Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats.
Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats.
复制标题
DOI：
10.1016/j.neuroscience.2016.02.014
复制
发表时间：
2017-03-14
期刊：
影响因子：
3.3
通讯作者：
Bizon JL
中科院分区：
文献类型：
--
作者：
Beas BS;McQuail JA;Ban Uelos C;Setlow B;Bizon JL
前额叶皮质(PFC)对于灵活适应已建立的行为模式以应对环境突发事件的变化的能力至关重要。行为灵活性受损会导致不适应策略，如坚持不再产生预期结果的反应选项。在动物模型中，前额叶皮质GABA能信号的药物操作调节行为灵活性，前额叶皮质间神经元功能障碍与伴随神经精神疾病的行为灵活性受损有关。由于在正常的衰老过程中也会出现行为灵活性的缺陷，本研究的目的是确定GABA能信号，特别是通过前额叶皮质的GABA(B)受体，在这种与年龄相关的缺陷中所起的作用。年轻和老年大鼠在手术室中进行固定的转换任务训练。首先，老鼠学会了根据正确的控制杆上方的提示灯来区分两个反应控制杆，以获得食物奖励。在获得这种最初的辨别后，改变了偶然性，使大鼠不得不忽略提示灯，并根据它们的左/右位置在操纵杆上做出反应。年轻大鼠和老年大鼠获得了相似的初始辨别能力；然而，在SET转换之后，老年大鼠相对于年轻大鼠受到了损害。在老年大鼠中，内侧前额叶皮质(MPFC)GABA(B)受体的表达与SET转移密切相关，因此低表达与较差的表现有关。随后的实验表明，mPFC内注射GABA(B)受体激动剂巴氯芬可增强老年大鼠的SET转移能力。这些数据通过GABA(B)受体直接将GABA能信号与正常衰老相关的行为灵活性受损联系起来。
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.