatory pain to further clarify potential clinical applications. We found that direct current could effectively suppress activity relating to painful stimuli in both pain models tested. These findings strongly support the use of direct current neuromodulation for chronic pain relief, and suggest that it may be effective at treating a broader range of aberrant pain conditions than existing devices.
Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B
Authors: Pal Prosenjit , Taylor Matthew , Lam Pui Yiu , Tonelli Francesca , Hecht Chloe A. , Lis Pawel , Nirujogi Raja S. , Phung Toan K. , Dickie Emily A. , Wightman Melanie , Macartney Thomas , Pfeffer Suzanne R. , Alessi Dario R. 
Published: June 2023

AbstractThe Parkinson’s VPS35[D620N] mutation causes lysosome dysfunction enhancing LRRK2 kinase activity. We find the VPS35[D620N] mutation alters expression of ∼350 lysosomal proteins and stimulates LRRK2 phosphorylation of Rab proteins at the lysosome. This recruits the phosphoRab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35 [D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition. Knock-out of RILPL1 enhances phosphorylation of Rab substrates and knock-out of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe, also induced LRRK2 kinase mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
Effects of psychogenic stress on oxidative stress and antioxidant capacity at different growth stages
Authors: Lee Sangun , Itagaki Atsunori , Satoh Atsuko , Sugimoto Issei , Saito Takumi , Tatehana Haruka 
Published: June 2023

AbstractThis study examined the psychogenic stress (PS) effects on changes in oxidative stress and the antioxidant capacity of an organism at different growth stages. The experimental animals were male Wistar rats of five different ages from growth periods (GPs) to old age. The growth stages were randomly classified into control (C) and experimental (PS) groups. PS was performed using restraint and water immersion once daily for 3 h for 4 weeks. Reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) were measured before and after the experiment. In addition, the liver and adrenal glands were removed, and the wet weight was measured. The d-ROM and BAP of all growth stages given PS increased significantly. The d-ROM in the C group without PS increased significantly in GPs while decreased significantly in old-aged. In addition, the BAP of the C group in GP and early adulthood were all significantly elevated. There were significant differences in organ weights between the C and PS groups at all growth stages. Oxidative stress and antioxidant capacity differed depending on the organism’s developmental status and growth stage, and PS also showed different effects. In particular, the variability in oxidative stress was remarkable, suggesting that the effect of PS was more significant in the organism’s immature organs.