Adult Single-nucleus Neuronal Transcriptomes of Insulin Signaling Mutants Reveal Regulators of Behavior and Learning

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 7, 2024

Abstract The insulin/insulin-like signaling (IIS) pathway regulates many of C. elegans’ adult functions, including learning and memory 1 . While whole-worm tissue-specific transcriptomic analyses have identified IIS targets 2,3 , a higher-resolution single-cell approach is required to identify changes that confer neuron-specific improvements in the long-lived insulin receptor mutant, daf-2 To understand how behaviors are controlled by small number neurons change mutants, we used deep resolution single-nucleus RNA sequencing define each neuron type’s transcriptome wild-type mutants. First, found surprising differences between L4 larval young chemoreceptor expression, synaptic genes, genes. These Day transcriptomes allowed us AWC-specific regulators chemosensory function predict neuron-to-neuron peptide/receptor pairs. We then gene expression correlate with daf-2’s improved cognitive particularly AWC sensory controls associative 4 behavioral assays test their roles function. Combining single-neuron transcriptomics, genetic manipulation, enabled genes may single control behavior, conserved memory. One-Sentence Summary Single-nucleus elegans reveals functionally relevant transcriptional changes, chemosensation, learning,

Language: Английский

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Body-to-brain Insulin and Notch signaling regulates memory through neuronal CREB activity

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 17, 2024

While we think of memory regulation as autonomous to neurons, factors outside the brain can also affect neuronal function. In C. elegans, insulin/IGF-1-like signaling (IIS) pathway regulates longevity¹, metabolism^2,3, and memory^4,5: long-lived daf-2 insulin/IGF-1 receptor mutants more than double duration after a single training session. It was assumed that this strictly neuronal, but discovered degradation DAF-2 in hypodermis greatly extends via expression diffusible Notch ligand, OSM-11, which turn activates neurons. Single-nucleus RNA-sequencing neurons revealed activation CREB genes itself. Finally, found hypodermal IIS/Notch/CREB well OSM-11 overexpression aged animals rescues both learning memory. Thus, insulin liver-like hypodermis⁶ non-autonomously function, providing systemic connection between metabolism through from body brain.

Language: Английский

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Male-specific features ofC. elegansneuronal aging

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 18, 2023

Summary Aging is a complex biological process, with sexually dimorphic aspects. For example, men and women differ in their vulnerabilities cognitive decline, suggesting sex may contribute to the heterogeneous nature of aging. Although we know great deal about aging hermaphrodites model system C. elegans, less known decline males. Through behavioral analyses, found that process has both sex-shared sex-dimorphic characteristics. neuron-specific sequencing, identified neuronal age-associated sex-differential targets. In addition genes, males differentially downregulate mitochondrial metabolic genes upregulate GPCR age. addition, X chromosome exhibits increased gene expression altered dosage compensation age, indicating possible X-chromosomal dysregulation contributes sexual dimorphism Finally, sex-differentially expressed hrg-7 , which encodes an aspartic-type endopeptidase, regulates male behavior during but does not affect hermaphrodites’ behaviors. Overall, these results suggest exhibit different age-related changes. This study will strengthen our understanding sex-specific vulnerability resilience help identify new pathways target novel treatments could benefit sexes.

Language: Английский

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Early-adulthood intermittent fasting and reduced insulin/IGF-1 signalling additively increase lifespan and slow down reproductive ageing

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 23, 2023

Summary The developmental theory of ageing proposes that age-specific decline in the force natural selection results suboptimal levels gene expression adulthood, leading to functional senescence. This explicitly predicts optimising adulthood can ameliorate senescence and improve fitness. Reduced insulin/IGF-1 signalling (rIIS) extends reproductive lifespan Caenorhabditis elegans at cost reduced reproduction. Here, we show adulthood-only rIIS improves late-life reproduction without any detrimental effects on other life-history traits both benign stressful conditions. Remarkably, additively when animals are exposed a fluctuating food environment – intermittent fasting (IF) resulting intake early adulthood. Full factorial genome-wide RNA-Seq across life course demonstrated IF modulate pro-longevity genes. IF, combined + treatment downregulated genes involved peptide metabolism differentially regulated immunity later life. Importantly, uniquely large cluster mid-life associated with immune response. These suggest decelerate increase

Language: Английский

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