Calcineurin Promotes Neuroplastic Changes in the Amygdala Associated with Weakened Cocaine-Cue Memories
Calcineurin Promotes Neuroplastic Changes in the Amygdala Associated with Weakened Cocaine-Cue Memories
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DOI：
10.1523/jneurosci.0453-19.2019
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发表时间：
2020-02-05
影响因子：
5.3
通讯作者：
Torregrossa, Mary M.
中科院分区：
文献类型：
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作者：
Rich, Matthew T.;Huang, Yanhua H.;Torregrossa, Mary M.
干扰记忆再巩固或诱导记忆消退是削弱成瘾和创伤后应激障碍等疾病中适应不良记忆的两种方法。消退和再巩固都受细胞内蛋白激酶和磷酸酶的调节，干扰这些信号分子可以改变记忆强度。钙依赖性蛋白磷酸酶，钙调神经磷酸酶（CaN），已被牵连在巩固和消失的恐惧记忆。然而，CaN在调节药物线索联想记忆中的作用尚未研究。先前的研究表明，在丘脑-杏仁核外侧（T-LA）突触的可塑性是至关重要的可卡因线索记忆的调节。因此，在本研究中，我们测试了LA管理的激活剂的CaN，绿原酸（CGA），可卡因线索记忆再巩固和灭绝的行为和电生理指标的影响。训练雄性Sprague-Dawley大鼠自我施用可卡因，并伴有视听提示。提示记忆，然后短暂地重新激活，熄灭，或不操纵，随后立即由左心房灌注CGA。24小时后测试大鼠的线索诱导的恢复，或准备LA切片进行电生理记录。我们发现，提示消退或再巩固后LA内输注CGA减少了提示诱导的恢复，这被CaN抑制剂FK-506的共同输注所阻断。同样，CGA输注后线索重新曝光显着衰减EPSC振幅T-LA突触，表明CaN影响可卡因线索的记忆再巩固和灭绝通过改变T-LA突触强度。因此，LA中的CaN信号可能代表了一种新的靶点，用于破坏可卡因相关记忆以减少复发。
Interfering with memory reconsolidation or inducing memory extinction are two approaches for weakening maladaptive memories in disorders such as addiction and post-traumatic stress disorder. Both extinction and reconsolidation are regulated by intracellular protein kinases and phosphatases, and interfering with these signaling molecules can alter memory strength. The calcium-dependent protein phosphatase, calcineurin (CaN), has been implicated in both the consolidation and extinction of fear memories. However, the role of CaN in regulating drug-cue associative memories has not been investigated. Prior studies have demonstrated that plasticity at thalamo-lateral amygdala (T-LA) synapses is critically involved in the regulation of cocaine-cue memories. Therefore, in the present study, we tested the effects of LA administration of an activator of CaN, chlorogenic acid (CGA), on behavioral and electrophysiological indices of cocaine cue memory reconsolidation and extinction. Male, Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. The cue memory was then either briefly reactivated, extinguished, or not manipulated, followed immediately by LA infusion of CGA. Rats were tested 24 h later for cue-induced reinstatement, or LA slices were prepared for electrophysiological recordings. We found that intra-LA infusions of CGA following cue extinction or reconsolidation reduced cue-induced reinstatement, which was blocked by co-infusion of the CaN inhibitor, FK-506. Similarly, CGA infusions following cue re-exposure significantly attenuated EPSC amplitude at T-LA synapses, suggesting that CaN affects cocaine-cue memory reconsolidation and extinction by altering T-LA synaptic strength. Therefore, CaN signaling in the LA may represent a novel target for disrupting cocaine-associated memories to reduce relapse.