Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, 19122, USA.
Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, 16802, USA.
Neuropsychopharmacology. 2020 Apr;45(5):866-876. doi: 10.1038/s41386-019-0574-6. Epub 2019 Nov 21.
Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.
认知灵活性是指在不断变化的环境中自适应地转换策略响应的能力。在尼古丁戒断期间，神经回路适应可能会导致认知僵化，从而促进成瘾者的不适应尼古丁摄入。我们系统地检查了在 14 天内暴露于尼古丁（6.3 或 18mg/kg/天）或盐水的小鼠自发戒断对认知灵活性的影响，使用操作性策略转换任务。由于额皮质纹状体回路对于认知灵活性至关重要，并且脑源性神经营养因子（BDNF）调节这些回路中的谷氨酸可塑性，因此我们还探索了尼古丁戒断对这些神经化学底物的影响。经历尼古丁戒断的小鼠需要更多的试验才能达到策略转换标准。错误分析表明，两种尼古丁剂量的戒断动物都会犯更多的坚持错误，这与焦虑的测量值相关。然而，接受更高尼古丁剂量的动物也表现出更多的策略维持错误，这些错误独立于负面情绪。BDNF mRNA 表达在尼古丁戒断后增加了内侧前额叶皮质（mPFC）。令人惊讶的是，BDNF 蛋白在 mPFC 中下降，但在背侧纹状体（DS）中升高。DS BDNF 蛋白与坚持和维持错误呈正相关，表明在戒断期间 BDNF 从 mPFC 到 DS 的溢出。BDNF 诱导的谷氨酸释放和突触素磷酸化在 DS 突触中减弱，但在伏隔核中增强，表明 BDNF 信号在纹状体区域中具有二分作用。总的来说，这些数据表明，自发的尼古丁戒断会损害认知集转换的不同成分，这些缺陷可能与 BDNF 介导的谷氨酸信号动态在离散的额皮质纹状体回路中的改变有关。
