Cognitive control and corticostriatal BDNF signaling during nicotine withdrawal

描述(申请人提供)：尼古丁的成瘾性质仍然是一个全球健康问题，与吸烟有关的疾病是最大的可预防的死亡原因。尽管有戒烟的治疗方法，戒烟后的复吸率仍然很高。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，描述在尼古丁戒断过程中决定复发的认知机制可能会为尼古丁成瘾的神经生物学提供有益的见解。额纹状体回路辅助执行功能，包括认知控制和 决策过程和这些回路的中断可能会导致强迫性药物使用和成瘾失控。虽然尼古丁戒断对动机状态和依赖海马体的学习的影响已经被很好地研究了，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(R03)申请寻求支持专注于研究尼古丁戒断对灵活决策的影响的研究。由于脑源性神经营养因子(BDNF)是一种对突触可塑性、学习和条件性奖赏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信号的变化有关。目标1的实验将证明早期(24小时)由于执行新的学习策略的障碍，戒除慢性尼古丁将在执行可操作的认知灵活性任务的小鼠的策略集转移方面产生缺陷。这些缺陷被预测与脑源性神经营养因子基因的表观遗传学变化和皮质纹状体回路中脑源性神经营养因子表达增加有关。在延长的(30d)戒断期间，学习障碍和脑源性神经营养因子的表达将得到恢复。Aim 2中的实验将利用Cre/loxP重组在小鼠中产生区域特异性的BDNF基因缺失。这些研究将确定前额叶皮质BDNF基因敲除以及随后纹状体中BDNF蛋白水平的降低是否会恢复早期戒断相关的策略集转换缺陷。总而言之，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缺陷与皮质纹状体BDNF信号之间的因果联系。这项研究将告诉我们尼古丁戒断背后的认知机制，导致吸烟者更高的复发率，以及靶向BDNF信号戒烟的可能性。

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.