Chronic stress plasticity in the hypothalamic paraventricular nucleus

Herman, James P.; Flak, Jonathan N.; Jankord, Ryan

doi:10.1016/s0079-6123(08)00429-9

Cited by 122 publications

(87 citation statements)

References 84 publications

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“…Recent data suggest that occupation of this element by phosphorylated CREB is by itself not sufficient to drive CRH expression, but that additional transcription factors and coregulators are necessary (9). If the in vitro effect underlies some of our in vivo data, SRC-1 may act as a coactivator for a CRE-associated transcription factor, but only in the context of chronic stressors (40).…”

Section: Discussionmentioning

confidence: 79%

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Lachize

Apostolakis

Laan

et al. 2009

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

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Adaptation to stress in vertebrates occurs via activation of hormonal and neuronal signaling cascades in which corticotropinreleasing hormone (CRH) plays a central role. Expression of brain CRH is subject to strong, brain-region specific regulation by glucocorticoid hormones and neurogenic intracellular signals. We hypothesized that Steroid Receptor Coactivator 1 (SRC-1), a transcriptional coregulator of the glucocorticoid receptor, is involved in the sensitivity of CRH regulation by stress-related factors. In the brains of SRC-1 knockout mice we found basal CRH mRNA levels to be lower in the central nucleus of the amygdala. Hypothalamic CRH up-regulation after chronic (but not acute) stress, as well as region-dependent up-and down-regulation induced by synthetic glucocorticoids, were significantly attenuated compared with wild type. The impaired induction of the crh gene by neurogenic signals was corroborated in AtT-20 cells, where siRNA and overexpression experiments showed that SRC-1 is necessary for full induction of a CRH promoter reporter gene by forskolin, suggestive of involvement of transcription factor CREB. In conclusion, SRC-1 is involved in positive and negative regulation of the crh gene, and an important factor for the adaptive capacity of stress.adaptation ͉ amygdala ͉ HPA axis ͉ neuroendocrinology ͉ transcription B rain corticotropin-releasing hormone (CRH) plays a pivotal role in the mammalian response to stress. CRH synthesized by neurons in the central nucleus of the amygdala (CeA) mediates the effect of stress on emotional states, including fear and anxiety (1, 2). From the paraventricular nucleus of the hypothalamus (PVN) CRH coordinates autonomic outflow and the activity of the hypothalamus-pituitary-adrenal (HPA) axis. The latter leads to secretion of the adrenal glucocorticoid hormones, which in turn orchestrate the adaptation to stress of virtually all tissues in the body (3-5).As part of adaptation, CRH expression itself is strongly regulated in response to stress-induced elevations of glucocorticoids and neurogenic signals. In the core of the HPA-axis, activation of the glucocorticoid receptor (GR) can repress transcription from the crh gene as part of negative feedback, whereas stress-related noradrenergic and glutamatergic excitatory signals can activate the gene, in part via activation of the transcription factor CREB. In the CeA, both GR activation and excitatory signals can lead to an increased CRH expression (6, 7). These modulations are considered crucial for stress adaptation, and a considerable amount of research has been devoted to understand how transcriptional signals are integrated at the level of the CRH promoter, both in vitro and in vivo (8, 9). Nevertheless, the regulation of the crh gene in vivo is far from understood.Transcriptional coregulators constitute an expanding class of molecules that act as mediators and integrators of signals carried by nuclear receptors, such as GR (10). The p160 coregulator Steroid Receptor Coactivator (SRC-1) is strongly expressed in br...

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Section: Discussionmentioning

confidence: 79%

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Lachize

Apostolakis

Laan

et al. 2009

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

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“…To support this contention, it is known that neurons in the HYPO change their morphology and molecular expression in response to chronic stress (26). HYPO neurons in diabetic animals can undergo degeneration (46), showing distension of rough endoplasmic reticulum, swollen mitochondria, and enhanced electron density of their cytoplasm (17).…”

Section: /Cd39mentioning

confidence: 99%

Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

Thinschmidt

Caballero

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Hu P, Thinschmidt JS, Caballero S, Adamson S, Cole L, Chan-Ling T, Grant MB. Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. Am J Physiol Endocrinol Metab 308: E688 -E698, 2015. First published February 24, 2015 doi:10.1152/ajpendo.00504.2014.-Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12-and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P Ͻ 0.05) and reduced neuronal expression of IGFBP-3 (Ϫ32%, P Ͻ 0.05) and IGF-I (Ϫ15%, P Ͻ 0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P Ͻ 0.01), and IDO ϩ cell density rose by (62%, P Ͻ 0.05). CD39 expression dropped by 30% (P Ͻ 0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P Ͻ 0.05). Our results suggest that increased IDO and early loss of CD39 ϩ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.

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“…Upon HPA axis activation, the neurosecretory neurons in the hypothalamic paraventricular nucleus (PVN) release corticotropin-releasing hormone (CRH) into the hypophyseal portal blood stream. CRH triggers secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which then stimulates the adrenal glands to release glucocorticoids into the peripheral blood stream [3][4][5] . Excess circulating glucocorticoids in turn negatively affects CRH release and ACTH secretion, so modulating further glucocorticoid release by the adrenal glands.…”

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confidence: 99%

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

et al. 2014

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Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity leads to debilitating neuroendocrine or metabolic disorders such as Cushing's syndrome (CS). Glucocorticoids control HPA axis activity through negative feedback to the pituitary gland and the central nervous system (CNS). However, the cellular mechanisms involved are poorly understood, particularly in the CNS. Here we show that, in mice, selective loss of TrkB signalling in cholecystokinin (CCK)-GABAergic neurons induces glucocorticoid resistance, resulting in increased corticotrophin-releasing hormone expression, chronic hypercortisolism, adrenocortical hyperplasia, glucose intolerance and mature-onset obesity, reminiscent of the human CS phenotype. Interestingly, obesity is not due to hyperphagia or decreased energy expenditure, but is associated with increased de novo lipogenesis in the liver. Our study therefore identifies CCK neurons as a novel and critical cellular component of the HPA axis, and demonstrates the requirement of TrkB for the transmission of glucocorticoid signalling.

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Chronic stress plasticity in the hypothalamic paraventricular nucleus

Cited by 122 publications

References 84 publications

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

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