Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

McEwen, Bruce S.; Nasca, Carla; Gray, Jason D.

doi:10.1038/npp.2015.171

Cited by 1,073 publications

(859 citation statements)

References 216 publications

(247 reference statements)

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“…Though we did not test the effect of chronic stress exposure in other developmental periods, our findings corroborate other studies indicating that the prefrontal cortex is particularly sensitive to stress exposure during infancy and adolescence [60,61]. Chronic stress can be induced in the laboratory by continuously submitting animals to stressful situations, such as physical immobilization, and observing the effects on brain and/or behavior.…”

Section: Discussionsupporting

confidence: 81%

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Folha

Bahia

Aguiar

et al. 2017

Behavioural Brain Research

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h i g h l i g h t s• Chronic stress impairs the development of the adolescent brain.• Chronic stress delays the maturation of extracellular structures called perineuronal nets, which stabilize synaptic contacts on inhibitory neurons, and prefrontal cortex-associated behavior.• These negative effects of chronic stress on the prefrontal cortex can theoretically occur in humans. Critical periods of plasticity (CPPs) are defined by developmental intervals wherein neuronal circuits are most susceptible to environmental influences. The CPP of the prefrontal cortex (PFC), which controls executive functions, extends up to early adulthood and, like other cortical areas, reflects the maturation of perineuronal nets (PNNs) surrounding the cell bodies of specialized inhibitory interneurons. The aim of the present work was to evaluate the effect of chronic stress on both structure and function of the adolescent's rat PFC. We subjected P28 rats to stressful situations for 7, 15 and 35 days and evaluated the spatial distribution of histochemically-labeled PNNs in both the Medial Prefrontal Cortex (MPFC) and the Orbitofrontal Cortex (OFC) and PFC-associated behavior as well. Chronic stress affects PFC development, slowing PNN maturation in both the (MPFC) and (OFC) while negatively affecting functions associated with these areas. We speculate upon the risks of prolonged exposure to stressful environments in human adolescents and the possibility of stunted development of executive functions.

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Section: Discussionsupporting

confidence: 81%

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Folha

Bahia

Aguiar

et al. 2017

Behavioural Brain Research

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“…Of note, mGluR2/3 antagonists have demonstrated ketamine-like antidepressant effects (Duman, 2014;McEwen et al, 2016). Finally, we propose that the decrease in intrasynaptic glutamate also leads to further atrophy and loss of intrasynaptic NMDA receptors.…”

Section: Conceptual Convergence: a Working Modelmentioning

confidence: 99%

“…Increased extrasynaptic glutamate can also bind to presynaptic neuronal metabotropic mGluR2/3 autoreceptors inhibiting glutamate release leading to chronic reductions in intrasynaptic glutamate, loss of excitatory synaptic activity, and ultimately result in synaptic loss (Duman, 2014;Duman et al, 2016;McEwen et al, 2016). Of note, mGluR2/3 antagonists have demonstrated ketamine-like antidepressant effects (Duman, 2014;McEwen et al, 2016).…”

Section: Conceptual Convergence: a Working Modelmentioning

confidence: 99%

“…This glutamate spillover in combination with glutamate released by activated or primed glial and immune cells can activate extrasynaptic N-methyl-D-aspartate (NMDA) receptors and lead to atrophy and regression of dendritic spines and processes and loss of synaptic integrity, ultimately resulting in neuronal loss (Hardingham and Bading, 2010;Malarkey and Parpura, 2008). Moreover, increases in extrasynaptic glutamate can also stimulate presynaptic metabotropic glutamate receptors (mGluR2/3) leading to reductions in synaptic glutamate transmission (Duman, 2014;McEwen et al, 2016). In addition, alterations in the ratio between synaptic and extrasynaptic activation of ionotropic receptors by glutamate can result in the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction (Allam et al, 2015;Allam et al, 2012; Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

383

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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“…However, there are underlying changes that can be seen at the level of gene expression and epigenetic regulation that indicate that the brain is continually changing (9, 10). Epigenetic modifications, such as acetylation of histones, have also been involved in the consolidation of contextual memories that allow the brain to respond and adapt to changes in the environment (11).Among the large number of mediators of brain structural and functional plasticity, the glutamatergic system and BDNF play a key role in mediating the effects of stress on both cognition and psychopathology (1,(12)(13)(14)(15). Animal models have shown that chronic stress effects on dendritic remodeling are blocked by blocking NMDA receptors (1,16) and that adrenalectomy attenuates the acute stress-induced elevations of extracellular glutamate levels in the hippocampus (1, 17).…”

mentioning

confidence: 99%

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Nasca

Zelli

Bigio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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124

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Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety-and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up-and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up-and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.S tress effects on higher brain regions, such as hippocampus, are known to involve actions of excitatory amino acids to induce structural and functional changes depending upon the type, intensity, and duration of the stressor (1). These differential responses, including determining susceptibility versus resilience to stress, contribute to the pathophysiology of debilitating stress-related disorders (2-5). The hippocampus is a brain region noted for its plasticity in response to stress and sensitivity to adrenal steroid hormones (6). Acute stress enhances synaptic plasticity that is associated with improved cognition and other adaptive functions whereas chronic stress produces opposite effects mediating, in the hippocampus, spine synapse turnover, dendritic shrinkage, impaired long-term potentiation (LTP), and suppression of adult neurogenesis in the dentate gyrus (DG) (1, 7). Importantly, neuroanatomical changes in response to repeated stress recover in young adult animals, based upon the restoration of dendritic length and branching and spine density (8). However, there are underlying changes that can be seen at the level of gene expression and epigenetic regulation that indicate that the brain is continually changing (9, 10). Epigenetic modifications, such as acetylation of histones, have also been involved in the consolidation of contextual memories that allow the brain to respond and adapt to changes in ...

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Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

Cited by 1,073 publications

References 216 publications

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

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