scholarly journals EPAC2 is required for corticotropin-releasing hormone-mediated spine loss

2019 ◽  
Author(s):  
Zhong Xie ◽  
Peter Penzes ◽  
Deepak P. Srivastava
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Cortical Neurons ◽  
Acute Stress ◽  
Critical Role ◽  
Small Gtpase ◽  
Corticotropin Releasing Hormone ◽  
Rapid Loss ◽  
Primary Cortical Neurons ◽  
Releasing Hormone

AbstractCorticotropin-releasing hormone (CRH) is produced in response to stress. This hormone plays a key role in mediating neuroendocrine, behavioral, and autonomic responses to stress. The CRH receptor 1 (CRHR1) is expressed in multiple brain regions including the cortex and hippocampus. Previous studies have shown that activation of CRHR1 by CRH results in the rapid loss of dendritic spines. Exchange protein directly activated by cAMP (EPAC2, also known as RapGEF4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rap, has been linked with CRHR1 signaling. EPAC2 plays a critical role in regulating dendritic spine morphology and number in response to several extracellular signals. But whether EPAC2 links CRHR1 with dendritic spine remodeling is unknown. Here we show that CRHR1 is highly enriched in the dendritic spines of primary cortical neurons. Furthermore, we find that EPAC2 and CRHR1 co-localize in cortical neurons. Critically, short hairpin RNA-mediated knockdown of Epac2 abolished CRH-mediated spine loss in primary cortical neurons. Taken together, our data indicate that EPAC2 is required for the rapid loss of dendritic spines induced by CRH. These findings identify a novel pathway by which acute exposure to CRH may regulate synaptic structure and ultimately responses to acute stress.

Protection conferred by Corticotropin-releasing hormone in rat primary cortical neurons against chemical ischemia involves opioid receptor activation

2009 ◽  
Vol 1257 ◽  
pp. 117-127 ◽  
Author(s):  
Charlaine Charron ◽  
Sarah C. Schock ◽  
Geneviève Proulx ◽  
Charlie S. Thompson ◽  
Antoine M. Hakim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Cortical Neurons ◽  
Receptor Activation ◽  
Corticotropin Releasing Hormone ◽  
Primary Cortical Neurons ◽  
Releasing Hormone

scholarly journals Long-range inputome of cortical neurons containing corticotropin-releasing hormone

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Peilin Zhao ◽  
Mengting Zhao ◽  
Huading Wang ◽  
Tao Jiang ◽  
Xueyan Jia ◽  
...  
Keyword(s):  
Long Range ◽  
Cortical Neurons ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone

scholarly journals 0306 Corticotropin-Releasing Hormone Receptor 1 Gene Polymorphism Modulates Cognitive Flexibility Following Acute Stress and Total Sleep Deprivation

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A115-A116
Author(s):  
B C Satterfield ◽  
I Anlap ◽  
S L Esbit ◽  
W D Killgore
Keyword(s):  
Stress Response ◽  
Sleep Deprivation ◽  
Cognitive Flexibility ◽  
Acute Stress ◽  
Relevant Information ◽  
Corticotropin Releasing Hormone ◽  
Reversal Performance ◽  
Releasing Hormone ◽  
Total Sleep Deprivation ◽  
Stimulus Response

Abstract Introduction Dynamic decision processes requiring flexible updating of information are impaired by stress and sleep loss, both of which activate the hypothalamic-pituitary-adrenal (HPA) stress response. Corticotropin-releasing hormone (CRH) initiates the HPA pathway. The CRH receptor (CRHR1) gene contains a single nucleotide polymorphism that modulates this response. We investigated whether cognitive flexibility is affected by CRHR1 polymorphism following a night of acute stress and total sleep deprivation (TSD). Methods N=46 healthy, young adults (21.8±3.4y; 21 females) participated in an in-laboratory 31h sleep deprivation study. Beginning at 19:30 until 07:30, the Maastricht Acute Stress Test (MAST) was administered every 4h. The MAST alternates a cold pressor task with an oral subtraction task five times in a single bout. At 29h wakefulness, subjects performed a novel go/no-go reversal learning task. Stimulus-response rules were presented at the beginning of the task, and subjects were asked to either respond or withhold a response to the presented stimuli while receiving accuracy feedback. Halfway through the task, the stimulus-response rules were reversed. Performance was assessed by discriminability index (d’), hit rate (HR), and false alarm rate (FAR). Saliva samples were collected immediately prior, immediately after, and 30min after each MAST and assayed for cortisol. One saliva sample from each subject was assayed for CRHR1 genotype. Results CRHR1 genotypes were in Hardy-Weinberg equilibrium (χ 2=2.97, p=0.08). Mixed effects ANOVA with fixed effects of CRHR1 genotype, pre/post-reversal, and their interaction found a significant CRHR1 by reversal interaction for d’ (F2,319=3.88, p=0.022) and HR (F2,319=3.16, p=0.044) following a night of stress and TSD. No such interaction was found at well-rested baseline (d’: F2,319=2.51, p=0.083; HR: F2,319=1.55, p=0.213). Subjects homozygous for the T allele had higher mean post-MAST cortisol levels (0.40±0.06 µg/dL) with better pre-reversal performance, but worse post-reversal performance compared to heterozygous and homozygous G allele carriers. Conclusion CRHR1 genotype modulates dynamic decision making following a night of acute stress and TSD. A higher cortisol stress response (T/T genotype) is beneficial to maintaining task relevant information (stability), but significantly impairs the ability to update task-relevant information following a change in situational demands (flexibility). Support CDMRP grant W81XWH-17-C-0088

scholarly journals Potential link between the RagA-mTOR-p70S6K axis and depressive-behaviors during bacterial liposaccharide challenge

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Jia Zhao ◽  
Lixing Lao ◽  
Wei Cui ◽  
Jianhui Rong
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Pc12 Cells ◽  
Cortical Neurons ◽  
Forced Swim Test ◽  
Mammalian Target Of Rapamycin ◽  
Tail Suspension Test ◽  
Small Gtpase ◽  
Primary Cortical Neurons ◽  
Lps Challenge

Abstract Background Bacterial infection is a potential risk factor for depression. However, little is known about the mechanistic link between bacterial endotoxin and depressive-like behaviors. The aim of the present study was to clarify whether liposaccharide (LPS) could induce depressive-like behaviors in mice via sequentially activating small GTPase RagA, mammalian target of rapamycin (mTOR), and p70S6K. Methods C57BL/6 N mice were treated with 0.83 mg/kg LPS by intraperitoneal injection for 24 h. The animals were assessed for depressive-like behaviors by forced swim test and tail suspension test. The expression levels of RagA, mTOR, and p70S6K were determined in mice, primary cortical neurons, neural stem cells, and PC12 cells. Results LPS effectively induced depressive-like behaviors in mice. Biochemical examination revealed that LPS not only upregulated RagA expression but also activated mTOR/p70S6K pathway in mouse brains. LPS challenge also achieved a similar effect in primary cortical neurons, neural stem cells, and PC12 cells. Following the silencing of RagA expression with specific siRNA, LPS failed to induce mTORC1 translocation to the lysosomal membranes in PC12 cells. These results suggested that LPS might sequentially upregulate RagA and activate mTOR and p70S6K pathways in mice and neural stem cells. Conclusions This study for the first time demonstrated that LPS might induce depressive-like behaviors in mice via the upregulation of RagA and subsequent activation of mTOR/p70S6K pathway. Such information may highlight the RagA-mTOR-p70S6K signaling cascade as a novel therapeutic target for the development of new anti-depressant therapeutics.

scholarly journals Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus

2017 ◽  
Vol 232 (3) ◽  
pp. R161-R172 ◽  
Author(s):  
Roman A Romanov ◽  
Alán Alpár ◽  
Tomas Hökfelt ◽  
Tibor Harkany
Keyword(s):  
Paraventricular Nucleus ◽  
Acute Stress ◽  
Corticotropin Releasing Hormone ◽  
Hormonal Responses ◽  
Releasing Hormone ◽  
Rapid Induction ◽  
Hypothalamic Nuclei ◽  
Molecular Machinery ◽  
As Stress ◽  
Corticosterone Release

Hormonal responses to acute stress rely on the rapid induction of corticotropin-releasing hormone (CRH) production in the mammalian hypothalamus, with subsequent instructive steps culminating in corticosterone release at the periphery. Hypothalamic CRH neurons in the paraventricular nucleus of the hypothalamus are therefore considered as ‘stress neurons’. However, significant morphological and functional diversity among neurons that can transiently produce CRH in other hypothalamic nuclei has been proposed, particularly as histochemical and molecular biology evidence associates CRH to both GABA and glutamate neurotransmission. Here, we review recent advances through single-cell RNA sequencing and circuit mapping to suggest that CRH production reflects a state switch in hypothalamic neurons and thus confers functional competence rather than being an identity mark of phenotypically segregated neurons. We show that CRH mRNA transcripts can therefore be seen in GABAergic, glutamatergic and dopaminergic neuronal contingents in the hypothalamus. We then distinguish ‘stress neurons’ of the paraventricular nucleus that constitutively express secretagogin, a Ca2+ sensor critical for the stimulus-driven assembly of the molecular machinery underpinning the fast regulated exocytosis of CRH at the median eminence. Cumulatively, we infer that CRH neurons are functionally and molecularly more diverse than previously thought.

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