@article{192e3a2d876a40eb915edabdf783aae2,
title = "The role of ventral striatal cAMP signaling in stress-induced behaviors",
abstract = "The cAMP and cAMP-dependent protein kinase A (PKA) signaling cascade is a ubiquitous pathway acting downstream of multiple neuromodulators. We found that the phosphorylation of phosphodiesterase-4 (PDE4) by cyclin-dependent protein kinase 5 (Cdk5) facilitated cAMP degradation and homeostasis of cAMP/PKA signaling. In mice, loss of Cdk5 throughout the forebrain elevated cAMP levels and increased PKA activity in striatal neurons, and altered behavioral responses to acute or chronic stressors. Ventral striatum-or D1 dopamine receptor-specific conditional knockout of Cdk5, or ventral striatum infusion of a small interfering peptide that selectively targeted the regulation of PDE4 by Cdk5, produced analogous effects on stress-induced behavioral responses. Together, our results demonstrate that altering cAMP signaling in medium spiny neurons of the ventral striatum can effectively modulate stress-induced behavioral states. We propose that targeting the Cdk5 regulation of PDE4 could be a new therapeutic approach for clinical conditions associated with stress, such as depression.",
author = "Florian Plattner and Kanehiro Hayashi and Adan Hern{\'a}ndez and Benavides, {David R.} and Tassin, {Tara C.} and Chunfeng Tan and Jonathan Day and Fina, {Maggy W.} and Yuen, {Eunice Y.} and Zhen Yan and Goldberg, {Matthew S.} and Nairn, {Angus C.} and Paul Greengard and Nestler, {Eric J.} and Ronald Taussig and Akinori Nishi and Houslay, {Miles D.} and Bibb, {James A.}",
note = "Funding Information: We thank N. Heintz (Rockefeller University) and GenSat for D1R-Cre mice, K. Deisseroth (Stanford University) for the Dio-Cre vector, C. Burger (University of Wisconsin-Madison) for AAV vectors, H. Ball and Y. Li (University of Texas Southwestern (UTSW) Protein Technology Center) for peptides, the UTSW Animal Resource Center for help with phosphorylation state–specific antibody generation, D.M. Dietz, M. Lutter, M. Kouser and J. Kumar for help with the social defeat procedure, and T. Singh and G. Mettlach for technical assistance. We thank M. Trivedi and the UTSW Depression Center for support. This work was supported by a Brain and Behavior Research Foundation NARSAD Young Investigator Award (K.H.), a pre-doctoral National Research Service Award from the National Institute on Drug Abuse (D.R.B.), a grant from the Darrell K Royal Research Fund for Alzheimer{\textquoteright}s Research (F.P.) and the California Metabolic Research Foundation (M.D.H.), as well as by US National Institutes of Health grants to A.C.N. and P.G. (MH090963, DA10044), E.J.N. (MH51399), R.T. (GM084249) and J.A.B. (MH79710, MH083711, DA016672, DA018343, DA033485, NS073855). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = aug,
day = "30",
doi = "10.1038/nn.4066",
language = "English",
volume = "18",
pages = "1094--1100",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "8",
}