Disterhoft J F, Moyer J R, Thompson L T, Kowalska M
Department of Cell, Molecular, and Structural Biology, Northwestern University Medical School, Chicago, IL 60611-3008.
Clin Neuropharmacol. 1993;16 Suppl 1:S12-24. doi: 10.1097/00002826-199316001-00003.
Associative learning is accompanied by a number of changes in the brain, many mediated by calcium. We have used eyeblink conditioning, a well-controlled learning task in animals and humans, to elucidate these changes. Our studies have focused on the hippocampus, a temporal lobe structure known to be important for storage of new information during learning in mammalian brain. Hippocampal neurons show an enhanced firing rate during learning correlated with behavioral acquisition; they also show reduction in a calcium-mediated after-hyperpolarization (AHP), a likely mechanism for their enhanced activity. Aging animals and humans exhibit learning deficits; aging hippocampal neurons show increased AHPs and altered calcium buffering, which contribute to the behavioral learning deficits. Intravenous administration of the calcium antagonist nimodipine causes aging rabbits to learn the eyeblink conditioning task as quickly as young controls. Oral nimodipine enhances learning rates in aging rabbits, rats, and monkeys. In each case, the type of learning task analyzed is dependent on hippocampal processing for acquisition and is impaired with aging. Nimodipine also reverses aging-related alterations in open field behavior of both rats and rabbits. We have done a series of physiological studies focused on the possible role of nimodipine in enhancing neuronal activity in the hippocampus of aging rabbits. The purpose of these studies was to determine how nimodipine may be functioning at a cellular level to increase the learning rate. Four major conclusions may be drawn from our data: (a) Nimodipine strongly enhanced the firing rate of single hippocampal pyramidal neurons recorded in vivo in an aging- and concentration-dependent fashion. Other calcium-channel blockers, such as nifedipine and flunarizine, given to control for cerebral blood flow changes, had essentially no effect on the hippocampal firing rate. (b) The slow AHP, mediated by an outward calcium-activated potassium current, was markedly larger in pyramidal neurons in hippocampal slices prepared from aging rabbits. Nimodipine, at concentrations as low as 100 nM, reliably reduced the AHPs of aging pyramidal cells. Aging neurons also showed more spike frequency adaptation, or accommodation, than young neurons. Nimodipine partially blocked accommodation at concentrations as low as 10 nM in aging neurons. (c) The calcium action potential was larger in aging neurons. Nimodipine modulated the calcium action potential in an age- and concentration-dependent fashion; concentrations as low as 100 nM reduced the calcium action potential in aging CA1 neurons without effects on young cells. (d) Nimodipine blocked the high threshold, noninactivating calcium current (L-type calcium current) in acutely dissociated hippocampal pyramidal neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
联合学习伴随着大脑中的一系列变化，其中许多变化由钙介导。我们利用眨眼条件反射，这是一种在动物和人类中得到良好控制的学习任务，来阐明这些变化。我们的研究集中在海马体，这是一个颞叶结构，已知在哺乳动物大脑学习过程中对新信息的存储很重要。海马神经元在学习过程中表现出放电率增强，这与行为习得相关；它们还表现出钙介导的超极化后电位（AHP）降低，这可能是其活动增强的机制。衰老的动物和人类表现出学习缺陷；衰老的海马神经元表现出AHP增加和钙缓冲改变，这导致了行为学习缺陷。静脉注射钙拮抗剂尼莫地平可使衰老的兔子像年轻对照组一样快速学会眨眼条件反射任务。口服尼莫地平可提高衰老兔子、大鼠和猴子的学习率。在每种情况下，所分析的学习任务类型依赖于海马体的处理来进行习得，并且会随着衰老而受损。尼莫地平还可逆转大鼠和兔子在旷场行为中与衰老相关的改变。我们进行了一系列生理学研究，重点关注尼莫地平在增强衰老兔子海马体神经元活动方面的可能作用。这些研究的目的是确定尼莫地平在细胞水平上可能如何发挥作用以提高学习率。从我们的数据中可以得出四个主要结论：（a）尼莫地平以年龄和浓度依赖性方式强烈增强了体内记录的单个海马锥体神经元的放电率。给予其他钙通道阻滞剂，如硝苯地平和氟桂利嗪，以控制脑血流变化，它们对海马放电率基本没有影响。（b）由外向钙激活钾电流介导的慢AHP在衰老兔子制备的海马切片中的锥体神经元中明显更大。尼莫地平在低至100 nM的浓度下可靠地降低了衰老锥体细胞的AHP。衰老神经元也比年轻神经元表现出更多的放电频率适应性或适应性变化。尼莫地平在低至10 nM的浓度下部分阻断了衰老神经元中的适应性变化。（c）衰老神经元中的钙动作电位更大。尼莫地平以年龄和浓度依赖性方式调节钙动作电位；低至100 nM的浓度可降低衰老CA1神经元中的钙动作电位，而对年轻细胞无影响。（d）尼莫地平阻断了急性分离的海马锥体神经元中的高阈值、非失活钙电流（L型钙电流）。（摘要截断于400字）
