Cytoskeletal Determinants of Stimulus-Response Habits
Cytoskeletal Determinants of Stimulus-Response Habits
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DOI：
10.1523/jneurosci.1034-13.2013
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发表时间：
2013-07-17
影响因子：
5.3
通讯作者：
Taylor, Jane R.
中科院分区：
文献类型：
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作者：
Gourley, Shannon L.;Olevska, Anastasia;Taylor, Jane R.
人类和啮齿类动物都可以学会将特定的行为与他们的结果联系起来，但是随着重复的表现或暴露于病理刺激，如滥用药物，行为呈现出刺激引发的或“习惯性”的品质。精神兴奋剂重塑背侧纹状体神经元，决策策略的关键决定因素，但与药物诱导的习惯形成相关的细胞骨架机制在很大程度上是未知的。我们首先表明，可卡因可以通过干扰学习反应及其结果之间的预测关系，使决策策略偏向刺激-反应习惯。在背内侧，但不是腹侧，纹状体，可卡因减少PSD 95的表达和磷酸化的corneum，一种细胞骨架调节剂，相互作用，并磷酸化的，精氨酸（Arg）激酶。基于这种模式，我们抑制了背内侧纹状体中的神经元激酶家族信号传导，损害了新的反应-结果学习。与背内侧纹状体促进反应-结果决策而背外侧隔室促进刺激-反应习惯的证据一致，抑制背外侧纹状体中的β-家族激酶恢复过度训练的“习惯性”小鼠的目标敏感性。这些发现提供了一种结构性机制，通过这种机制，即使急性暴露于滥用药物也可以重新组织行为反应策略，并促进对结果不敏感的刺激反应习惯。
Both humans and rodents can learn to associate specific actions with their outcomes, but with repeated performance or exposure to pathological stimuli, such as drugs of abuse, behaviors assume stimulus-elicited, or "habitual," qualities. Psychostimulants remodel dorsal striatal neurons, critical determinants of decision-making strategies, but cytoskeletal mechanisms associated with drug-induced habit formation are largely unknown. We first show that cocaine can bias decision-making strategies toward stimulus-response habits by interfering with learning about the predictive relationship between a response and its outcome. In the dorsomedial, but not ventral, striatum, cocaine decreases PSD95 expression and phosphorylation of cortactin, a cytoskeletal regulator that interacts with, and is phophorylated by, the Abl2 (Arg) kinase. Based on this pattern, we inhibited Abl-family kinase signaling in the dorsomedial striatum, impairing new response-outcome learning. Consistent with evidence that the dorsomedial striatum promotes response-outcome decision-making while the dorsolateral compartment promotes stimulus-response habits, inhibition of Abl-family kinases in the dorsolateral striatum reinstates goal sensitivity in over-trained "habitual" mice. These findings provide a structural mechanism by which even acute exposure to drugs of abuse can reorganize behavioral response strategies and promote outcome-insensitive stimulus-response habits.