Beas B S, McQuail J A, Ban Uelos C, Setlow B, Bizon J L
Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States.
Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychology, University of Florida, Gainesville, FL, United States.
Neuroscience. 2017 Mar 14;345:274-286. doi: 10.1016/j.neuroscience.2016.02.014. Epub 2016 Feb 9.
The prefrontal cortex (PFC) is critical for the ability to flexibly adapt established patterns of behavior in response to a change in environmental contingencies. Impaired behavioral flexibility results in maladaptive strategies such as perseveration on response options that no longer produce a desired outcome. Pharmacological manipulations of prefrontal cortical GABAergic signaling modulate behavioral flexibility in animal models, and prefrontal cortical interneuron dysfunction is implicated in impaired behavioral flexibility that accompanies neuropsychiatric disease. As deficits in behavioral flexibility also emerge during the normal aging process, the goal of this study was to determine the role of GABAergic signaling, specifically via prefrontal cortical GABA(B) receptors, in such age-related deficits. Young and aged rats were trained in a set shifting task performed in operant chambers. First, rats learned to discriminate between two response levers to obtain a food reward on the basis of a cue light illuminated above the correct lever. Upon acquisition of this initial discrimination, the contingencies were shifted such that rats had to ignore the cue light and respond on the levers according to their left/right positions. Both young and aged rats acquired the initial discrimination similarly; however, aged rats were impaired relative to young following the set shift. Among aged rats, GABA(B) receptor expression in the medial prefrontal cortex (mPFC) was strongly correlated with set shifting, such that lower expression was associated with worse performance. Subsequent experiments showed that intra-mPFC administration of the GABA(B) receptor agonist baclofen enhanced set shifting performance in aged rats. These data directly link GABAergic signaling via GABA(B) receptors to impaired behavioral flexibility associated with normal aging.
前额叶皮质（PFC）对于灵活适应既定行为模式以应对环境偶发变化的能力至关重要。行为灵活性受损会导致适应不良策略，例如执着于不再产生预期结果的反应选项。前额叶皮质GABA能信号的药理学操作可调节动物模型中的行为灵活性，并且前额叶皮质中间神经元功能障碍与神经精神疾病伴随的行为灵活性受损有关。由于行为灵活性缺陷也会在正常衰老过程中出现，本研究的目的是确定GABA能信号，特别是通过前额叶皮质GABA(B)受体，在这种与年龄相关的缺陷中的作用。将年轻和老年大鼠在操作箱中进行的一组转换任务中进行训练。首先，大鼠学会根据正确杠杆上方亮起的提示灯来区分两个反应杠杆以获得食物奖励。在获得这种初始辨别能力后，条件发生了改变，使得大鼠必须忽略提示灯并根据杠杆的左/右位置对杠杆做出反应。年轻和老年大鼠获得初始辨别的情况相似；然而，在转换任务后，老年大鼠相对于年轻大鼠受损。在老年大鼠中，内侧前额叶皮质（mPFC）中的GABA(B)受体表达与转换任务密切相关，表达越低，表现越差。随后的实验表明，向mPFC内注射GABA(B)受体激动剂巴氯芬可提高老年大鼠的转换任务表现。这些数据直接将通过GABA(B)受体的GABA能信号与正常衰老相关的行为灵活性受损联系起来。
