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

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). Crhr1loxP/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.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

Uribe-Mariño A,Gassen NC,Wiesbeck MF,Balsevich G,Santarelli S,Solfrank B,Dournes C,Fries GR,Masana M,Labermeier C,Wang XD,Hafner K,Schmid B,Rein T,Chen A,Deussing JM,Schmidt MV

doi

10.1016/j.biopsych.2016.03.2106

subject

Has Abstract

pub_date

2016-11-15 00:00:00

pages

743-753

issue

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(16)32270-3

journal_volume

pub_type

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