Mechanisms of stress in the brain

McEwen, Bruce S.; Bowles, Nicole; Gray, Jason D.; Hill, Matthew N.; Hunter, Richard G.; Karatsoreos, Ilia N.; Nasca, Carla

doi:10.1038/nn.4086

Cited by 1,068 publications

(824 citation statements)

References 143 publications

(193 reference statements)

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“…The window of epigenetic plasticity offers opportunity for behavioral and pharmacological interventions that can increase resilience by correcting imbalances of excitatory transmission through regulation of gene transcription via histone modifications and related epigenetic alterations. Thereby, this window of epigenetic plasticity can be capitalized by behavioral and pharmacological interventions to reestablish balanced neural circuitry in the hippocampus, prefrontal cortex, and amygdala that become unbalanced in stress-related disorders (3,(35)(36)(37)(38). Pharmacological interventions may include acetyl-Lcarnitine (LAC), a donor of acetyl groups that has been shown to rapidly counteract depressive-like behavior and rectify glutamate dysregulation (18).…”

Section: Discussionmentioning

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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121

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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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Section: Discussionmentioning

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.

Self Cite

121

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“…[26] Chronic stress upregulates amygdala activity in rodents and this excitatory state is linked with dendritic remodeling, including a persistent expansion of basolateral dendrites. [27] Hypertrophy of the amygdala is also observed in humans and non-human primates that have experienced prolonged exposure to stress. [28,29] Such changes in amygdala structure are likely to compound the effects of ongoing stress because the amygdala has an important role in regulating the body's hormonal stress response via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system.…”

Section: The Amygdalamentioning

confidence: 99%

“…[28,29] Such changes in amygdala structure are likely to compound the effects of ongoing stress because the amygdala has an important role in regulating the body's hormonal stress response via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. [27] …”

Section: The Amygdalamentioning

confidence: 99%

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

et al. 2017

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The amygdala is a key brain area regulating responses to stress and emotional stimuli, so improving our understanding of how it is regulated could offer novel strategies for treating disturbances in emotion regulation. As we review here, a growing body of evidence indicates that the gut microbiota may contribute to a range of amygdala-dependent brain functions from pain sensitivity to social behavior, emotion regulation, and therefore, psychiatric health. In addition, it appears that the microbiota is necessary for normal development of the amygdala at both the structural and functional levels. While further investigations are needed to elucidate the exact mechanisms of microbiota-to-amygdala communication, ultimately, this work raises the intriguing possibility that the gut microbiota may become a viable treatment target in disorders associated with amygdala dysregulation, including visceral pain, post-traumatic stress disorder, and beyond. Also see the video abstract here: https://youtu.be/O5gvxVJjX18

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“…A third theme is that glutamate release and actions, along with glucocorticoids and other interacting mediators, play an essential role in adaptive plasticity of neurons to stressors, where there is resilience in a healthy brain (9,10). However, a deficiency in BDNF leads to a loss of the normal responsiveness to stressors and to some antidepressant drugs (24,25).…”

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confidence: 99%

Preserving neuroplasticity: Role of glucocorticoids and neurotrophins via phosphorylation

McEwen

2015

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

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The interaction between neurotrophins and glucocorticoids has been at the center of studies of neuroplasticity in stress-related disorders for several decades (1). The report in PNAS by shows that brainderived neurotrophic factor (BDNF) facilitates glucocorticoid receptor (GR)-mediated signaling and enables glucocorticoids, primed by BDNF, to activate gene transcription and possibly other cellular actions mediated by the GR. As a first step, according to ArangoLievano et al., glucocorticoids allow the detachment of the protein phosphatase, PP5, from GR complexes, permitting increased GR phosphorylation by MAP kinases. Then, the coincidence of BDNF and glucocorticoids is necessary to activate genomic GR responses because GR is not translocated into the nucleus of neurons stimulated only with BDNF, without the glucocorticoid being present.The Arango-Lievano et al. (2) paper "closes a loop" that was begun by a previous study by Jeanneteau, Garabedian, and Chao (3), showing that glucocorticoids can selectively activate tropomyosin receptor kinase B (TrkB) after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. This activation did not require increased production of BDNF and was dependent on the genomic action of the GR. Thus, there is a positive feedback loop in which glucocorticoids and BDNF synergistically potentiate each other's concurrent actions, and Arango-Lievano et al. (2) suggest that failure of this loop underlies loss of plasticity and resilience in mood-related disorders, and possibly also the lack of response to antidepressant medications (Fig. 1). Taken together with other recent work on hormone action, this paper illustrates a number of important emerging themes concerning the positive and modulatory actions of glucocorticoids, as well as other steroid hormones, together with other signaling pathways, on a large number of important cellular processes in neural cells and the capacity of the adult, as well as the developing brain, for adaptive plasticity and resilience in the face of stress.The first theme is that we now recognize interconnections among steroid hormone actions on gene expression with other actions of these same hormones, as well as other modulators, that involve cellular signaling pathways at or near the cell surface. In the 1960s, steroid hormone receptors were recognized that regulate gene expression in the cell nucleus (4), and neurotransmitters and neuromodulators were shown to operate at or near the cell surface to regulate signaling pathways in which phosphorylation was a key element (5). However, we know now that nuclear and cellular signaling pathways interact in many ways. For example, dopamine activates progestin receptors in a ligand-independent manner and facilitates estrogen-primed lordosis behavior in the female rat in the absence of progesterone (6). Fig. 1. Glucocorticoids produce direct and indirect genomic actions as well as nongenomic signaling actions via glucocorticoid (GR) and mineralocorticoid (MR) receptors. These involve n...

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Mechanisms of stress in the brain

Cited by 1,068 publications

References 143 publications

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

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

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

Preserving neuroplasticity: Role of glucocorticoids and neurotrophins via phosphorylation

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