Selective p38α MAPK Deletion in Serotonergic Neurons Produces Stress Resilience in Models of Depression and Addiction

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• 作者：Michael  ; R. Bruchas¹ ; ⁶ ; ^{bruchasm@wustl.edu"" rel=""nofollow} ; Abigail  ; G. Schindler¹ ; Haripriya Shankar¹ ; Daniel  ; I. Messinger¹ ; Mayumi Miyatake¹ ; Benjamin  ; B. Land¹ ; ² ; Julia  ; C. Lemos¹ ; ² ; Catherine E. Hagan³ ; John  ; F. Neumaier¹ ; ² ; ⁴ ; Albert Quintana⁵ ; Richard  ; D. Palmiter⁵ ; Charles Chavkin¹ ; ² ; ^{cchavkin@uw.edu"" rel=""nofollow}
• 刊名：Neuron
• 出版年：2011
• 出版时间：11 August 2011
• 年：2011
• 卷：71
• 期：3
• 页码：498-511
• 全文大小：1885 K

文摘

Summary

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.