Biology subjects

Pletcher, S. D.

Publications and source records attributed to Pletcher, S. D..

7 recordsLinked to original sources

bioRxiv2026

Neuronal FICD shapes motivated behavior through modulation of dopamine receptor dynamics

Motivated behaviors rely on dopaminergic signaling, which in turn depends on the correct folding and trafficking of receptors through the endoplasmic reticulum (ER). Within the ER, the AMPylase enzyme FICD acts as a molecular rheostat through its modification of the chaperone BiP, dynamically tuning the organelle's responsiveness to folding perturbations and cellular stress. While the biochemistry of FICD is well-established, its role in complex animal behavior remains poorly understood. Here, we identify FICD as a conserved contributor to the generation of motivated behavior. In Drosophila, pan-neuronal knockdown of dFic significantly reduces feeding, spontaneous locomotion, and reward-seeking behavior. These alterations occur without disrupting circadian architecture, motor capacity, or homeostatic hunger, indicating a specific loss of motivational drive. Depleting dFic within subsets of dopamine receptor-expressing (Dop1R1) neurons recapitulates these behavioral alterations. Transcriptomic profiling reveals that dFic depletion does not induce a canonical unfolded protein response, pointing to a specific post-transcriptional alteration rather than global ER stress. At the molecular level, dysregulated dFic alters the localization and abundance of Dop1R1. Finally, we demonstrate that this regulatory axis is evolutionarily conserved, as loss of FICD similarly diminishes motivated behaviors in C. elegans and mice. Together, these findings implicate FICD in the generation of motivated behavior and link dynamic control of ER proteostasis to dopamine-receptor maturation.

neuroscience↗

bioRxiv2026

Learning fly pose from vision-language annotations

Animal pose estimation typically requires manual annotation of body parts to train neural networks for each new recording system or environmental condition. Here we use a general-purpose vision-language model (VLM) to generate annotations in multi-animal recordings of fruit flies (Drosophila melanogaster). Initial annotations follow written anatomical descriptions and are reviewed by an independent VLM session using neighboring video frames. On 120 held-out fly images, AI annotations had a median distance of 2.28 pixels from human labels, with 84.0% agreement within eight pixels, averaged across landmark types. The comparison included 10 landmarks, with head and eyes analyzed separately because of systematic differences in placement. Review improved agreement primarily at the feet, with the largest remaining discrepancies at positions with limited visual evidence. Visual inspection revealed cases in which the AI annotations were more anatomically accurate than those of an experienced human annotator, particularly at the feet. A convolutional network trained using SLEAP on 300 AI-annotated fly images showed similar agreement with human labels and closely reproduced the AI annotations on held-out images, with a median distance of 1.56 pixels. We also applied the procedure to recordings from another laboratory, using new AI annotations to train a separate pose network. Although VLM annotation required minutes per fly, the trained networks enabled pose estimation throughout more than 700,000 frames. These results demonstrate that VLM annotations can support fast animal pose estimation without manually labeled training images.

animal behavior and cognition↗

bioRxiv2025

A stem cell-based platform for functional analysis of genetic variants in lung disease

Advances in genetic and transcriptomic technologies have identified large numbers of genes and variants of potential importance to human disease. Determining the function of these genes and variants is a critical bottleneck in understanding disease etiology. Variants of uncertain significance (VUS) are highly prevalent in our genomes, but our ability to identify them significantly outpaces our ability to determine their molecular and clinical consequences. We developed a genetically tractable induced pluripotent stem cell (iPSC) based platform to investigate gene variant pathogenicity in lung disease, using primary ciliary dyskinesia (PCD) as a model. We identified an individual with a clinical diagnosis of PCD and a VUS in the gene Multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS). Through gene-editing of iPSC-derived airway basal stem cells (iBCs), we precisely defined the molecular and cellular pathogenicity of the variant providing a successful application of the iPSC system to diagnose a lung disease.

cell biology↗

bioRxiv2022

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single cell RNA sequencing of airway epithelium and mouse modeling, we find that IL-13 expands and programs airway tuft cells towards eicosanoid metabolism, and that tuft cell deficiency leads to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bear a signature of prostaglandin E2 activation, and PGE2 activation leads to CFTR-dependent ion and fluid secretion and accelerated mucociliary transport. Together these data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

immunology↗

bioRxiv2020

Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

genetics↗

bioRxiv2019

High throughput small molecule screening reveals NRF2-dependent and -independent pathways of cellular stress resistance

Biological aging is the dominant risk factor for most chronic diseases. Development of anti-aging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in C. elegans. Transcriptomic analysis implicated Nrf2 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Molecules that conferred stress resistance also induced cellular inflammatory pathways, and other core pathways such as AMPK signaling. Small molecules identified in this work may represent attractive candidates to evaluate for their potential pro-health and pro-longevity effects in mammals.

cell biology↗

bioRxiv2019

Perception of naturally dead conspecifics impairs health and longevity through serotonin signaling in Drosophila

Sensory perception modulates health and aging across taxa. Understanding the nature of relevant cues and the mechanisms underlying their action may lead to novel interventions that improve the length and quality of life. In humans, psychological trauma is often associated with the recognition of dead individuals, with chronic exposure leading to persistent mental health issues including depression and post-traumatic stress disorder. The mechanisms that link mental and physical health, and the degree to which these are shared across species, remain largely unknown. Here we show that the vinegar fly, Drosophila melanogaster, has the capability to perceive dead conspecifics in its environment and that this perceptive experience induces both short- and long-term effects on health and longevity. Death perception is mediated by visual and olfactory cues, and remarkably, its effects on aging are eliminated by targeted attenuation of serotonin signaling. Our results suggest a complex perceptive ability in Drosophila that reveals deeply conserved mechanistic links between psychological state and aging, the roots of which might be unearthed using invertebrate model systems.

animal behavior and cognition↗