eLife最新文献

Previously, we showed that adult human olfaction retains plasticity in the unilateral processing of molecular chirality (Feng and Zhou, 2019). Using a similar unilateral discrimination protocol across three experiments with human adults (n = 96; 1295 sessions), we now reveal distinct patterns of specificity, generalization, and persistence in olfactory learning, independent of adaptation or task difficulty. Training with binary odor mixtures at varying ratios consistently produced durable gains that transferred across nostrils and generalized to novel mixtures differing in both structure and perceptual quality. Conversely, training with odor enantiomers or concentration differences yielded neither transfer nor generalization, and concentration discrimination learning was short-lived. These results indicate that mixture configural quality is a distinct olfactory attribute from chirality or relative concentration, and that discrimination learning engages plasticity at different stages of olfactory processing depending on the task-relevant attribute. Moreover, they identify mixture discrimination training as a promising strategy for rehabilitating smell loss and cultivating olfactory expertise.

Facial expression recognition develops rapidly during infancy and improves from childhood to adulthood. As a critical component of social communication, this skill enables individuals to interpret others' emotions and intentions. However, the brain mechanisms driving the development of this skill remain largely unclear due to the difficulty of obtaining data with both high spatial and temporal resolution from young children. By analyzing intracranial EEG data collected from childhood (5-10 years old) and post-childhood groups (13-55 years old), we find differential involvement of high-level brain area in processing facial expression information. For the post-childhood group, both the posterior superior temporal cortex (pSTC) and the dorsolateral prefrontal cortex (DLPFC) encode facial emotion features from a high-dimensional space. However, in children, the facial expression information is only significantly represented in the pSTC, not in the DLPFC. Furthermore, the encoding of complex emotions in pSTC is shown to increase with age. Taken together, young children rely more on low-level sensory areas than on the prefrontal cortex for facial emotion processing, suggesting that the prefrontal cortex matures with development to enable a full understanding of facial emotions, especially complex emotions that require social and life experience to comprehend.

Humans and animals can flexibly choose their actions based on different information, ranging from objective states of the environment (e.g., apples are bigger than cherries) to subjective preferences (e.g., cherries are tastier than apples). Whether the brain instantiates these different choices by recruiting either specialised or shared neural circuitry remains debated. Specifically, domain-general accounts of prefrontal cortex (PFC) function propose that prefrontal areas flexibly process either perceptual or value-based evidence depending on what is required for the present choice, whereas domain-specific theories posit that PFC sub-areas, such as the left superior frontal sulcus (SFS), selectively integrate evidence relevant for perceptual decisions. Here, we comprehensively test the functional role of the left SFS for choices based on perceptual- and value-based evidence, by combining functional magnetic resonance imaging with a behavioural paradigm, computational modelling, and transcranial magnetic stimulation (TMS). Confirming predictions by a sequential sampling model, we show that TMS-induced excitability reduction of the left SFS selectively changes the processing of decision-relevant perceptual information and associated neural processes. In contrast, value-based decision-making and associated neural processes remain unaffected. This specificity of SFS function is evident at all levels of analysis (behavioural, computational, and neural, including functional connectivity), demonstrating that the left SFS causally contributes to evidence integration for perceptual but not value-based decisions.

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.