Bunce J G, Sabolek H R, Chrobak J J
Department of Psychology, University of Connecticut, Storrs, CT 06269, USA.
Neuroscience. 2003;121(2):259-67. doi: 10.1016/s0306-4522(03)00462-7.
The medial septal nucleus is part of the forebrain circuitry that supports memory. This nucleus is rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive-enhancing drugs. Septal neurons, primarily cholinergic and GABAergic, innervate the entire hippocampal formation and regulate hippocampal formation physiology and emergent function. Direct intraseptal drug infusions can produce amnestic or promnestic effects depending upon the type of drug administered. However, intraseptal infusion of the cholinomimetic oxotremorine has been reported to produce both promnestic and amnestic effects when administered prior to task performance. The present study examined whether post-acquisition intraseptal infusion of oxotremorine would be promnestic or amnestic in a delayed-non-match-to-sample radial maze task. In this task rats must remember information about spatial locations visited during a daily sample session and maintain that information over extended retention intervals (hours) in order to perform accurately on the daily test session. Treatments may then be administered during the retention interval. Alterations in maze performance during the test session an hour or more after treatment evidences effects on memory. In the present study, intraseptal infusion of oxotremorine (1.0-10.0 microg) produced a linear dose-related impairment of memory performance. Importantly, we also observed disrupted performance on the day after treatment. This persistent deficit was related only to memory over the retention interval and did not affect indices of short-term memory (ability to avoid repetitive or proactive errors during both the pre- and post-delay sessions). The persistent deficit contrasts with the acute amnestic effects of other intraseptally administered drugs including the cholinomimetics carbachol and tacrine. Thus, intraseptal oxotremorine produced a preferential disruption of memory consolidation as well as a persistent alteration of medial septal circuits. These findings are discussed with regards to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related decline and Alzheimer's dementia.
内侧隔核是支持记忆的前脑回路的一部分。该核富含胆碱能受体，是拟胆碱能认知增强药物开发的潜在靶点。隔区神经元主要是胆碱能和γ-氨基丁酸能的，支配整个海马结构，并调节海马结构的生理功能和新兴功能。直接向隔区内注射药物，根据给药药物的类型，可产生遗忘或促记忆作用。然而，据报道，在任务执行前注射拟胆碱能药物氧化震颤素，会产生促记忆和遗忘两种效果。本研究考察了在延迟非匹配样本放射状迷宫任务中，在习得后向隔区内注射氧化震颤素是会产生促记忆还是遗忘作用。在这个任务中，大鼠必须记住关于每天样本训练期间访问的空间位置的信息，并在延长的保留间隔（数小时）内保持该信息，以便在每天的测试训练中准确执行。然后可以在保留间隔期间进行治疗。治疗后一小时或更长时间的测试训练中迷宫表现的改变证明了对记忆的影响。在本研究中，向隔区内注射氧化震颤素（1.0 - 10.0微克）产生了与剂量相关的线性记忆表现损伤。重要的是，我们还观察到治疗后一天的表现受到干扰。这种持续的缺陷仅与保留间隔期间的记忆有关，并不影响短期记忆指标（在延迟前和延迟后训练期间避免重复或主动错误的能力）。这种持续的缺陷与其他隔区内注射药物（包括拟胆碱能药物卡巴胆碱和他克林）的急性遗忘作用形成对比。因此，隔区内注射氧化震颤素会优先破坏记忆巩固以及内侧隔区回路的持续改变。关于海马依赖性记忆形成的多阶段模型以及治疗轻度认知障碍以及与年龄相关的衰退和阿尔茨海默病的治疗策略的进一步发展，对这些发现进行了讨论。
