Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior

Misiewicz, R. Zuzanna; Iurato, Stella; Kulesskaya, Natalia; Salminen, Laura; Rodrigues, Luís Filipe; Maccarrone, Giuseppina; Martins, Jade; Laine, Mikaela; Sokołowska, Ewa; Trontti, Kalevi; Rewerts, Christiane; Novak, Božidar; Volk, Naama; Park, Dong Ik; Jokitalo, Eija; Paulín, Lars; Auvinen, Petri; Võikar, Vootele; Chen, Alon; Erhardt, Angelika; Turck, Christoph W.; Hovatta, Iiris

doi:10.1371/journal.pgen.1008358

Cited by 43 publications

(29 citation statements)

References 102 publications

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“… 21 SE 24 62.27 2000 PRJNA506950 93 Misiewicz et al . 31 SE 14 39.08 500 PRJNA516641 94 Nollet et al . 25 PE 48 170.85 2500 The table shows the main characteristics of each BioProject, including the library layout and platform used for RNA-sequencing, the number of SRA-experiments selected from each BioProject and their total size (paired ends, PE; single ends, SE).…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Table 2, the selected BioProjects were very heterogeneous and included several types of stress: acute 16,20 , sub-chronic 21 or chronic 22,23 restraint, cold swim 16 , sub-chronic 15 , or chronic 24 variable stress, unpredictable chronic mild stress 25 , chronic social defeat [26][27][28][29][30][31][32] , early life stress 29,32 , electric footshock (or contextual fear conditioning) [33][34][35] , auditory fear conditioning with or without immobilization 36 . Fear conditioning is a classical associative memory test in mice, however it is also widely used as preclinical animal model of PTSD, as it involves delivery of mild electric footshocks that represent an aversive experience, thus it was included in our selection of stressors 37 .…”

Section: Analysis Of Stress-related Changes In the Brain Transcriptommentioning

confidence: 99%

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A gene expression atlas for different kinds of stress in the mouse brain

et al. 2020

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Stressful experiences are part of everyday life and animals have evolved physiological and behavioral responses aimed at coping with stress and maintaining homeostasis. However, repeated or intense stress can induce maladaptive reactions leading to behavioral disorders. Adaptations in the brain, mediated by changes in gene expression, have a crucial role in the stress response. Recent years have seen a tremendous increase in studies on the transcriptional effects of stress. The input raw data are freely available from public repositories and represent a wealth of information for further global and integrative retrospective analyses. We downloaded from the Sequence Read Archive 751 samples (SRA-experiments), from 18 independent BioProjects studying the effects of different stressors on the brain transcriptome in mice. We performed a massive bioinformatics re-analysis applying a single, standardized pipeline for computing differential gene expression. This data mining allowed the identification of novel candidate stress-related genes and specific signatures associated with different stress conditions. The large amount of computational results produced was systematized in the interactive “Stress Mice Portal”.

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Section: Resultsmentioning

confidence: 99%

Section: Analysis Of Stress-related Changes In the Brain Transcriptommentioning

confidence: 99%

A gene expression atlas for different kinds of stress in the mouse brain

et al. 2020

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“…Only a few studies have investigated alterations in the transcriptional expression of mitochondria-associated genes in the brain of major depression disorder (MDD) subjects 33 , including the PFC 34 . In rodent models of chronic stress, a recent multi-omics study including genome-wide analyses identified mitochondrial-related alterations in gene expression in the bed nucleus of stria terminalis, an anxiety-related brain region 35 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Weger

Alpern

Cherix

et al. 2020

Sci Rep

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Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

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“…However, that inference is somewhat undermined by the gamut of research that has used this procedure to study 'anxiety.' 26,27 As with CUMS procedures, a major concern about these studies is that there are appreciable differences in the protocols used in different laboratories, particularly in respect of the time for which the animals are left to interact. In some laboratories, as is the case in the UK, the animals are separated immediately after the first contact but retain sight and smell of each other.…”

Section: Social Defeat Stressmentioning

confidence: 99%

“…24,25 On that basis, this is widely described as a model of ‘depression-like’ behaviour. However, that inference is somewhat undermined by the gamut of research that has used this procedure to study ‘anxiety.’ 26,27…”

Section: Some Procedures That Are Used To Produce Animal ‘Models’ Of mentioning

confidence: 99%

Some Reasons Why Preclinical Studies of Psychiatric Disorders Fail to Translate: What Can Be Rescued from the Misunderstanding and Misuse of Animal ‘Models’?

Stanford

2020

Altern Lab Anim

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The repeated failure of animal models to yield findings that translate into humans is a serious threat to the credibility of preclinical biomedical research. The use of animals in research that lacks translational validity is unacceptable in any ethical environment, and so this problem needs urgent attention. To reproduce any human illness in animals is a serious challenge, but this is especially the case for psychiatric disorders. Yet, many authors do not hesitate to describe their findings as a ‘model’ of such a disorder. More cautious scientists describe the behavioural phenotype as ‘disorder-like’, without specifying the way(s) in which the abnormal behaviour could be regarded as being analogous to any of the diagnostic features of the disorder in question. By way of discussing these problems, this article focuses on common, but flawed, assumptions that pervade preclinical research of depression and antidepressants. Particular attention is given to the difference between putative ‘models’ of this illness and predictive screens for candidate drug treatments, which is evidently widely misunderstood. However, the problems highlighted in this article are generic and afflict research of all psychiatric disorders. This dire situation will be resolved only when funders and journal editors take action to ensure that researchers interpret their findings in a less ambitious, but more realistic, evidence-based way that would parallel changes in research of the cause(s), diagnosis and treatment of psychiatric problems in humans.

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Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior

Cited by 43 publications

References 102 publications

A gene expression atlas for different kinds of stress in the mouse brain

A gene expression atlas for different kinds of stress in the mouse brain

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Some Reasons Why Preclinical Studies of Psychiatric Disorders Fail to Translate: What Can Be Rescued from the Misunderstanding and Misuse of Animal ‘Models’?

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