ausblenden:
Schlagwörter:
Cortico-tropin-releasing factor receptor 1, executiv dysfunction, prefrontal cortex, reversal learning,stress, temporal order memory
Zusammenfassung:
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.
