Glucocorticoid Receptor Stimulation Resulting from Early Life Stress Affects Expression of DNA Methyltransferases in Rat Prefrontal Cortex

Urb, Mari; Anier, Kaili; Matsalu, Terje; Aonurm-Helm, Anu; Tasa, Gunnar; Koppel, Indrek; Zharkovsky, Alexander; Timmusk, Tõnis; Kalda, Anti

doi:10.1007/s12031-019-01286-z

Cited by 20 publications

(10 citation statements)

References 57 publications

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“…Furthermore, hippocampal damage resulting from the accumulation of abnormally aggregated proteins, which can occur as a result of impairing the process of proteostasis, is a hallmark of several neurodegenerative diseases (Moodley and Chan, 2014 ; Heckmann et al, 2020 ). While the cerebral cortex also plays a role in mediating the neurochemical stress response and is known to be functionally and structurally affected by ELS (Arnsten, 2009 ; Takatsuru and Koibuchi, 2015 ; Urb et al, 2019 ), experimental evidence indicates that it can be more resilient to stress (Takatsuru et al, 2009 ; Wang et al, 2014 ). Interestingly, a recent study involving adult male rats also found differential effects on autophagic activity by neuroanatomical region in response to MatSep, showing inhibition of the autophagy pathway in the hippocampus and activation in the prefrontal cortex (Liu et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Maternal Separation Modifies Proteostasis Marker Expression in the Adult Hippocampus

Sierra-Fonseca

Hamdan

Cohen

et al. 2021

Front. Mol. Neurosci.

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Exposure to early-life stress (ELS) can persistently modify neuronal circuits and functions, and contribute to the expression of misfolded and aggregated proteins that are hallmarks of several neurodegenerative diseases. The healthy brain is able to clear dysfunctional proteins through the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Accumulating evidence indicates that impairment of these pathways contributes to enhanced protein aggregation and neurodegeneration. While stress is a known precipitant of neurological decline, few specific mechanistic links underlying this relationship have been identified. We hypothesized that neonatal maternal separation (MatSep), a well-established model of ELS, has the ability to alter the levels of UPS and ALP components in the brain, and thus has the potential to disrupt proteostasis. The expression of proteostasis-associated protein markers was evaluated by immunoblotting in the hippocampus and cortex of adult Wistar rats that were previously subjected to MatSep. We observed multiple sex- and MatSep-specific changes in the expression of proteins in the ALP, mitophagy, and UPS pathways, particularly in the hippocampus of adult animals. In contrast, MatSep had limited influence on proteostasis marker expression in the cortex of adult animals. Our results indicate that MatSep can selectively modify the intracellular protein degradation machinery in ways that may impact the development and progression of neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Neonatal Maternal Separation Modifies Proteostasis Marker Expression in the Adult Hippocampus

Sierra-Fonseca

Hamdan

Cohen

et al. 2021

Front. Mol. Neurosci.

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“…In re-evaluating the animal modelling literature another striking convergent feature is alterations to these same epigenetic processes in either the developing brain or placenta. There is even likely to be some crosstalk between de novo gene methylation and foetal brain corticosteroids with data only now emerging showing corticosterone recruits the glucocorticoid receptor (GR) onto promoters of DNMT1 124 .…”

Section: Most Models Produce Early and Possible Persistent Alterationmentioning

confidence: 99%

How do established developmental risk-factors for schizophrenia change the way the brain develops?

Eyles

2021

Transl Psychiatry

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The recognition that schizophrenia is a disorder of neurodevelopment is widely accepted. The original hypothesis was coined more than 30 years ago and the wealth of supportive epidemiologically data continues to grow. A number of proposals have been put forward to suggest how adverse early exposures in utero alter the way the adult brain functions, eventually producing the symptoms of schizophrenia. This of course is extremely difficult to study in developing human brains, so the bulk of what we know comes from animal models of such exposures. In this review, I will summarise the more salient features of how the major epidemiologically validated exposures change the way the brain is formed leading to abnormal function in ways that are informative for schizophrenia symptomology. Surprisingly few studies have examined brain ontogeny from embryo to adult in such models. However, where there is longitudinal data, various convergent mechanisms are beginning to emerge involving stress and immune pathways. There is also a surprisingly consistent alteration in how very early dopamine neurons develop in these models. Understanding how disparate epidemiologically-validated exposures may produce similar developmental brain abnormalities may unlock convergent early disease-related pathways/processes.

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“…Together, these findings support human studies demonstrating that individuals with Val66Met polymorphism in BDNF are more sensitive to childhood adversity and depression in adulthood. [85][86][87] Early adversity induces age-dependent and sexspecific effects on several regulators of DNA methylation, including DNMTs, [88][89][90] and DNMT inhibitors have been used to prevent the deleterious effects of ELS 80,81 and adult stress 91 in rodents. One study found that MS induces a short-term increase in expression of Dnmt1, Dnmt3a, and Dnmt3b in rat mPFC, an effect that depends on GR binding.…”

Section: Early Life Stress: Epigenetic Fingerprint In Depression -Torres-berrío Et Almentioning

confidence: 99%

“…One study found that MS induces a short-term increase in expression of Dnmt1, Dnmt3a, and Dnmt3b in rat mPFC, an effect that depends on GR binding. 89 Similarly, adolescent males previously exposed to early maltreatment display decreased mRNA levels of MECP2 (a methylated DNA binding protein) in mPFC. In adulthood, levels of Dnmt1, Dnmt3a, Mecp2, Gadd45b, and Hdac1 mRNA were decreased in male rats with early maltreatment, whereas adult females only exhibit a significant decrease in Gadd45b.…”

Section: Early Life Stress: Epigenetic Fingerprint In Depression -Torres-berrío Et Almentioning

confidence: 99%

Unraveling the epigenetic landscape of depression: focus on early life stress

Torres‐Berrío

Issler

Parise

et al. 2019

Dialogues in Clinical Neuroscience

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Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. Early life stress (ELS) in particular is known to “scar” the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. Epigenetic processes lead to changes in gene expression that are not due to changes in DNA sequence, but achieved via modulation of chromatin modifications, DNA methylation, and noncoding RNAs. Here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. We then describe recent developments in understanding how ELS leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. We conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to ELS for the development of much-needed novel therapeutic strategies and biomarker discovery.

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Glucocorticoid Receptor Stimulation Resulting from Early Life Stress Affects Expression of DNA Methyltransferases in Rat Prefrontal Cortex

Cited by 20 publications

References 57 publications

Neonatal Maternal Separation Modifies Proteostasis Marker Expression in the Adult Hippocampus

Neonatal Maternal Separation Modifies Proteostasis Marker Expression in the Adult Hippocampus

How do established developmental risk-factors for schizophrenia change the way the brain develops?

Unraveling the epigenetic landscape of depression: focus on early life stress

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