Nishimura Kenji J, Ortiz J Bryce, Conrad Cheryl D
Department of Psychology, Arizona State University, Tempe, AZ 85287, United States.
Department of Psychology, Arizona State University, Tempe, AZ 85287, United States.
Neurobiol Learn Mem. 2017 Nov;145:114-118. doi: 10.1016/j.nlm.2017.09.002. Epub 2017 Sep 7.
Chronic stress leads to a dysregulated inhibitory tone that could impact hippocampal-dependent spatial learning and memory. The present study examined whether spatial memory deficits resulting from chronic stress could be overcome by antagonizing the GABA receptor, a prominent inhibitory receptor of GABA in the hippocampus. Young adult male Sprague-Dawley rats were chronically stressed (STR, wire mesh restraint, 6h/d/21d) or placed in a no-stress control group (CON). When chronic restraint ended, rats were tested on a 2-trial object placement (OP) task at a delay (3h) that would result in chance performance without intervention and then on novel object recognition (NOR) and the elevated plus maze (EPM) to assess non-spatial memory and anxiety profile. In CON rats, Bicuculline (BIC, 0, 0.25, 0.5mg/kg), a GABA antagonist, injected 30min prior to training led to facilitated OP performance with 0.25 and 0.5mg/kg doses. In contrast, STR rats required BIC at the highest dose (0.5mg/kg) to improve OP performance. While overall object exploration was decreased by chronic stress, motivation or anxiety profile were unlikely to explain these results. These findings reveal two different dose response functions for BIC in control and chronically stressed rats, with the dose response function of BIC being shifted to the right for chronically stressed rats compared to controls in order to improve spatial memory. While the literature demonstrates that chronic stress disrupts hippocampal inhibitory tone, the current study reveals that a single injection to antagonize the GABA receptor can restore hippocampal-dependent spatial memory in chronically stressed subjects.
慢性应激会导致抑制性调节失调，这可能会影响海马体依赖的空间学习和记忆。本研究调查了慢性应激导致的空间记忆缺陷是否可以通过拮抗海马体中一种主要的抑制性受体——GABA受体来克服。将年轻成年雄性Sprague-Dawley大鼠进行慢性应激处理（STR组，采用金属丝网束缚，6小时/天，共21天），或置于无应激对照组（CON组）。慢性束缚结束后，对大鼠进行两项试验的物体放置（OP）任务测试，延迟时间为3小时，若不进行干预，此延迟时间下的表现应为随机水平，然后进行新物体识别（NOR）和高架十字迷宫（EPM）测试，以评估非空间记忆和焦虑状况。在CON组大鼠中，在训练前30分钟注射GABA拮抗剂荷包牡丹碱（BIC，0、0.25、0.5毫克/千克），0.25和0.5毫克/千克剂量可促进OP任务表现。相比之下，STR组大鼠需要最高剂量（0.5毫克/千克）的BIC才能改善OP任务表现。虽然慢性应激会降低整体物体探索能力，但动机或焦虑状况不太可能解释这些结果。这些发现揭示了BIC在对照组和慢性应激大鼠中的两种不同剂量反应函数，与对照组相比，慢性应激大鼠中BIC的剂量反应函数向右偏移，以改善空间记忆。虽然文献表明慢性应激会破坏海马体的抑制性调节，但当前研究表明，单次注射拮抗GABA受体可以恢复慢性应激受试者中海马体依赖的空间记忆。
