Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction

Michael R. Bruchas, Abigail G. Schindler, Haripriya Shankar, Daniel I. Messinger, Mayumi Miyatake, Benjamin B. Land, Julia C. Lemos, Catherine E. Hagan, John F. Neumaier, Albert Quintana, Richard D. Palmiter, Charles Chavkin

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167 Scopus citations

Abstract

Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain regions or by promoter-driven excision of p38α MAPK in serotonergic neurons (by Slc6a4-Cre or ePet1-Cre) or astrocytes (by Gfap-CreERT2). Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus. Stress-induced activation of p38α MAPK translocated the serotonin transporter to the plasma membrane and increased the rate of transmitter uptake at serotonergic nerve terminals. These findings suggest that stress initiates a cascade of molecular and cellular events in which p38α MAPK induces a hyposerotonergic state underlying depression-like and drug-seeking behaviors.

Original languageEnglish (US)
Pages (from-to)498-511
Number of pages14
JournalNeuron
Volume71
Issue number3
DOIs
StatePublished - Aug 11 2011

Bibliographical note

Funding Information:
The authors would like to thank Drs. Larry Zweifel and Ali Guler (University of Washington) for helpful discussion. The floxed p38α (p38α lox ) transgenic mice were provided by Dr. K. Otsu (Osaka University) though the RIKEN Bioresearch Center. The SERT-Cre mice were provided by Dr. Xiaoxi Zhuang (University of Chicago). The GFAP-CreERT2 mice were provided by Dr. Hans Kirchoff (University of Leipzig). Dr. Evan Deneris (Case Western Reserve University) provided the ePET1-Cre driver line. Support was provided by USPHS grants from the National Institute on Drug Abuse RO1-DA030074, R21-DA025970, RO1-DA016898, T32-DA07278, KO5-DA020570 (C.C.), K99-DA025182 (M.R.B.), and the Hope for Depression Research Foundation (C.C.).

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