Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.
Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.
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DOI：
10.1016/j.biopsych.2013.05.003
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发表时间：
2014-06-01
影响因子：
10.6
通讯作者：
Chen, Jiang-Fan
中科院分区：
文献类型：
--
作者：
Wei, Catherine J.;Augusto, Elisabete;Gomes, Catarina A.;Singer, Philipp;Wang, Yumei;Boison, Detlev;Cunha, Rodrigo A.;Yee, Benjamin K.;Chen, Jiang-Fan
腺苷A2 A受体（A2 AR）在纹状体中富集，但在纹状体外前脑中也以较低水平存在（即，海马，皮质），整合多巴胺，谷氨酸和脑源性神经营养因子（BDNF）信号，因此是必要的纹状体神经可塑性和恐惧和焦虑行为。我们测试了两个脑区域特异性A2 AR敲除系，其中A2 AR仅在纹状体（st-A2 AR KO）或整个前脑（纹状体、海马和皮质，fb-A2 AR KO）中选择性失活，以产生恐惧和焦虑相关的反应。我们还通过将AAV 5-Cre局部注射到条件性（floxed）-A2 AR敲除小鼠中来检查海马特异性A2 AR缺失的作用。st-A2 AR KO小鼠中纹状体A2 AR的选择性缺失增加了巴甫洛夫恐惧条件反射（上下文和音调），但当A2 AR缺失扩展到包括fb-A2 AR KO小鼠中的纹状体外区域时，上下文恐惧条件反射正常化，音调恐惧条件反射减弱。此外，通过AAV 5-Cre注射的海马A2 AR的局灶性缺失选择性地减弱了背景（但不是音调）恐惧条件反射。在fb-A2 AR KO小鼠的整个前脑中缺失A2 AR也在高架十字迷宫和旷场试验中产生抗焦虑表型，并增加惊吓反应。这些纹状体外前脑A2 AR行为效应与fb-A2 AR KO海马中BDNF水平降低相关。这项研究提供了第一个证据表明，纹状体A2 ARs的失活促进巴甫洛夫恐惧条件反射，而前脑纹状体外A2 ARs的失活抑制恐惧条件反射，也影响焦虑相关的行为。
Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extra-striatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. We tested two brain region-specific A2AR knockout lines with A2ARs selectively inactivated either in the striatum only (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex, fb-A2AR KO) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of AAV5-Cre into conditional (floxed)-A2AR knockout mice. Selective deletion of striatal A2ARs in st-A2AR KO mice increased Pavlovian fear conditioning (both context and tone), but when the A2AR deletion was extended to include extra-striatal regions in fb-A2AR KO mice, context fear conditioning was normalized and tone fear conditioning was attenuated. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests and increased the startle response. These extra-striatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. This study provides the first evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning while inactivation of extra-striatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.
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影响因子：
1.6
作者：
Hagenbuch, Niels;Feldon, Joram;Yee, Benjamin K.
通讯作者：
Yee, Benjamin K.
影响因子：
5.3
作者：
Assaife-Lopes, Natalia;Sousa, Vasco C.;Sebastiao, Ana M.
通讯作者：
Sebastiao, Ana M.
DOI：
10.1523/jneurosci.3145-08.2008
发表时间：
2008-09-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bozdagi O;Rich E;Tronel S;Sadahiro M;Patterson K;Shapiro ML;Alberini CM;Huntley GW;Salton SR
通讯作者：
Salton SR
影响因子：
4.7
作者：
Aso, Ester;Ozaita, Andres;Valverde, Olga
通讯作者：
Valverde, Olga
影响因子：
1.7
作者：
Hauber, W;Koch, M
通讯作者：
Koch, M