Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.
Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.
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在两个敏感发育时期，多巴胺和5-羟色胺信号传导差异影响小鼠的成人侵略性和情感行为。
DOI：
10.1038/mp.2014.10
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发表时间：
2014-06
影响因子：
11
通讯作者：
Ansorge, M. S.
中科院分区：
文献类型：
--
作者：
Yu, Q.;Teixeira, C. M.;Mahadevia, D.;Huang, Y.;Balsam, D.;Mann, J. J.;Gingrich, J. A.;Ansorge, M. S.
药物阻断单胺氧化酶A(MAOA)或5-羟色胺转运体(5-HTT)在成年期具有抗抑郁和缓解焦虑的作用。然而，遗传的MAOA或5-HTT活性低下与改变的攻击性和增加的焦虑/抑郁有关。在这里，我们测试的假设是，在发育过程中增加单胺信号会导致这些自相矛盾的攻击性和情感表型。我们发现，在出生后早期(P2-P21)而不是在青春期(P22-41)的药物MAOA阻断增加了成年(>；P90)小鼠的焦虑和抑郁样行为，模拟了P2-21 5-HTT抑制的效果。此外，在青春期阻断MAOA而不是P2-21或P182-201会增加成人的攻击行为，而从P22-P41开始的5-HTT阻断会减少成人的攻击行为。在P22-41期间阻断多巴胺转运体，而不是去甲肾上腺素转运体，也会增加成人的攻击行为。因此，P2-21是5-羟色胺调节成人焦虑/抑郁样行为的敏感期，P22-41是DA和5-羟色胺双向调节成人攻击行为的敏感期。由于P22-P41单胺信号的增加而导致的永久性的DA能功能改变可能是改变的攻击行为的基础。为了支持这一假设，我们发现成年后改变的攻击性与对苯丙胺攻击的运动反应呈正相关。我们证明了DA功能改变和攻击性是有因果关系的，我们证明了VTA DA能神经元的光遗传激活增加了攻击性。因此，在敏感发育时期影响多巴胺和5-羟色胺信号的遗传和药物因素可以调节成人的单胺能功能，从而改变攻击性和情绪障碍的风险。
Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.
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影响因子：
25
作者：
Buckholtz, Joshua W.;Treadway, Michael T.;Cowan, Ronald L.;Woodward, Neil D.;Benning, Stephen D.;Li, Rui;Ansari, M. Sib;Baldwin, Ronald M.;Schwartzman, Ashley N.;Shelby, Evan S.;Smith, Clarence E.;Cole, David;Kessler, Robert M.;Zald, David H.
通讯作者：
Zald, David H.
影响因子：
10.6
作者：
Holmes, A;Murphy, DL;Crawley, JN
通讯作者：
Crawley, JN
影响因子：
6.9
作者：
Dawe, Sharon;Davis, Penelope;McKetin, Rebecca
通讯作者：
McKetin, Rebecca
影响因子：
56.9
作者：
Caspi, A;McClay, J;Poulton, R
通讯作者：
Poulton, R
影响因子：
4.8
作者：
Chen, Kevin;Cases, Olivier;Shih, Jean Chen
通讯作者：
Shih, Jean Chen