Stem cells rapidly proliferate after injury to repair damaged tissue, and chronic injury predisposes to cancer. However, injury-activated mitogens, the mechanisms that keep them inactive until injury, and their role in cancer are not understood. Here we identify Igf2 as the injury-activated mitogen for neuroendocrine stem cells, a facultative airway stem cell and origin of small cell lung cancer. Igf2 is constitutively produced by the stem cells but sequestered in inactive form by co-expressed Igf binding proteins. Injury releases Igf2 and induces proliferation by activating its receptors and repressing Rb tumor suppressor, which normally enforces stem cell quiescence. Persistent pathway activation initiates oncogenesis. Thus, in addition to its classical hormonal roles in physiology, growth, and aging, Igf operates locally with Igf binding proteins and Rb to control injury-induced stem cell activation and cancer. This pathway may also control related stem cells and cancers of the body and brain.

Animals reprioritize behavioral goals in response to internal physiological states. Using larval zebrafish, we investigated whether engagement with a visuomotor task, the optomotor response (OMR), is coupled to cardiac dynamics. We discovered that threats lead to tachycardia that is synchronized with behavioral suppression. The change in heart rate is represented in the activity of specific neuronal populations. Severing the input to the sympathetic ganglia or ablating the vagus nerve revealed that the threat-related changes to behavioral state do not require interoceptive pathways. Direct tachycardic optopacing of the heart similarly suppressed the OMR response, but by reducing cardiac filling during diastole, thereby impacting oxygen delivery to the CNS. Optopacing also changed the activity of specific brain regions but in neurons distinct from those associated with threat-induced tachycardia. These cardiac function-associated central changes may have relevance to autonomic imbalances in anxiety, stress, and orthostatic disorders.

Assigning valence-appeal or aversion-to gustatory stimuli and relaying it to higher-order brain regions to guide flexible behaviors is crucial to survival. Yet the neural circuits that transform taste into motivationally relevant signals remain poorly defined in any model system. In Drosophila melanogaster, substantial progress has been made in mapping the sensorimotor pathways encoding intrinsic valence for feeding and the architecture of the dopaminergic reinforcement system. However, where and how "effective" (i.e., real-time) valence is first imposed on a taste has long been a mystery. Here, we identified a pair of subesophageal zone interneurons in Drosophila, termed Fox, that impart reinforcing positive valence to sweet taste and convey this signal to the mushroom body, the fly's associative learning center. We show that Fox neuron activity is necessary and sufficient to drive appetitive behaviors and can override a tastant's intrinsic neutral or aversive valence without impairing taste quality discrimination. Furthermore, Fox neurons relay the positive valence to specific dopaminergic neurons that mediate appetitive memory formation. Our findings reveal a circuit mechanism through which effective valence is bestowed upon sweet sensation and transformed into a reinforcing signal that supports learned sugar responses. The Fox neurons form a convergent-divergent "hourglass" circuit motif, acting as a bottleneck for valence assignment and distributing motivational signals to higher-order centers. This architecture confers both robustness and flexibility in reward processing-an organizational principle that may generalize across species.

Insecticides remain indispensable for crop protection and food security, yet their widespread use may contribute to the global decline of beneficial insect populations. Efforts to mitigate these impacts are hampered by a fragmented understanding of how insects metabolise insecticides and how sublethal exposures affect physiology, behaviour, and fitness. Here, we synthesise current understanding of metabolic detoxification and highlight critical gaps: the tissue- and time-dependent dynamics of insecticide entry and processing, the triggers and architecture of xenobiotic transcriptional responses, the role of rapid non-transcriptional regulation, and the population-level consequences of sublethal effects. We also outline emerging experimental strategies for addressing these questions and propose a next-generation research pipeline centred on multi-endpoint phenomics across life stages and sentinel species, integrated with AI-driven predictive toxicology, as a framework for identifying safer chemicals. We propose an integrated framework unifying molecular, physiological, and ecological responses to sublethal exposure to guide the design of insecticides that maintain effective pest control while safeguarding insect biodiversity and the ecosystems it underpins.

Dendrites transform local electrical activity into intracellular Ca2+ signals that drive plasticity1,2, yet the voltage→Ca2+ mapping during natural behavior remains poorly defined. Here, we measure this transfer function via simultaneous voltage and Ca2+ imaging throughout the dendritic arbors of hippocampal CA2 pyramidal neurons in behaving mice. Dendritic Ca2+ exhibited a hierarchical activation pattern dominated by back-propagating action potentials: simple spikes primarily drove somatic and proximal Ca2+, whereas complex spikes produced larger somatic Ca2+ signals and propagated farther into distal dendrites, sometimes in a branch-selective manner. Dendrite-restricted co-activation of voltage and Ca2+ without concurrent somatic events was rare. A biophysics-inspired model accurately predicted local Ca2+ transients from local voltage waveforms. Our data and model provide a quantitative understanding of when – and why – dendritic Ca2+ signals in CA2 pyramidal cells arise during behavior.

The cytoskeleton is a key mediator of mechanical interactions in cells, but specific contributions of septins remains unclear. Septins preferentially localize with a subset of actin stress fibers positioned under the nucleus, where they are situated between the membrane and stress fibers. Removing the nucleus from the cell results in the loss of these subnuclear septin-decorated stress fibers. Surprisingly, however, their formation can be rescued using a large glass bead in place of the nucleus. Similarly, applying a compressive force to the cell via confinement, whether externally or through internally generated actomyosin forces, results in increased septin accumulation in regions where the nucleus engages the cell cortex. Finally, loss of septin filaments via knockdown of SEPT7 increases the likelihood of nuclear membrane rupture during confinement. Together these data suggest that septins act as a dynamic mechanosensitive protective mechanism to buffer mechanical forces on the nucleus.

Spiking neural networks (SNNs) offer a promising paradigm for modeling brain dynamics and developing neuromorphic intelligence, yet an online learning system capable of training rich spiking dynamics over long horizons with low memory footprints has been missing. Existing online approaches either incur quadratic memory growth, sacrifice biological fidelity through oversimplified models, or lack end-to-end automated tooling. Here, we introduce BrainTrace, a model-agnostic, linear-memory, and automated online learning system for spiking neural networks. BrainTrace standardizes model specification to encompass diverse neuronal and synaptic dynamics; implements a linear-memory online learning rule by exploiting intrinsic properties of spiking dynamics; and provides a compiler that automatically generates optimized online-learning code for arbitrary user-defined models. Across diverse dynamics and tasks, BrainTrace achieves strong learning performance with a low memory footprint and high computational throughput. Critically, these properties enable online fitting of a whole-brain-scale Drosophila SNN that recapitulates region-level functional activity. By reconciling generality, efficiency, and usability, BrainTrace establishes a foundation for spiking network modeling at scale.

The first step to probing any potential interaction between two biomolecules is to determine their spatial association. In other words, if two biomolecules localize similarly within a cell, then it is plausible they could interact. Traditionally, this is quantified through various colocalization metrics. These measures infer this association by estimating the degree to which fluorescent signals from each biomolecule overlap or correlate. However, these metrics are, at best, proxies, and they depend strongly on various experimental choices. Here, we define a new strategy that leverages multispectral imaging and phasor analysis, termed the phasor mixing coefficient (PMC). The PMC measures the precise mixing of fluorescent signals in each pixel. We demonstrate how the PMC captures complex biological subtlety by offering two distinct values, a global measure of overall color mixing and the homogeneity thereof. We additionally show that the PMC exhibits less sensitivity to signal-to-noise ratio, intensity threshold and background signal compared to canonical methods. Moreover, this method provides a means to visualize color mixing at each pixel. We show that the PMC offers users a nuanced and robust metric to quantify biological association.

To successfully forage for food, animals must balance the energetic cost of searching for food sources with the energetic benefit of exploiting those sources. While the Marginal Value Theorem provides one normative account of this balance by specifying that a forager should leave a food patch when its energetic yield falls below the average yield of other patches in the environment, it assumes the presence of other readily reachable patches. In natural settings, however, a forager does not know whether it will encounter additional food patches, and it must balance potential energetic costs and benefits accordingly. Upon first encountering a patch of food, it faces a decision of whether and when to leave the patch in search of better options, and when to return if no better options are found. Here, we explore how a forager should structure its search for new food patches when the existence of those patches is unknown, and when searching for those patches requires energy that can only be harvested from a single known food patch. We identify conditions under which it is more favorable to explore the environment in several successive trips rather than in a single long exploration, and we show how the optimal sequence of trips depends on the forager’s beliefs about the distribution and nutritional content of food patches in the environment. This optimal strategy is well approximated by a local decision that can be implemented by a simple neural circuit architecture. Together, this work highlights how energetic constraints and prior beliefs shape optimal foraging strategies, and how such strategies can be approximated by simple neural networks that implement local decision rules.

Across social species, social touch enhances well-being and reduces pain — two seemingly distinct benefits that enhance survival. Yet where and how the nervous system integrates these functions, and whether a single mechanism could serve both, remains unknown. Here we show that massage triggers oxytocin release, which shapes both pain and touch reward at the earliest stage of central processing — the spinal cord — through a single, state-dependent circuit mechanism. We report that in humans, massage enhances well-being, effects that correlate with endogenous oxytocin release. In mice, gentle touch activates hypothalamic oxytocin neurons that project directly to the spinal dorsal horn. Genetic manipulation of spinal oxytocin circuits alters behavioral responses to both gentle touch and noxious stimuli. Spinal calcium imaging and slice electrophysiology reveal that oxytocin acts on both excitatory and inhibitory spinal neurons to sculpt the relative activity of spinal ascending systems that convey both social touch and pain to the brain. Extending these findings to humans, we show that oxytocin receptors are also expressed on spinal excitatory and inhibitory neurons, and that endogenous oxytocin during massage correlates with altered spinal touch processing. Thus, spinal oxytocin signaling provides an evolutionarily conserved mechanism for the therapeutic benefits of massage.