Cognitive control and corticostriatal BDNF signaling during nicotine withdrawal

尼古丁的成瘾性仍然是一个全球性的健康问题，与吸烟有关的疾病是最大的可预防的死亡原因。尽管有戒烟治疗方法，但尝试戒烟后复吸的几率仍然很高。成瘾的神经回路与支持认知功能的神经回路广泛重叠。因此，描述尼古丁戒断期间决定复发的认知机制可能为尼古丁成瘾的神经生物学提供有益的见解。额纹状体回路有助于执行功能，包括认知控制和 决策过程的障碍以及这些回路的中断可能会导致强迫性吸毒和成瘾失控。虽然尼古丁戒断对动机状态和依赖于大脑的学习的影响已经得到了很好的研究，但它如何影响额纹状体回路和自上而下的认知控制尚不清楚。这一小额赠款（RO 3）申请寻求对研究的支持，重点是研究尼古丁戒断对灵活决策的影响。由于脑源性神经营养因子（BDNF），一种对突触可塑性，学习和条件性奖励至关重要的神经营养因子与成瘾有关，我们还将确定尼古丁戒断后的认知变化是否与皮质纹状体BDNF信号转导的改变有关。目的1的实验将证明，早期（24小时），由于在执行新的学习策略中的损伤，从慢性尼古丁戒断将在执行操作性认知灵活性任务的小鼠中产生策略设置转换的缺陷。这些缺陷被预测与BDNF基因的表观遗传变化和皮质纹状体回路中BDNF表达增加有关。在延长的停药期（30天），学习缺陷和BDNF表达将恢复。目的2中的实验将利用Cre/loxP重组在小鼠中产生BDNF基因的区域特异性缺失。这些研究将确定前额叶皮质中BDNF的敲除以及随后纹状体中BDNF蛋白水平的降低是否会恢复策略转换中与早期退缩相关的缺陷。总的来说，从这个小gant产生的试点数据将成为未来研究的基础，以建立慢性尼古丁和戒断诱导的执行功能和皮质纹状体BDNF信号转导缺陷之间的因果关系。这项研究将告诉我们尼古丁戒断的认知机制，导致吸烟者复发率较高，以及靶向BDNF信号传导戒烟的潜力。

DESCRIPTION (provided by applicant): The addictive nature of nicotine remains a global health problem and smoking-related illness is the largest preventable cause of death. Despite the availability of treatments for smoking cessation, relapse to smoking after quit attempts still remains very high. Neural circuits of addiction extensively overlap with those that support cognitive functions. Therefore, delineation of cognitive mechanisms that determine relapse during nicotine withdrawal is likely to provide gainful insights into the neurobiology of nicotine addiction. The frontostriatal circuits subserve executive functions including cognitive control and decision-making processes, and disruption in these circuits may contribute to compulsive drug use and loss of control in addiction. Although the effects of nicotine withdrawal on motivational states and hippocampus-dependent learning are well studied, how it affects frontostriatal circuits and top-down cognitive control is not known. This small grant (RO3) application seeks support for research focused on examining the effects of nicotine withdrawal on flexible decision-making. Because brain-derived neurotrophic factor (BDNF), a neurotrophic factor critical for synaptic plasticity, learning and conditioned reward is implicated in addiction, we will also determine whether cognitive changes following nicotine withdrawal are associated with alterations in corticostriatal BDNF signaling. The experiments of aim 1 will demonstrate that early (24 hr.) withdrawal from chronic nicotine will produce deficits in strategy set-shifting in mice performing an operant cognitive flexibility task due to impairments in execution of a new learning strategy. These deficits are predicted to be associated with epigenetic changes in the BDNF gene and increased BDNF expression in the corticostriatal circuits. Learning deficits and BDNF expression will be restored during the extended (30 d) withdrawal period. Experiments in Aim 2 will utilize Cre/loxP recombination to produce region-specific deletion of the BDNF gene in mice. These studies will determine whether BDNF knockdown in the prefrontal cortex and consequent reduction of BDNF protein levels in the striatum would restore early withdrawal-related deficits in strategy set-shifting. Collectively, the pilot data generated from this small gant will form the basis for future research to establish a causal link between chronic nicotine- and withdrawal-induced deficits in executive functions and corticostriatal BDNF signaling. This research would inform us about cognitive mechanisms underlying nicotine withdrawal that lead to higher relapse rate among smokers and the potential of targeting BDNF signaling for smoking cessation.