The Mitochondrion as Potential Interface in Early-Life Stress Brain Programming

Hoffmann, Anke; Spengler, Dietmar

doi:10.3389/fnbeh.2018.00306

Cited by 49 publications

(34 citation statements)

References 148 publications

(170 reference statements)

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“…The mechanisms underlying decreased brain CCO activity after exposure to early stress are currently speculative, although mitochondria have been proposed as key mediators in brain programming by exposure to ELS [ 56 ]. Mitochondrial bioenergetics, glucocorticoid, and neurosteroid synthesis and metabolism, and reactive oxygen species (ROS) production have been proposed as main mechanisms explaining the relationship between ELS and reduced mitochondrial function [ 16 , 18 , 20 , 56 ]. It is known that ELS can induce epigenetic changes in brain regions associated with the physiological stress response, and program hippocampal and HPA axis functions leading to increased stress responsivity in adulthood [ 1 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial bioenergetics, glucocorticoid, and neurosteroid synthesis and metabolism, and reactive oxygen species (ROS) production have been proposed as main mechanisms explaining the relationship between ELS and reduced mitochondrial function [ 16 , 18 , 20 , 56 ]. It is known that ELS can induce epigenetic changes in brain regions associated with the physiological stress response, and program hippocampal and HPA axis functions leading to increased stress responsivity in adulthood [ 1 , 56 ]. Prolonged increased energy demands in brain cell mitochondria driven by the stress response system (including enhanced HPA axis and sympathetic system functions) could cause increased reactive oxygen species (ROS) production that can overwhelm antioxidant cellular response [ 17 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

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Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

et al. 2020

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Sex differences have been reported in the susceptibility to early life stress and its neurobiological correlates in humans and experimental animals. However, most of the current research with animal models of early stress has been performed mainly in males. In the present study, prolonged maternal separation (MS) paradigm was applied as an animal model to resemble the effects of adverse early experiences in male and female rats. Regional brain mitochondrial function, monoaminergic activity, and neuroinflammation were evaluated as adults. Mitochondrial energy metabolism was greatly decreased in MS females as compared with MS males in the prefrontal cortex, dorsal hippocampus, and the nucleus accumbens shell. In addition, MS males had lower serotonin levels and increased serotonin turnover in the prefrontal cortex and the hippocampus. However, MS females showed increased dopamine turnover in the prefrontal cortex and increased norepinephrine turnover in the striatum, but decreased dopamine turnover in the hippocampus. Sex differences were also found for pro-inflammatory cytokine levels, with increased levels of TNF-α and IL-6 in the prefrontal cortex and hippocampus of MS males, and increased IL-6 levels in the striatum of MS females. These results evidence the complex sex- and brain region-specific long-term consequences of early life stress.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

et al. 2020

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“…Mitochondria have been shown to coordinate many of the metabolic features of stress that can play a causal role in mental health disorders 27 , 59 , 60 . Mitochondria are the hub of the wheel of cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Mocking

Naviaux

et al. 2021

Transl Psychiatry

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Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69–1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

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“…Energy production in eukaryotic cells takes place mainly in mitochondria, depending on a series of oxygen-dependent enzymes of the electron transport chain located in these organelles, and cytochrome c oxidase (CCO) is the key enzyme complex responsible for oxygen consumption in cells. The pivotal role of oxidative metabolism in mitochondria as a potential interface in neurodevelopmental programming after early life stress has been recently acknowledged [18–20]. Quantitative cytochrome c oxidase (CCO) histochemistry is a widely used method to evaluate sustained or long-term changes in brain regional oxidative metabolic capacity [21].…”

Section: Introductionmentioning

confidence: 99%

Environmental enrichment effects after early stress on behavior and functional brain networks in adult rats

González-Pardo¹,

Árias²,

Vallejo³

et al. 2019

PLoS ONE

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Early life stress is associated with long-term and pervasive adverse effects on neuroendocrine development, affecting normal cognitive and emotional development. Experimental manipulations like environmental enrichment (EE) may potentially reverse the effects of early life stress induced by maternal separation (MS) paradigm in rodents. However, the functional brain networks involved in the effects of EE after prolonged exposure to MS have not yet been investigated. In order to evaluate possible changes in brain functional connectivity induced by EE after MS, quantitative cytochrome c oxidase (CCO) histochemistry was applied to determine regional brain oxidative metabolism in adult male rats. Unexpectedly, results show that prolonged MS during the entire weaning period did not cause any detrimental effects on spatial learning and memory, including depressive-like behavior evaluated in the forced-swim test, and decreased anxiety-like behavior. However, EE seemed to alter anxiety- and depression-like behaviors in both control and MS groups, but improved spatial memory in the latter groups. Analysis of brain CCO activity showed significantly lower metabolic capacity in most brain regions selected in EE groups probably associated with chronic stress, but no effects of MS on brain metabolic capacity. In addition, principal component analysis of CCO activity revealed increased large-scale functional brain connectivity comprising at least three main networks affected by EE in both MS and control groups. Moreover, EE induced a pattern of functional brain connectivity associated with stress and anxiety-like behavior as compared with non-enriched groups. In conclusion, EE had differential effects on cognition and emotional behavior irrespective of exposure to MS. In view of the remarkable effects of EE on brain function and behavior, implementation of rodent housing conditions should be optimized by evaluating the balance between scientific validity and animal welfare.

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The Mitochondrion as Potential Interface in Early-Life Stress Brain Programming

Cited by 49 publications

References 148 publications

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Environmental enrichment effects after early stress on behavior and functional brain networks in adult rats

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