eLife最新文献

Adaptive goal-directed behavior requires dynamic coordination of movement, motivation, and environmental cues. Among these, cautious actions, where animals adjust their behavior in anticipation of predictable threats, are essential for survival. Yet, their underlying neural mechanisms remain less well understood than those of appetitive behaviors, where caution plays little role. Using calcium imaging in freely moving mice, we show that glutamatergic neurons in the subthalamic nucleus (STN) are robustly engaged by contraversive movement during cue-evoked avoidance and exploratory behavior. Model-based analyses controlling for movement and other covariates revealed that STN neurons additionally encode salient sensory cues, punished errors, and especially cautious responding, where their activity anticipates avoidance actions. Targeted lesions and optogenetic manipulations reveal that STN projections to the midbrain are necessary for executing cued avoidance. These findings identify a critical role for the STN in orchestrating adaptive goal-directed behavior by integrating sensory, motor, and punitive signals to guide timely, cautious actions via its midbrain projections.

Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. Fusion of satellite cell-derived myoblasts (SCMs) is indispensable for generating the multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain incompletely understood. Here, we reveal a critical role for branched actin polymerization in SCM fusion during mouse skeletal muscle regeneration. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors N-WASP and WAVE, we demonstrate that branched actin polymerization is specifically required for SCM fusion but dispensable for satellite cell proliferation, differentiation, and migration. We show that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion and that branched actin polymerization is essential for generating invasive protrusions at fusogenic synapses in SCMs. Together, our study identifies branched-actin regulators as key components of the myoblast fusion machinery and establishes invasive protrusion formation as a critical mechanism enabling myoblast fusion during skeletal muscle regeneration.

Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are associated with cardiometabolic disease risk. However, the mechanism(s) linking TMAO production to human disease are incompletely understood. Initiation of the metaorganismal TMAO pathway begins when dietary choline and related metabolites are converted to trimethylamine (TMA) by gut bacteria. Gut microbe-derived TMA can then be further oxidized by host flavin-containing monooxygenases to generate TMAO. Previously, we showed that drugs lowering both TMA and TMAO protect mice against obesity via rewiring of host circadian rhythms (Schugar et al., 2022). Although most mechanistic studies in the literature have focused on the metabolic end product TMAO, here we have instead tested whether the primary metabolite TMA alters host metabolic homeostasis and circadian rhythms via trace amine-associated receptor 5 (TAAR5). Remarkably, mice lacking the host TMA receptor (Taar5^-/-) have altered circadian rhythms in gene expression, metabolic hormones, gut microbiome composition, and diverse behaviors. Also, mice genetically lacking bacterial TMA production or host TMA oxidation have altered circadian rhythms. These results provide new insights into diet-microbe-host interactions relevant to cardiometabolic disease and implicate gut bacterial production of TMA and the host receptor that senses TMA (TAAR5) in the physiologic regulation of circadian rhythms in mice.

Motility endows microorganisms with the ability to swim to nutrient-rich environments, but many species are sessile. Existing hydrodynamic arguments in support of either strategy, to swim or to attach and generate feeding currents, are often built on a limited set of experimental or modeling assumptions. Here, to assess the hydrodynamics of these 'swim' or 'stay' strategies, we propose a comprehensive methodology that combines mechanistic modeling with a survey of published shape and flow data in ciliates. Model predictions and empirical observations show small variations in feeding rates in favor of either motile or sessile cells. Case-specific variations notwithstanding, our overarching analysis shows that flow physics imposes no constraint on the feeding rates that are achievable by the swimming versus sessile strategies - they can both be equally competitive in transporting nutrients and wastes to and from the cell surface within flow regimes typically experienced by ciliates. Our findings help resolve a long-standing dilemma of which strategy is hydrodynamically optimal and explain patterns occurring in natural communities that alternate between free swimming and temporary attachments. Importantly, our findings indicate that the evolutionary pressures that shaped these strategies acted in concert with, not against, flow physics.

Functional MRI (fMRI) research has traditionally investigated task processing using static blocked or event-related designs. Consequently, our understanding of threat processing remains limited to findings from paradigms with restricted dynamics. In this paper, we applied switching linear dynamical systems (SLDSs) to uncover the dynamics of threat processing during a continuous threat-of-shock paradigm. Unlike typical systems neuroscience studies that assume systems are decoupled from external inputs, we characterized both endogenous and exogenous contributions to the dynamics. We first demonstrated that the SLDS model learned the regularities of the experimental paradigm; states and state transitions estimated from fMRI data across 85 regions of interest reflected both threat proximity and direction (approach vs. retreat). After establishing that the model captured key properties of threat-related processing, we characterized the dynamics of states and their transitions. The results reveal how threat processing can be viewed as dynamic multivariate patterns whose trajectories are determined by intrinsic and extrinsic factors that jointly drive how the brain temporally evolves. Furthermore, we developed a measure of region importance to quantify individual brain region contributions to system dynamics, complementing the system-level SLDS formalism. Finally, we demonstrated that an SLDS model trained on one paradigm successfully generalizes to a separate experiment, capturing fMRI dynamics across distinct threat-processing tasks. We propose that viewing threat processing through the lens of dynamical systems offers vital avenues to uncover properties of threat dynamics not unveiled by standard experimental designs.

Despite the growing public health threat of electronic cigarettes (e-cigs), the cell-specific immune responses to differently flavored e-cig exposure remain poorly understood. To bridge this gap, we characterized the lung immune landscape following acute nose-only exposure to flavored e-cig aerosols in vivo using single-cell RNA sequencing (scRNA seq) in mice. Metal analysis of daily generated aerosols revealed flavor-dependent, day-to-day variation in metal (Ni, Cu, K, and Zn) leaching. scRNA seq profiling of 71,725 lung cells from control and exposed mice revealed pronounced dysregulation of myeloid cell function in menthol (324 differentially expressed genes, DEGs) and tobacco (553 DEGs) flavors, and lymphoid cell dysregulation in fruit-flavor (112 DEGs) e-cig aerosol exposed mouse lung, compared to air controls. Flow cytometry corroborated these findings, showing increased neutrophil frequencies and reduced eosinophil counts in menthol- and tobacco-exposed lungs. Flavored e-cig exposure also increased CD8⁺ T-cell proportions, upregulated inflammatory gene expression (Stat4, Il1b, Il1bos, Il1ra, and Cxcl3), and enriched terms like 'Th1 cytokine signaling' and 'NK cell degranulation'. Notably, tobacco-flavored e-cig aerosol exposure increased immature (Ly6G⁻) neutrophils and reduced S100A8 expression, suggesting altered neutrophil activation in vivo. Overall, this study identifies flavor-dependent immune alterations in the lung following acute e-cig aerosol exposure and provides a foundation for future mechanistic studies.

The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in human glioblastoma multiforme (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential (ΔΨm) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.

Natural populations are often spatially structured, meaning they exist as metapopulations composed of subpopulations connected by migration. Little is known about the impact of spatial structure, in particular the topology of connections among subpopulations, on adaptive evolution. Typically, spatial structure slows adaptation, although some models suggest topologies that concentrate dispersing individuals through a central hub can accelerate adaptation above that of a well-mixed system. We provide evidence to support this claim and show acceleration is accompanied by high rates of parallel evolution. Our results suggest metapopulation topology can be a potent force driving evolutionary dynamics and patterns of genomic repeatability in structured landscapes such as those involving the spread of pathogens or invasive species.