Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress

Ramot, Assaf; Jiang, Zhiying; Tian, Jin Bin; Nahum, Tali; Kuperman, Yael; Justice, Nicholas J.; Chen, Alon

doi:10.1038/nn.4491

Cited by 90 publications

(82 citation statements)

References 22 publications

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“…Above we considered evidence from reporter mice and functional studies that support presynaptic receptor expression in the central nucleus of the amygdala as a potential way to reconcile discrepant site‐of‐action and cellular (mRNA) localization data at this locus. Similarly, stress‐related functional data have recently been provided to support indications from reporter mice of cellular CRF 1 expression in the paraventricular nucleus of the hypothalamus (Justice et al, ; Ramot et al, ). Neither the central nor the paraventricular nucleus exhibited detectable [ 125 I]‐PD‐Svg binding in the present experiments, making it difficult to view as decisive our failure to resolve radioligand binding in any of the other areas of structure‐function mismatch among the central autonomic structures listed above.…”

Section: Discussionmentioning

confidence: 91%

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine

Tan

Vaughan

Perrin

et al. 2017

J of Comparative Neurology

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The corticotropin-releasing factor (CRF) family of peptides includes CRF and three urocortins, which signal through two distinct G-protein coupled receptors, CRF and CRF . Although the cellular distribution of CRF receptor expression has been well characterized at the mRNA level, the localization of receptor protein, and, by inference, of functional receptors, has been limited by a lack of reliable immunohistochemical evidence. Recently, a CRF-related peptide, termed PD-sauvagine, was isolated from the skin of the frog, Pachymedusa dacnicolor, and validated as a high-affinity ligand for CRF receptor studies. A radiolabeled analog, [ I]-PD-sauvagine, with high signal-to-noise ratio, was used in autoradiographic studies to map the distribution of CRF receptor binding sites in the mouse brain. Through the use of receptor-deficient mice and subtype-specific antagonists, CRF and CRF binding sites were isolated, and found to be readily reconcilable with regional patterns of mRNA expression. Binding site distributions within a given structure sometimes differed from mRNA patterns, however, particularly in laminated structures of the isocortex, hippocampus, and cerebellum, presumably reflecting the trafficking of receptors to their operational homes on neuronal (mostly dendritic) processes. Binding patterns of [ I]-PD-sauvagine provided independent assessments of controversial receptor localizations, failing to provide support for CRF expression in central autonomic components of the limbic forebrain, the locus coeruleus and cerebellar Purkinje cells, or for CRF in any aspect of the cerebellar cortex. Though lacking in ideal resolution, in vitro binding of the PD-sauvagine radioligand currently provides the most sensitive and accurate available tool for localizing CRF receptors in rodent brain.

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Section: Discussionmentioning

confidence: 91%

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine

Tan

Vaughan

Perrin

et al. 2017

J of Comparative Neurology

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“…We then investigated how sympathetic activation at the specific vessels under stress condition is regulated. It is reported that PVN neurons include TH+ neurons are activated by several stresses, especially chronic ones ( Herman and Cullinan, 1997 ; Ramot et al, 2017 ; Shi et al, 2013 ; Ulrich-Lai and Herman, 2009 ). Consistent with these results, we found that PVN TH+ neurons were specifically activated by stress condition even without EAE induction ( Figure 5C ).…”

Section: Resultsmentioning

confidence: 99%

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

Arima

Ohki

Nishikawa

et al. 2017

eLife

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Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.DOI: http://dx.doi.org/10.7554/eLife.25517.001

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“…All behavioral paradigms were performed as previously described 24 – 26 with modifications. For a detailed description of the behavioral tests, see SI Methods.…”

Section: Methodsmentioning

confidence: 99%

“…In situ hybridization 27 – 29 and immunohistochemistry 26 , 30 were performed as described. For a full description of the protocols and antibodies used, see SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Inferior olive CRF plays a role in motor performance under challenging conditions

et al. 2018

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A well-coordinated stress response is pivotal for an organisms’ survival. Corticotropin-releasing factor (CRF) is an essential component of the emotional and neuroendocrine stress response, however its role in cerebellar functions is poorly understood. Here, we explore the role of CRF in the inferior olive (IO) nucleus, which is a major source of input to the cerebellum. Using a CRF reporter line, in situ hybridization and immunohistochemistry, we demonstrate very high levels of the CRF neuropeptide expression throughout the IO sub-regions. By generating and characterizing IO-specific CRF knockdown and partial IO-CRF knockout, we demonstrate that reduction in IO-CRF levels is sufficient to induce motor deficiency under challenging conditions, irrespective of basal locomotion or anxiety-like behavior. Furthermore, we show that chronic social defeat stress induces a persistent decrease in IO-CRF levels, and that IO-CRF mRNA is upregulated shortly following stressful situations that demand a complex motor response. Taken together our results indicate a role for IO-CRF in challenge-induced motor responses.

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Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress

Cited by 90 publications

References 22 publications

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

Inferior olive CRF plays a role in motor performance under challenging conditions

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Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress

Cited by 90 publications

References 22 publications

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [125I]‐PD‐Sauvagine

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [125I]‐PD‐Sauvagine

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

Inferior olive CRF plays a role in motor performance under challenging conditions

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Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine

Distribution of corticotropin‐releasing factor (CRF) receptor binding in the mouse brain using a new, high‐affinity radioligand, [¹²⁵I]‐PD‐Sauvagine