Search bioRxiv⌕ Search

Biology subjects

Park, H.

Publications and source records attributed to Park, H..

At least 145 records · Page 8Linked to original sources

Gli2 and Gli3 Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium

The olfactory epithelium (OE) is a specialized neuroepithelium that is replenished by two stem cell populations: globose basal cells (GBCs) and horizontal basal cells (HBCs). Previous work indicated that HBCs contain primary cilia, organelles that mediate Hedgehog (HH) pathway activity. However, a role for HH signaling in HBCs has not been investigated. We find that GLI2 and GLI3, transcriptional effectors of the HH pathway, are expressed in HBCs in the adult OE and that their expression expands following injury. Further, Gli2-expressing descendants contribute to all major OE cell types during OE regeneration. HBC-specific expression of constitutively active GLI2 drives inappropriate HBC proliferation, alters HBC identity, and culminates in a failure of HBCs to differentiate into olfactory sensory neurons (OSNs) following injury. HBC- specific deletion of endogenous Gli2 and Gli3 results in decreased HBCs and OSNs following OE injury. These data identify GLI2 and GLI3 as key regulators of HBC-mediated OE regeneration.

cell biology↗

Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase {delta}. Mutation accumulation assays revealed a [~]5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. When challenged with KAE609, high-level resistance was obtained more rapidly and at lower inoculum than wild-type parasites. Selections were also successful with an "irresistible" compound, MMV665794 that failed to yield resistance with other strains. Mutations in a previously uncharacterized gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), were validated as causal for resistance to MMV665794 and an analog, MMV007224. The increased genetic repertoire available to this "mutator" parasite can be leveraged to drive P. falciparum resistome discovery.

microbiology↗

The neurocognitive role of working memory load when Pavlovian motivational control affects instrumental learning

Research suggests that a fast, capacity-limited working memory (WM) system and a slow, incremental reinforcement learning (RL) system jointly contribute to instrumental learning. Thus, situations that strain WM resources alter instrumental learning: under WM loads, learning becomes slow and incremental, the reliance on computationally efficient learning increases, and action selection becomes more random. It is also suggested that Pavlovian learning influences peoples behavior during instrumental learning by providing hard-wired instinctive responses including approach to reward predictors and avoidance of punishment predictors. However, it remains unknown how constraints on WM resources affect instrumental learning under Pavlovian influence. Thus, we conducted a functional magnetic resonance imaging (fMRI) study (N=49) in which participants completed an instrumental learning task with Pavlovian-instrumental conflict (the orthogonalized go/no-go task) both with and without extra WM load. Behavioral and computational modeling analyses revealed that WM load reduced the learning rate and increased random choice, without affecting Pavlovian bias. Model-based fMRI analysis revealed that WM load strengthened RPE signaling in the striatum. Moreover, under WM load, the striatum showed weakened connectivity with the ventromedial and dorsolateral prefrontal cortex when computing reward expectations. These results suggest that the limitation of cognitive resources by WM load promotes slow and incremental learning through the weakened cooperation between WM and RL; such limitation also makes action selection more random, but it does not directly affect the balance between instrumental and Pavlovian systems. Author SummaryAmong multiple decision-making systems of humans and animals, the Pavlovian system is known for promoting automatic and instinctive behaviors. Understanding the Pavlovian influence on decision-making can offer valuable insights into the mechanism of impulsive and addictive behaviors. Previous studies suggested that prefrontal executive control can be important in regulating the Pavlovian influence. We tested if reducing cognitive resources available for executive control modulates the Pavlovian influence, by adding WM load to an instrumental learning task where Pavlovian influence is beneficial in some conditions but detrimental in others. Contrary to our expectation, constraining cognitive resources with WM load failed to significantly change the contribution of Pavlovian system. Nonetheless, with behavioral analysis and computational modeling, we revealed that WM load promotes slower learning and makes decisions noisier in an instrumental learning task with Pavlovian components. FMRI analysis revealed that WM load strengthens the RPE signaling in striatum upon observing the outcome and weakens the functional connectivity between the prefrontal cortex and the striatum before making a decision. The current study contributes to understanding how cognitive resource constraints alter learning and decision-making under Pavlovian influence as well as the neural mechanisms of those effects.

neuroscience↗

Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments

Monkeypox virus (MPXV) is a zoonotic orthopoxvirus that causes smallpox-like symptoms in humans and caused an outbreak in May 2022 that led the WHO to declare global health emergency. In this study, from a screening of approved-drug libraries using an MPXV infection cell system, atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 M, which is more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process to impair intracellular virion accumulation. Inhibitors of dihydroorotate dehydrogenase, an atovaquones target enzyme, showed conserved anti-MPXV activities. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations. Moreover, atovaquone and molnupiravir exhibited pan-Orthopoxvirus activity against vaccinia and cowpox viruses. These data suggest that atovaquone would be potential candidates for treating monkeypox.

microbiology↗

High-order thalamic and motor cortex inputs integrate sublinearly into tuft dendrites of pyramidal neurons in mouse somatosensory cortex

Tuft dendrites of pyramidal neurons housed in layer 1 of the neocortex form extensive excitatory synaptic connections with long-range cortical and high-order thalamic axons, along with diverse inhibitory inputs. Recently, we reported that synapses from the vibrissal primary motor cortex (vM1) and posterior medial thalamic nucleus (POm) are spatially clustered together in the same set of distal dendrites, suggesting a close functional interaction. In this study, we evaluated how these two types of synapses interact with each other using in vivo two-photon Ca2+ imaging and electrophysiology. We observed that dendritic Ca2+ responses could be efficiently evoked by electrical stimulation of POm or vM1 in the overlapping set of dendritic branches, rejecting the idea of branch-wise origin-selective synaptic wiring. Surprisingly, the Ca2+ responses upon coincident POm and vM1 stimulation summed sublinearly. We attribute this sublinearity to mutual inhibition via inhibitory neurons because synaptic currents generated by POm and vM1 also integrated sublinearly, but pharmacologically isolated direct synaptic currents summed linearly. Inhibitory neurons receiving POm inputs in the superficial cortical layer negatively regulated vM1-evoked responses. Finally, POm and vM1 innervated overlapping but distinct populations of somatostatin-expressing inhibitory neurons. Thus, POm and vM1 inputs negatively modulate each other in the mouse somatosensory cortex.

neuroscience↗

Differential roles of delta and theta oscillations in understanding semantic gist during natural audiovisual speech perception: Functional and anatomical evidence

Understanding the main topic of naturalistic speech in a multi-speaker environment is demanding though the availability of visual speech can be beneficial for speech comprehension. Recent studies provided evidence that low-frequency brain rhythms play an important role in the processing of acoustic speech features. However, at present, the neural dynamics of brain rhythms implementing a higher-order semantic system during naturalistic audiovisual speech perception is unknown. Here we investigated information processing carried by low-frequency oscillations in delta and theta bands for audiovisual speech integration for high-level semantic gist processing using a representational interaction approach. By manipulating the degree of high-level semantic content (speech chunks with high versus low topic probability) using Latent Dirichlet Allocation (LDA) topic modelling algorithm and complexity of speaker environment (single versus multi-speaker), we first found that delta and theta phase exert distinctive roles in high-level semantic processing where delta phase represents auditory and visual inputs synergistically whereas theta band does so redundantly. Next, we show both forms of representational interaction are observed to be greater for speech with low semantic gist, supported by speech comprehension and white matter tractography. Furthermore, we show that the delta phase-specific synergistic interaction in the right auditory, temporal, and inferior frontal areas is sensitive to the speaker environment, whereas theta band activity showing redundant representations is sensitive to semantic content. Our results shed new light on dynamic neural mechanisms of implementing higher-order semantic systems through representational interactions between audiovisual speech information and differential roles of delta and theta bands depending on the speaker environment.

neuroscience↗

EWSR1 prevents the induction of aneuploidy by regulating the localization of Aurora B at inner centromere

EWSR1 (Ewing sarcoma breakpoint region 1) was originally identified as a part of an aberrant EWSR1/FLI1 fusion gene in Ewing sarcoma, the second most common pediatric bone cancer. Due to formation of the EWSR1/FLI1 fusion gene in the tumor genome, the cell loses one wild type EWSR1 allele. Our previous study demonstrated that the loss of ewsr1a (homologue of human EWSR1) in zebrafish leads to the high incidence of mitotic dysfunction, of aneuploidy, and of tumorigenesis in the tp53 mutant background. To dissect the molecular function of EWSR1, we successfully established a stable DLD-1 cell line that enables a conditional knockdown of EWSR1 using Auxin Inducible Degron (AID) system. When both EWSR1 genes of DLD-1 cell were tagged with mini-AID at its 5-end using CRISPR/Cas9 system, treatment of the (AID-EWSR1/AID-EWSR1) DLD-1 cells with a plant-based Auxin (AUX) led to the significant levels of degradation of AID-EWSR1 proteins. During anaphase, the EWSR1 knockdown (AUX+) cells displayed higher incidence of lagging chromosomes compared to the control (AUX-) cells. This defect was proceeded by a lower incidence of the localization of Aurora B at inner centromeres, and by a higher incidence of the protein at kinetochores compared to the control cells during pro/metaphase. Despite these defects, the EWSR1 knockdown cells did not undergo mitotic arrest, suggesting that the cell lacks the error correction mechanism. Significantly, the EWSR1 knockdown (AUX+) cells induced higher incidence of aneuploidy compared to the control (AUX-) cells. Since our previous study demonstrated that EWSR1 interacts with the key mitotic kinase, Aurora B, we generated replacement lines of EWSR1-mCherry and EWSR1:R565A-mCherry (a mutant that has low affinity for Aurora B) in the (AID-EWSR1/AID-EWSR1) DLD-1 cells. The EWSR1-mCherry rescued the high incidence of aneuploidy of EWSR1 knockdown cells, whereas EWSR1-mCherry:R565A failed to rescue the phenotype. Together, we demonstrate that EWSR1 is essential to prevent aneuploidy through interaction with Aurora B, most likely by regulating the localization of Aurora B at centromere.

cell biology↗

Single cell transcriptomics reveals functionally specialized vascular endothelium in brain

The blood-brain barrier (BBB) limits the entry of leukocytes and potentially harmful substances from the circulation into the central nervous system (CNS). While BBB defects are a hallmark of many neurological disorders, the cellular heterogeneity at the neurovascular interface and the mechanisms governing neuroinflammation are not fully understood. Through single cell RNA sequencing of non-neuronal cell populations of the murine cerebral cortex during development, adulthood, ageing and neuroinflammation, we identify reactive endothelial venules (REVs), a compartment of specialised post-capillary endothelial cells (ECs) that are characterized by consistent expression of cell adhesion molecules, preferential leukocyte transmigration, association with perivascular macrophage populations, and endothelial activation initiating CNS immune responses. Our results provide novel insights into the heterogeneity of the cerebral vasculature and a useful resource for the molecular alterations associated with neuroinflammation and ageing.

physiology↗

Assessment of Human Renal Transporter Based Drug-Drug Interactions Using Proximal Tubule Kidney-Chip

Study of renal transporters is crucial for understanding drug disposition and toxicity, and more importantly, predicting potential drug-drug interactions (DDIs). However, conventional in vitro models often fail to predict renal transporter activity and are not scalable to a predictive clinical outcome due to in vitro-in vivo discrepancy. Here, we successfully developed a human Proximal Tubule Kidney-Chip model that emulated in vivo renal physiology and function to assess renal transporter-based DDIs. Active and improved functionality of key renal transporters including p-glycoprotein (P-gp), multidrug and toxin extrusion (MATE) 1 and 2-K, organic anion transporter (OAT) 1 and 3, and organic cation transporter (OCT) 2 were demonstrated using appropriate probe substrates in Kidney-Chips compared to transwell controls. Moreover, comparative transcriptomic analysis revealed that key efflux and uptake transporters were expressed significantly higher in the Kidney-Chip compared to the transwell. Additionally, key parameters obtained from substrate-inhibitor interactions in the model were used to predict clinical DDIs as well as clearance values, which were closer to in vivo clearances. Overall, these results support that the human Proximal Tubule Kidney-Chip can reliably assess the role of human renal transporters in drug disposition and drug interactions, providing a critical tool to assess renal transport in vitro.

cell biology↗

Get the gist of the story: Neural map of topic keywords in multi-speaker environment

Neural representation of lexico-semantics in speech processing has been revealed in recent years. However, to date, how the brain makes sense of the higher-level semantic gist (topic keywords) of a continuous speech remains mysterious. Capitalizing on a generative probabilistic topic modelling algorithm on speech materials to which participants listened while their brain activities were recorded by Magnetoencephalography (MEG), here we show spatio-temporal neural representation of topic keywords in a multi-speaker environment where task-relevant (attended) and -irrelevant (unattended) speech co-exits. We report the difference of neural representation between salient and less salient semantic gist of both attended and unattended speech. Moreover, we show that greater sensitivity to semantically salient unattended speech in the left auditory and motor cortices negatively mediates attended speech comprehension.

neuroscience↗

Early Endosome Capture Proteomics and its Application to Amyloid Precursor Protein Intramembrane Processing by β and γ-Secretases

Degradation and recycling of plasma membrane-localized proteins occurs via the endolysosomal system, wherein endosomes bud into the cytosol from the plasma membrane and subsequently mature into degradative lysosomal compartments. The endolysosomal system also participates in intracellular membrane protein trafficking, signaling, and protein degradation via autophagy. Our understanding of the endolysosomal system has been significantly advanced through the development of methods for selective capture of lysosomes (termed Lyso-IP), but methods for analogous isolation of early intermediates in the endolysosomal system are lacking. Here, we develop an approach for rapid isolation of early/sorting endosomes through affinity capture of the early endosome-associated protein EEA1 (Endo-IP) and provide proteomic and lipidomic snapshots of early endosomes in action. In addition to resident endosomal components, we identify numerous recycling, regulatory and membrane fusion complexes as well as candidate cargo, providing a proteomic landscape of early/sorting endosomes that we distinguished from lysosomes via comparative proteomics. The approach allows capture of internalized transferrin within minutes of its addition to cells, indicating the utility of the approach for dynamic analysis of early/sorting endosomes. Among the endocytic cargo identified by Endo-IP was the amyloid precursor protein (APP) genetically linked with Alzheimers disease. Processing of APP to amyloidogenic A{beta} peptides by {beta}- and {gamma}-Secretases can occur within the endolysosomal system among other compartments, but methods for spatial quantification of A{beta} products in individual organelles are lacking. We combined Endo- and Lyso-IP with targeted proteomics to provide a spatial digital snapshot of A{beta} products. This analysis revealed that products of A{beta} processing by {beta}- and {gamma}-Secretases, and alterations in the specificity of cleavage by small molecule {gamma}-Secretase modulators, can be quantified in both early/sorting endosomes and lysosomes. We anticipate that the Endo-IP approach will facilitate systematic interrogation of the many processes that are coordinated on early endosomes.

cell biology↗

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NF{kappa}B/IL1-signaling and activating interferon (IFN) gene expression. Repression of NF{kappa}B/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them. Statement of significanceCD11b agonists are a novel approach to reprogram myeloid cells in solid tumors. We show that GB1275, a CD11b-agonist, amplified STING/IFN signaling in TAMs to support anti-tumor immunity and this signaling is amplified further by cytotoxic therapy. These studies support new treatment strategies for advanced solid tumors with myeloid immunosuppression.

cancer biology↗

Subgroups of eating behavior traits independent of obesity defined using functional connectivity and feature representation learning

AO_SCPLOWBSTRACTC_SCPLOWEating behavior is highly heterogeneous across individuals, and thus, it cannot be fully explained using only the degree of obesity. We utilized unsupervised machine learning and functional connectivity measures to explore the heterogeneity of eating behaviors. This study was conducted on 424 healthy adults. We generated low-dimensional representations of functional connectivity defined using the resting-state functional magnetic resonance imaging, and calculated latent features using the feature representation capabilities of an autoencoder by nonlinearly compressing the functional connectivity information. The clustering approaches applied to latent features identified three distinct subgroups. The subgroups exhibited different disinhibition and hunger traits; however, their body mass indices were comparable. The model interpretation technique of integrated gradients revealed that these distinctions were associated with the functional reorganization in higher-order associations and limbic networks and reward-related subcortical structures. The cognitive decoding analysis revealed that these systems are associated with reward- and emotion-related systems. We replicated our findings using an independent dataset, thereby suggesting generalizability. Our findings provide insights into the macroscopic brain organization of eating behavior-related subgroups independent of obesity.

neuroscience↗

Continuous two-phase in vitro co-culture model of the enthesis

The enthesis is the interfacial tissue between ligament or tendon, and bone, which connects tissues of distinctly different mechanical properties. Although ligament and enthesis injury is commonplace, the development and healing mechanisms of these tissues are yet unclear. Current models for investigating these mechanisms are primarily in vivo animal models as in vitro models have been limited. In this study, an in vitro enthesis model was developed using a modified gel aspiration-ejection (GAE) method. Continuous two-phase aligned dense collagen (ADC) hydrogels with an overlapping interface were fabricated within 2 hours. The mechanical properties of acellular two-phase ADC confirmed the continuous nature of this model, as the mechanical properties showed no significant difference compared to single-phase ADC and maintained comparable structural and mechanical characteristics of immature ligaments and unmineralized bone. Human anterior cruciate ligament (ACL) fibroblasts and human spine vertebral osteoblasts were isolated from donor tissues and were seeded to form the enthesis model. These were cultured for 14 days, at which the viability and proliferation was observed to be 85 {+/-} 7.5% and 230 {+/-} 52%, respectively. Histological and immunofluorescence analyses at day 14 revealed extensive cell-driven matrix remodelling, and the seeded fibroblasts and osteoblasts maintained their phenotype within their compartments of the layered co-culture model. These results demonstrate the rapid fabrication of a two-phase co-culture system that can be utilized as an in vitro model to further understand the degenerative and regenerative mechanisms within the enthesis.

bioengineering↗

A new protocol for speed vernalisation of winter cereals

There are many challenges facing the development of high-yielding, nutritious crops for future environments. One limiting factor is generation time, which prolongs research and plant breeding timelines. Recent advances in speed breeding protocols have dramatically reduced generation time for many short-day and long-day species by optimising light and temperature conditions during plant growth. However, winter crops with a vernalisation requirement still require up to 6-10 weeks in low-temperature conditions before transition to reproductive development. Here, we tested a suite of environmental conditions and protocols to investigate if vernalisation can be satisfied more efficiently. We identified a vernalisation method consisting of exposing seeds at the soil surface to an extended photoperiod of 22 h day:2 h night at 10{degrees}C with transfer to speed breeding conditions that dramatically reduces generation time in both winter wheat (Triticum aestivum) and winter barley (Hordeum vulgare). Implementation of this protocol achieved up to five generations per year for winter wheat or barley, instead of the two typically obtained under standard vernalisation and plant growth conditions. The protocol has great potential to enhance training and to accelerate research, pre-breeding, and breeding outcomes focussed on winter crop improvement.

plant biology↗

A Nascent Peptide Code for Translational Control of mRNA Stability in Human Cells

Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human cells remain poorly defined. Here, we develop a massively parallel assay to measure mRNA effects of thousands of synthetic and endogenous coding sequence motifs in human cells. We identify several families of simple dipeptide repeats whose translation triggers acute mRNA instability. Rather than individual amino acids, specific combinations of bulky and positively charged amino acids are critical for the destabilizing effects of dipeptide repeats. Remarkably, dipeptide sequences that form extended {beta} strands in silico and in vitro drive ribosome stalling and mRNA instability in vivo. The resulting nascent peptide code underlies ribosome stalling and mRNA-destabilizing effects of hundreds of endogenous peptide sequences in the human proteome. Our work reveals an intrinsic role for the ribosome as a selectivity filter against the synthesis of bulky and aggregation-prone peptides.

molecular biology↗

Mechanical activation drives tenogenic differentiation of human mesenchymal stem cells in aligned dense collagen hydrogels

Tendons are force transmitting mechanosensitive tissues predominantly comprised of highly aligned collagen type I fibres. In this study, the recently introduced gel aspiration-ejection method was used to rapidly fabricate aligned dense collagen (ADC) hydrogel scaffolds. ADCs provide a biomimetic environment compared to traditional collagen hydrogels that are mechanically unstable and comprised of randomly oriented fibrils. The ADC scaffolds were shown to be anisotropic with comparable stiffness to immature tendons. Furthermore, the application of static and cyclic uniaxial loading, short-term (48 h) and high-strain (20%), resulted in a 3-fold increase in both the ultimate tensile strength and modulus of ADCs. Similar mechanical activation of human mesenchymal stem cell (MSC) seeded ADCs in serum- and growth factor-free medium induced their tenogenic differentiation. Both static and cyclic loading profiles resulted in a greater than 12-fold increase in scleraxis gene expression and either suppressed or maintained osteogenic and chondrogenic expressions. Following the 48 h mechanoactivation period, the MSC-seeded scaffolds were matured by tethering in basal medium without further external mechanical stimulation for 19 days, altogether making up 21 days of culture. Extensive cell-induced matrix remodeling and deposition of collagens type I and III, tenascin-C and tenomodulin were observed, where initial cyclic loading induced significantly higher tenomodulin protein content. Moreover, the initial short-term mechanical stimulation elongated and polarized seeded MSCs and overall cell alignment was significantly increased in those under static loading. These findings indicate the regenerative potential of the ADC scaffolds for short-term mechanoactivated tenogenic differentiation, which were achieved even in the absence of serum and growth factors that may potentially increase clinical translatability. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/470026v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1d52807org.highwire.dtl.DTLVardef@13716c5org.highwire.dtl.DTLVardef@1b7ffeforg.highwire.dtl.DTLVardef@103c183_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

Interneuron Control of C. elegans Developmental Decision-making

Animals integrate external stimuli to shape their physiological responses throughout development. In adverse environments, Caenorhabditis elegans larvae can enter a stress-resistant diapause state with arrested metabolism and reproductive physiology. Amphid sensory neurons feed into both rapid chemotactic and short-term foraging mode decisions, mediated by amphid and premotor interneurons, as well as the long-term diapause decision. We identify amphid interneurons that integrate pheromone cues and propagate this information via a neuropeptidergic pathways to influence larval developmental fate, bypassing the pre-motor system. AIA interneuron-derived FLP-2 neuropeptide signaling promotes reproductive growth and AIA activity is suppressed by pheromone. FLP-2 acts antagonistically to the insulin-like INS-1. FLP-2s growth promoting effects are inhibited by upstream metabotropic glutamatergic signaling and mediated by the broadly-expressed neuropeptide receptor NPR-30. Conversely, the AIB interneurons and their neuropeptide receptor NPR-9/GALR2 promote diapause entry. These neuropeptidergic outputs allow reuse of parts of a sensory system for a decision with a distinct timescale.

neuroscience↗