Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, New Jersey.
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, New Jersey.
Biol Psychiatry. 2021 May 15;89(10):1001-1011. doi: 10.1016/j.biopsych.2020.12.027. Epub 2021 Jan 8.
To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes.
A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction.
Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner.
We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders.
为了达到理想的目标，个体必须预测特定选择的结果，利用该信息指导适当的行动，并在不断变化的环境中相应地调整行为（行为灵活性）。物质使用障碍的特点是行为灵活性受损，以及前额皮质功能下降，这限制了治疗策略的效果。恢复前额皮质的低活动，理想情况下是非侵入性的，是改善灵活行为和治疗效果的一个有趣目标。
使用行为灵活性任务结合电生理学、光遗传学和一种新的经颅交流电刺激（tACS）大鼠模型，研究前额皮质（PrL）至伏隔核（NAc）核心回路在行为灵活性中的作用，并确定 tACS 是否可以恢复可卡因引起的神经和认知功能障碍。
光遗传学失活表明，PrL-NAc 核心回路对于灵活改变行为的能力是必要的。可卡因自我给药史导致 PrL-NAc 核心神经编码异常和灵活性缺陷。在学习之前选择性激活 PrL-NAc 核心途径的光遗传学挽救了可卡因引起的认知灵活性缺陷。值得注意的是，学习任务之前的 tACS 重新建立了 PrL-NAc 回路中的适应性信号，并以相对非侵入性和特定频率的方式恢复了灵活行为。
我们确立了 NAc 核心投射的 PrL 神经元在行为灵活性中的作用，并为大鼠提供了一种新的非侵入性脑刺激方法，以挽救可卡因引起的额叶功能低下并恢复灵活行为，支持 tACS 作为治疗物质使用障碍认知缺陷的一种治疗方法。
