Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut–brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut–brain axis. Further research is required to understand the complex mechanisms underlying gut–brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.

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Early life adversity, dispositional mindfulness, and longitudinal stress experience during the COVID-19 pandemic

10.31234/osf.io/5kt6z ◽

2020 ◽

Author(s):

Annika Benz ◽

Maria Meier ◽

Ulrike U. Bentele ◽

Stephanie J. Dimitroff ◽

Bernadette Denk ◽

...

Keyword(s):

Perceived Stress ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Dispositional Mindfulness ◽

Early Life Adversity ◽

Stress Buffering ◽

Psychopathological Symptoms ◽

Increased Risk ◽

The Impact

Experiencing severe or prolonged stressors in early life is associated with increased risk for mental and physical disorders in adulthood. Further, individuals who experienced early life stress (ELS) may use dysfunctional coping strategies like stress-related eating, in contrast to more beneficial stress buffering mechanisms e.g. based on mindfulness. Whether these mechanisms contribute to increased levels of perceived stress and symptoms of mental disorders in individuals with ELS in times of crisis is yet unclear. As part of a larger project, we assessed changes in perceived stress and psychopathological symptoms in a sample of N=102 participants (81% female; meanage=23.49, SDage= 7.11, range 18–62) from October/December 2019 (prior to the Covid-19 pandemic) to April/June 2020 (after the German government introduced Covid-19 related restrictions). Additionally, we assessed ELS and dispositional mindfulness.Perceived stress and depression significantly increased while anxiety levels decreased. No significant change was observed for somatization. ELS and dispositional mindfulness were not associated with change scores, but with perceived stress and psychopathological symptoms at both assessments. The increase in perceived stress during the pandemic in a majority of participants demonstrates the impact of the pandemic in the general population.

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Long-Term Impact of Early-Life Stress on Hippocampal Plasticity: Spotlight on Astrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms21144999 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4999

Author(s):

Gürsel Çalışkan ◽

Anke Müller ◽

Anne Albrecht

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Childhood Adversity ◽

Neuronal Circuits ◽

Long Term Effects ◽

Hippocampal Plasticity ◽

Local Circuits

Adverse experiences during childhood are among the most prominent risk factors for developing mood and anxiety disorders later in life. Early-life stress interventions have been established as suitable models to study the neurobiological basis of childhood adversity in rodents. Different models such as maternal separation, impaired maternal care and juvenile stress during the postweaning/prepubertal life phase are utilized. Especially within the limbic system, they induce lasting alterations in neuronal circuits, neurotransmitter systems, neuronal architecture and plasticity that are further associated with emotional and cognitive information processing. Recent studies found that astrocytes, a special group of glial cells, have altered functions following early-life stress as well. As part of the tripartite synapse, astrocytes interact with neurons in multiple ways by affecting neurotransmitter uptake and metabolism, by providing gliotransmitters and by providing energy to neurons within local circuits. Thus, astrocytes comprise powerful modulators of neuronal plasticity and are well suited to mediate the long-term effects of early-life stress on neuronal circuits. In this review, we will summarize current findings on altered astrocyte function and hippocampal plasticity following early-life stress. Highlighting studies for astrocyte-related plasticity modulation as well as open questions, we will elucidate the potential of astrocytes as new targets for interventions against stress-induced neuropsychiatric disorders.

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The impact of early-life stress on the expression of HPA-associated genes in the adult murine brain

Behaviour ◽

10.1163/1568539x-00003482 ◽

2018 ◽

Vol 155 (2-3) ◽

pp. 181-203 ◽

Cited By ~ 7

Author(s):

V.V. Reshetnikov ◽

A.A. Studenikina ◽

J.A. Ryabushkina ◽

T.I. Merkulova ◽

N.P. Bondar

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Long Term Memory ◽

Adult Mice ◽

Specific Manner ◽

Behavioural Phenotypes ◽

The Impact

Abstract Early life is an important period for the development of the nervous system and for the programming of behavioural phenotypes in adulthood. In our study, two types of early-life stress were used: prolonged separation of pups from their mothers (for 3 h/day, maternal separation (MS)) and brief separation (for 15 min/day, handling (HD)). We analysed the effects of early-life stress on behaviour and the expression of HPA-associated genes in the hypothalamus, hippocampus, and frontal cortex of male mice. Adult mice in the MS group demonstrated reduced locomotor activity and deficiencies in spatial long-term memory, while the HD showed no significant changes. Additionally, early-life MS resulted in reduced hippocampal Crhr1 mRNA, increased MR/GR mRNA in the hippocampus and hypothalamus. Both groups, HD and MS, showed increased Avp mRNA in the hypothalamus. Thus, prolonged maternal separation but not brief leads to adverse behavioural changes and influences the expression of HPA-associated genes in a brain region-specific manner.

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Early-life stress induces prodromal features of Parkinsonian with aging in rats

The Journals of Gerontology Series A ◽

10.1093/gerona/glab253 ◽

2021 ◽

Author(s):

Chao Ren ◽

Fen Wang ◽

Kai-Jie He ◽

Yu-Ting Zhang ◽

Ling-Xi Li ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Cell Counting ◽

Dopamine Level ◽

Long Term Effects ◽

Behavioral Alterations ◽

Transcriptional Changes

Abstract Early-life stress (ELS) can cause long-term effects on human health, ranging from adolescence to adulthood, and even to gerontic. Although clinical retrospective data suggest that ELS may be related to senile neurodegenerative diseases such as Parkinson’s disease (PD), there are few prospective investigations to explore its real contribution to PD. Here, we investigated the behavioral, histochemistical, neuromorphological and transcriptional changes induced by maternal separation (MS), an ELS model. Without neurotoxin, MS rats showed behavioral alterations in olfaction, locomotion and gait characters after depression compared with control rats. Based on neuroimaging and histochemistry, although we found that the dopaminergic system in striatum was impaired after MS, the decrease of striatal dopamine level was ~33%. Consistently, tyrosine hydroxylase immune-staining positive neurons of MS rats in the substantia nigra showed deficit by about 20% in cell counting. Furthermore, using transcriptome sequencing, we discovered many differentially expressed genes (DEGs) of MS rats in striatum significantly enriched in the pathway of dopaminergic synapse, and the biological process of locomotion and neuromuscular process controlling balance. Encouragingly, some representative DEGs relating to PD were singled out. These results suggest that ELS-depression rats potentially mimic some key features of prodromal stage of PD during natural senescence. In conclusion, our findings provide some novel insights into the future pathogenesis and therapeutic studies for PD related to depression.

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Early life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms

10.1101/369660 ◽

2018 ◽

Author(s):

A. Teissier ◽

C. Le Magueresse ◽

J. Olusakin ◽

B. L. S. Andrade da Costa ◽

A. M. De Stasi ◽

...

Keyword(s):

Neuronal Activity ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Short Term Memory ◽

Early Life Stress ◽

Postnatal Life ◽

Long Term Effects ◽

Cellular Mechanisms ◽

Neuron Excitability

ABSTRACTExposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here we focused on changes induced by chronic maternal separation during the first two weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first two postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalized it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors.

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The Effect of MAOA and Stress Sensitivity on Crime and Delinquency: A Replication Study

Journal of Contemporary Criminal Justice ◽

10.1177/1043986218770001 ◽

2018 ◽

Vol 34 (3) ◽

pp. 336-353 ◽

Cited By ~ 3

Author(s):

Christa C. Christ ◽

Joseph A. Schwartz ◽

Scott F. Stoltenberg ◽

Jonathan R. Brauer ◽

Jukka Savolainen

Keyword(s):

Life Stress ◽

Early Life ◽

Interactive Effect ◽

Early Life Stress ◽

Stress Sensitivity ◽

Long Term Effects ◽

Early Life Adversity ◽

Increased Risk ◽

Crime And Delinquency ◽

Meta Analyses

Across several meta-analyses, MAOA-uVNTR genotype has been associated with an increased risk for antisocial behavior among males who experienced early life adversity. Subsequently, early life stress and genetic susceptibility may have long-term effects on stress sensitivity later in life. In support of this assumption, a recent study found evidence, in two independent samples, for a three-way interaction effect (cG × E × E) such that proximate stress was found to moderate the interactive effect of MAOA-uVNTR and distal stress on crime and delinquency among males. In light of recent developments in cG × E research, we attempted to replicate these findings in an independent sample of university students. Our results failed to support any cG × E or cG × E × E effects reported in the original study. Implications of a failed replication and general concerns for future cG × E research are discussed.

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Long lasting anxiety following early life stress is dependent on glucocorticoid signaling in zebrafish

10.1101/2021.05.25.445598 ◽

2021 ◽

Author(s):

Jacqueline SR Chin ◽

Tram-Anh N Phan ◽

Lydia T Albert ◽

Alex C Keene ◽

Erik Rolando Duboue

Keyword(s):

Early Development ◽

Life Stress ◽

Early Life ◽

Time Window ◽

Early Life Stress ◽

Long Term Effects ◽

Zebrafish Model ◽

Critical Window ◽

Glucocorticoid Signaling

Chronic adversity in early childhood is associated with increased anxiety and a propensity for substance abuse later in adulthood, yet the effects of early life stress (ELS) on brain development remains poorly understood. The zebrafish, Danio rerio, is a powerful model for studying neurodevelopment and stress. Here, we describe a zebrafish model of ELS and identify a role for glucocorticoid signaling during a critical window in development that leads to long-term changes in brain function. Larval fish subjected to chronic stress in early development exhibited increased anxiety-like behavior and elevated glucocorticoid levels later in life. Increased stress-like behavior was only observed when fish were subjected to ELS within a precise time window in early development, revealing a temporal critical window of sensitivity. Moreover, enhanced anxiety-like behavior only emerges after two months post-ELS, revealing a developmentally specified delay in the effects of ELS. ELS leads to increased levels of baseline cortisol, and resulted in a dysregulation of cortisol receptors, suggesting long-term effects on cortisol signaling. Together, these findings reveal a critical window for ELS to affect developmental reprogramming of the glucocorticoid receptor pathway, resulting in chronic elevated stress.

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Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22041899 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1899 ◽

Cited By ~ 1

Author(s):

Hae Jeong Park ◽

Sang A. Kim ◽

Won Sub Kang ◽

Jong Woo Kim

Keyword(s):

Gut Microbiota ◽

Relative Abundance ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Female Rats ◽

Rrna Gene ◽

Dependent Manner ◽

Male And Female Rats

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

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