Role of Extinction in Circuit-Specific Modulation of Motivation and Mood in Cocaine Addiction

项目总结 吸毒成瘾是一种严重而多发的精神疾病，包括持续复发，尽管人们真诚地努力 弃权。戒毒训练已被用作减少药物渴求和复发的治疗方法， 尽管由于不能完全捕获个别药物独有的上下文方面而具有有限的有效性 用户。在不同的大脑回路中识别灭绝诱导的修饰可能会导致更好的 治疗药物成瘾的神经刺激方法。本研究对特定神经的修饰进行了研究 在可卡因成瘾大鼠模型中自我给药行为的消失。我们之前的数据 提示消退训练增强了兴奋性突触对伏核(NAC)壳神经元的输入， 这种效应可以减弱精神运动敏感化和对可卡因寻觅行为的复发。初级阶段 NAC壳的兴奋性输入起源于内侧前额叶皮质(PFC)、杏仁基底外侧核(BLA)。 和腹侧海马(VH)。使用光遗传低频刺激方法选择性地 去增强来自这些区域的兴奋性突触输入，这项研究将识别特定的 NAC壳中消退诱导神经可塑性的来源(S)(目标I)，并研究该电路特异性的作用 消退诱导的敏感化和复发行为减弱的神经可塑性(目标II)。以前的数据 研究还表明，消除可卡因的自我管理可能会逆转由以下因素产生的负面情绪影响 长期吸食可卡因。因此，研究将确定回路特异性神经可塑性在物种灭绝中的作用。 诱导的抗抑郁疗效(AIM III)。 目标1的研究将使用光遗传学来研究导致1)灭绝的灭绝电路-- AMPA GluA受体亚单位诱导突触运输，2)兴奋性消光增强 突触电流和3)决定了直接和/或间接的NAC输出神经元的消退。 AIM II的实验将确定消光增强电路在消光诱导的逆转中的作用 运动敏感化和5)消退诱导的上下文和可卡因启动的恢复的衰减 寻找可卡因的行为。AIM III中的实验将研究特定物种灭绝的作用 可卡因条件下焦虑症测试中逆转负性情绪效应的神经可塑性 厌恶感，在强迫游泳测试中学到的无助/行为绝望，以及蔗糖中的快感缺失 偏好测试。这些神经生物学和行为数据集的整合将决定 回路特异性神经可塑性在消退对动机有益影响中的重要作用 以及导致可卡因成瘾的情绪障碍。清楚地描绘了调解边缘回路的轮廓 这种有益的效果可以导致更好的行为和有针对性的神经刺激方法 治疗可卡因和其他成瘾。

PROJECT SUMMARY Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to abstain. Extinction training has been used as a therapeutic method to reduce drug craving and relapse, although with limited efficacy due to an inability to fully capture contextual aspects unique to individual drug users. The identification of extinction-induced modifications in distinct brain circuits could lead to better neurostimulation approaches to treat drug addiction. This research studies modification of specific neural circuits by the extinction of self-administration behavior in a rat model of cocaine addiction. Our previous data indicate that extinction training enhances excitatory synaptic input to nucleus accumbens (NAc) shell neurons, and this effect attenuates psychomotor sensitization and relapse to cocaine-seeking behavior. The primary excitatory inputs to the NAc shell originate in the medial prefrontal cortex (PfC), basolateral amygdala (BlA) and ventral hippocampus (VH). Using an optogenetic low frequency stimulation approach to selectively depotentiate excitatory synaptic input emanating from these regions, this research will identify the specific source(s) of extinction-induced neuroplasticity in the NAc shell (Aim I), and study the role of this circuit-specific neuroplasticity in extinction-induced attenuation of sensitization and relapse behaviors (Aim II). Previous data also suggest that extinction of cocaine self-administration may reverse negative mood effects produced by chronic cocaine use. Thus, studies will determine the role of circuit-specific neuroplasticity in extinction- induced antidepressive efficacy (Aim III). Studies in Aim 1 will employ optogenetics to study the extinction circuits responsible for 1) extinction- induced synaptic trafficking of AMPA GluA receptor subunits, 2) extinction-induced enhancement in excitatory synaptic currents and 3) determine the direct and/or indirect NAc output neurons modified by extinction. Experiments in Aim II will determine the role of extinction-potentiated circuits in 4) extinction-induced reversal of locomotor sensitization and 5) extinction-induced attenuation of context- and cocaine-primed reinstatement of cocaine-seeking behavior. Experiments in Aim III will investigate the role of extinction-specific neuroplasticity in reversing negative mood effects in tests of 6) dysphoria in cocaine-conditioned place aversion, 7) learned helplessness/behavioral despair in forced swim tests and 8) anhedonia in sucrose preference tests. The integration of these neurobiological and behavioral datasets will determine the significant role that circuit-specific neuroplasticity plays in the beneficial effects of extinction on motivational and mood disturbances that contribute to cocaine addiction. A clear delineation of limbic circuits that mediate such beneficial effects could lead to better behavioral and targeted neurostimulation approaches in the treatment of cocaine and other addictions.