Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults

Eagleson, Kathie L.; Villaneuva, Miranda; Southern, Rebecca M.; Levitt, Pat

doi:10.1016/j.ynstr.2020.100251

Cited by 18 publications

(23 citation statements)

References 100 publications

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“…Here, we used a well-validated model of limited bedding and nesting (LBN), applied from postnatal day (P)2-9 in mice. LBN disrupts maternal care and produces an early-life-stress (ELS) response in pup offspring (Eagleson et al, 2020; Heun-Johnson & Levitt, 2016; Rice et al, 2008). Care-as-usual (CAU) pup offspring were raised under normal conditions.…”

Section: Resultsmentioning

confidence: 99%

SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping

Ghoddousi

Levitt

Kamitakahara

et al. 2022

Preprint

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Spatial gene expression, achieved classically through in situ hybridization, is a fundamental tool for topographic phenotyping of cell types in the nervous system. Newly developed techniques allow for the visualization of multiple mRNAs at single-cell resolution, greatly expanding the ability to link gene expression to tissue topography. Yet, methods for efficient and accurate quantification and analysis of high dimensional in situ- hybridization are limited. To this end, the Single-Cell Automated Multiplex Pipeline for RNA (SCAMPR) was developed, facilitating rapid and accurate segmentation of neuronal cell bodies using a dual immunohistochemistry-RNAscope protocol and quantification of low and high abundance mRNA signals using open-source image processing and automated segmentation tools. Proof of principle using SCAMPR focused on spatial mapping of gene expression by peripheral (vagal nodose) and central (visual cortex) neurons. The analytical effectiveness of SCAMPR is demonstrated by identifying the impact of early life stress on differential gene expression by vagal neuron subtypes.

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Section: Resultsmentioning

confidence: 99%

SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping

Ghoddousi

Levitt

Kamitakahara

et al. 2022

Preprint

Self Cite

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“…In primed animals from the MIA model, eATP or poly(IC) exposure produced effects that lasted for days to weeks. The discovery of this latent memory response helps to understand how the cascade of mitochondrial and metabolic changes that occur acutely in response to stress or injury may initially be adaptive but can later lead to future hypersensitivities, developmental abnormalities, or lifelong health consequences [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

“…Because mitochondria serve as the substrate for metabolic memory [ 147 ], eATP effects on mitochondria will naturally affect metabolic memory. Mitochondrial adaptations to past stresses and quality control are crucial in regulating metabolism, innate immunity, cellular defense [ 148 ], neurodevelopment, and behavior from conception to old age [ 76 ]. The effect of eATP on mitochondrial metabolism is necessary to initiate both inflammation and the healing cycle.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder

et al. 2021

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Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.

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“…Its elevated activity was found in the cingulate cortex, anterior thalamus, and supramammillary area, but diminished activity was demonstrated in medial mammillary nucleus [ 120 ]. Comparative proteomic and functional analysis of hippocampus in juvenile and adult male and female mice that underwent ELS reveals that there is an enrichment in proteins associated with mitochondria and OXPHOS in females, increased OXPHOS in juvenile males and females, but reduced OXPHOS in adult females [ 121 ]. Thus, gender- and age-dependent mechanisms are activated by ELS exposure, thereby resulting in a wide spectrum of outcomes later in life.…”

Section: Developmental Aspects Of Brain Metabolism and Effects Of Elsmentioning

confidence: 99%

Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis

et al. 2021

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Early life stress (ELS) causes long-lasting changes in brain plasticity induced by the exposure to stress factors acting prenatally or in the early postnatal ontogenesis due to hyperactivation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system, development of neuroinflammation, aberrant neurogenesis and angiogenesis, and significant alterations in brain metabolism that lead to neurological deficits and higher susceptibility to development of brain disorders later in the life. As a key component of complex pathogenesis, ELS-mediated changes in brain metabolism associate with development of mitochondrial dysfunction, loss of appropriate mitochondria quality control and mitochondrial dynamics, deregulation of metabolic reprogramming. These mechanisms are particularly critical for maintaining the pool and development of brain cells within neurogenic and angiogenic niches. In this review, we focus on brain mitochondria and energy metabolism related to tightly coupled neurogenic and angiogenic events in healthy and ELS-affected brain, and new opportunities to develop efficient therapeutic strategies aimed to restore brain metabolism and reduce ELS-induced impairments of brain plasticity.

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Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults

Cited by 18 publications

References 100 publications

SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping

SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping

Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder

Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis

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