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  Prefrontal Cortex Corticotropin-Releasing Factor Receptor 1 Conveys Acute Stress-Induced Executive Dysfunction

Uribe-Marino, A., Gassen, N. C., Wiesbeck, M. F., Balsevich, G., Santarelli, S., Solfrank, B., et al. (2016). Prefrontal Cortex Corticotropin-Releasing Factor Receptor 1 Conveys Acute Stress-Induced Executive Dysfunction. BIOLOGICAL PSYCHIATRY, 80(10), 743-753. doi:10.1016/j.biopsych.2016.03.2106.

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 Creators:
Uribe-Marino, Andrés1, Author           
Gassen, Nils C.2, Author           
Wiesbeck, Maximilian F.1, Author           
Balsevich, Georgia1, Author           
Santarelli, Sara1, Author           
Solfrank, Beate1, Author           
Dournes, Carine1, Author           
Fries, Gabriel R.2, 3, Author           
Masana, Merce1, Author           
Labermaier, Christiana1, Author           
Wang, Xiao-Dong3, Author
Hafner, Kathrin2, Author           
Schmid, Bianca1, Author           
Rein, Theo2, Author           
Chen, Alon1, Author           
Deussing, Jan M.1, Author           
Schmidt, Mathias V.1, Author           
Affiliations:
1Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              
2Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
3external, ou_persistent22              

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Free keywords: Cortico-tropin-releasing factor receptor 1, executiv dysfunction, prefrontal cortex, reversal learning,stress, temporal order memory
 Abstract: BACKGROUND: The medial prefrontal cortex (mPFC) subserves complex cognition and is impaired by stress. Corticotropin-releasing factor (CRF), through CRF receptor 1 (CRFR1), constitutes a key element of the stress response. However, its contribution to the effects of stress in the mPFC remains unclear. METHODS: Mice were exposed to acute social defeat stress and subsequently to either the temporal order memory (n = 11-12) or reversal learning (n = 9-11) behavioral test. Changes in mPFC Crhr1 messenger RNA levels were measured in acutely stressed mice (n = 12). Crhr1(loxP/loxP) mice received either intra-mPFC adeno-associated virus-Cre or empty microinjections (n = 17-20) and then were submitted to acute stress and later to the behavioral tests. Co-immunoprecipitation was used to detect activation of the protein kinase A (PKA) signaling pathway in the mPFC of acutely stressed mice (n = 8) or intra-mPFC CRF injected mice (n = 7). Finally, mice received intra-mPFC CRF (n = 11) and/or Rp-isomer cyclic adenosine 3',5' monophosphorothioate (Rp-cAMPS) (n = 12) microinjections and underwent behavioral testing. RESULTS: We report acute stress-induced effects on mPFC-mediated cognition, identify CRF-CRFR1-containing microcircuits within the mPFC, and demonstrate stress-induced changes in Crhr1 messenger RNA expression. Importantly, intra-mPFC CRFR1 deletion abolishes acute stress-induced executive dysfunction, whereas intra-mPFC CRF mimics acute stress-induced mPFC dysfunction. Acute stress and intra-mPFC CRF activate the PKA signaling pathway in the mPFC, leading to cyclic AMP response element binding protein phosphorylation in intra-mPFC CRFR1-expressing neurons. Finally, PKA blockade reverses the intra-mPFC CRF-induced executive dysfunction. CONCLUSIONS: Taken together, these results unravel a molecular mechanism linking acute stress to executive dysfunction via CRFR1. This will aid in the development of novel therapeutic targets for stress-induced cognitive dysfunction.

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Language(s): eng - English
 Dates: 2016-11-15
 Publication Status: Issued
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Title: BIOLOGICAL PSYCHIATRY
Source Genre: Journal
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Pages: - Volume / Issue: 80 (10) Sequence Number: - Start / End Page: 743 - 753 Identifier: ISSN: 0006-3223