Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior in<i>Drosophila melanogaster</i>

Olivares, Gabriel; Núñez-Villegas, Franco; Candia, Noemi; Oróstica, Karen Y.; González-Ramírez, M. Constanza; Vega-Macaya, Franco; Zúñiga, Nolberto; Molina, Cristian; Mackay, Trudy F. C.; Verdugo, Ricardo A.; Olguı́n, Patricio

doi:10.1093/sleep/zsad016

Cited by 3 publications

(3 citation statements)

References 108 publications

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“…The DGRP has been used to identify variants associated with variation in a wide range of morphologic (Özsoy et al., 2021; Zwarts et al., 2015), physiologic (Carbone et al., 2016; Dembeck et al., 2015; Huang et al., 2012; Huang et al., 2020; Jordan et al., 2012; Olivares et al., 2023; Weber et al., 2012; Zhou et al., 2012), and behavioral (Arya et al., 2015; Baker, Carbone, et al., 2021; Chi et al., 2021; Harbison et al., 2013; Harbison et al., 2019; Highfill et al., 2019; Shorter et al., 2015; Spierer et al., 2021; Swarup et al., 2013) phenotypes. Genome‐wide associations seldom reach genome‐wide significance based on Bonferroni corrections for multiple tests.…”

Section: Quantitative and Systems Genetics Approaches To Identifying ...mentioning

confidence: 99%

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Rand,

Tennessen,

Mackay

et al. 2023

Current Protocols

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The use of Drosophila melanogaster for studies of toxicology has grown considerably in the last decade. The Drosophila model has long been appreciated as a versatile and powerful model for developmental biology and genetics because of its ease of handling, short life cycle, low cost of maintenance, molecular genetic accessibility, and availability of a wide range of publicly available strains and data resources. These features, together with recent unique developments in genomics and metabolomics, make the fly model especially relevant and timely for the development of new approach methodologies and movements toward precision toxicology. Here, we offer a perspective on how flies can be leveraged to identify risk factors relevant to environmental exposures and human health. First, we review and discuss fundamental toxicologic principles for experimental design with Drosophila. Next, we describe quantitative and systems genetics approaches to resolve the genetic architecture and candidate pathways controlling susceptibility to toxicants. Finally, we summarize the current state and future promise of the emerging field of Drosophila metabolomics for elaborating toxic mechanisms. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.

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Section: Quantitative and Systems Genetics Approaches To Identifying ...mentioning

confidence: 99%

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Rand,

Tennessen,

Mackay

et al. 2023

Current Protocols

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“…Early-life nutritional environment impacts neural development and can have long-lasting consequences on adult complex behaviors, such as sleep, locomotion, memory, and learning (Bale et al, 2010 ; Crossland et al, 2017 ; Olivares et al, 2023 ). In humans, prenatal severe nutritional restriction affects intellectual functioning (Li et al, 2016 ) and increases the risk of suffering from affective disorders and mental illness (Brown et al, 2000 ; Hulshoff Pol et al, 2000 ).…”

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confidence: 99%

Editorial: The role of early-life nutrition and metabolism in brain development and adult behavior

Olivares,

Olguín

2023

Front. Neurosci.

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“…In the NDD-and NPD-related sleep domain, the RBFOX1 SNP rs1478693 was significantly associated with sleep time in both males and especially females in an Australian twin cohort (Byrne et al, 2013). Moreover, rbfox1 exerted effects on night sleep duration and the morphology of sleep-regulating brain regions in fruit flies in a gene × environmentdependent manner, together with early-life nutrition status (Olivares et al, 2023).…”

Section: Introduction 67mentioning

confidence: 97%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

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Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes. To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance. To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences. In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.

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Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior inDrosophila melanogaster

Cited by 3 publications

References 108 publications

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Editorial: The role of early-life nutrition and metabolism in brain development and adult behavior

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

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