BALB/c和ICR小鼠的学习记忆能力等行为学研究

目的研究不同品系小鼠学习记忆能力的差异,为学习记忆的基础研究提供应用信息。方法80只BALB/c和80只ICR小鼠分别分为Morris水迷宫组、跳台组、穿梭组、ROTA-ROD组,每组20例,进行学习记忆能力及行动能力测试。结果水迷宫组在9轮水迷宫训练学习期BALB/c小鼠空间学习记忆能力没有明显提高。ICR小鼠从9轮水迷宫训练学习期的第4次开始,逃避潜伏期显著缩短,与前3次相比差异有显著性(P<0.001)。跳台组ICR和BALB/c小鼠训练前后5 min内错误次数及跳下潜伏期差异均具有显著性。穿梭组ICR小鼠学习期与记忆期主动逃避次数、被动逃避次数及电击时间的差异均有显著性,而BALB/c小鼠训练前后主动逃避次数、被动逃避次数及电击时间的差异均无显著性。ROTA-ROD组ICR小鼠的跑步动作维持时间显著高于BALB/c小鼠,其差异有显著性。结论以上结果提示在进行某些学习记忆实验时,使用ICR小鼠优于BALB/c小鼠。     

'Return to home cage' as a reward for maze learning in young and old genetically heterogeneous mice

Recent studies have shown that 'return to home cage' can serve as a reward for maze learning in adult male mice. The present study examined whether the same reward is an effective motivator of learning in young and old mice and included females in the study design. We tested 25- and 65-d-old HS mice and 85- and 800-d-old B6D2F2 mice in a Lashley III maze. Return to home cage motivated maze acquisition in all groups. Compared with 65-d-old HS mice, 25-d-olds acquired the maze more slowly, took longer to achieve the test criterion, and showed increased latency to reach the goal box. There was no difference between 85- and 800-d-old B6D2F2 mice in rate of acquisition. This reward procedure may reduce the potentially confounding effects of deprivation or aversive stimuli on maze performance and may be suitable as a motivational procedure for a wide range of subject groups.     

Characterizing spatial extinction in an abbreviated version of the Barnes maze

Adult male Wistar rats were trained to find an escape box in the Barnes maze in order to characterize the extinction process of a learned spatial preference. To do so, once they had fully acquired the spatial task, they were repeatedly exposed to the maze without the escape box. Multiple behavioral measurements (grouped into motor skill and spatial preference indicators) were followed up throughout the complete training process. Animals gained efficiency in finding the escape box during acquisition, as indicated by the reduction in the time spent escaping from the maze, the number of errors, the length of the traveled path, and by the increase in exploration accuracy and execution speed. When their retention and preference were tested 24 h later, all the subjects retained their enhanced performance efficiency and accuracy and displayed a clear-cut preference for the escape hole and its adjacent holes. Almost all motor skill indicators followed an inverse, though not monotonic, pattern during the extinction training, returning to basal levels after three trials without escape box, displaying a transient relapse during the fifth extinction trial. Preference indicators also followed a reverse pattern; however, it took seven trials for them to return to basal levels, relapsing during the eighth extinction trial. The abbreviated Barnes maze acquisition, evaluation, and extinction procedures described herein are useful tools for evaluating the effects of behavioral and/or pharmacological treatment on different stages of spatial memory, and could also be used for studying the neurophysiological and neurobiological underpinnings of this kind of memory.     

Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice

The radial arm water maze (RAWM) contains six swim paths (arms) extending out of an open central area, with an escape platform located at the end of one arm (the goal arm). The goal arm location remains constant for a given mouse. On day 1, mice are trained for 15 trials (spaced over 3 h), with trials alternating between visible and hidden platform. On day 2, mice are trained for 15 trials with the hidden platform. Entry into an incorrect arm is scored as an error. The RAWM has the spatial complexity and performance measurement simplicity of the dry radial arm maze combined with the rapid learning and strong motivation observed in the Morris water maze without requiring foot shock or food deprivation as motivating factors. With two sessions each day, 16 mice can be tested over 2 days.     

NGI重组DNA疫苗对转基因AD小鼠的治疗作用

目的研究NGI对转基因阿尔茨海默病小鼠的治疗作用。方法构建包含小鼠OMgp细胞外8LRP重复序列,人Tenascin-R的EGF-L结构域,以及人Nogo-A的氨基端和66个氨基酸细胞外域的重组质粒,肌肉注射AD小鼠,空载体组和空白对照组为对照组。水迷宫检测小鼠行为学差别,免疫组化检测其病理差别。结果4.5月龄AD小鼠经过水迷宫隐蔽平台实验,2d后疫苗组小鼠潜伏期比对照组缩短30%（P〈0.05）。探索实验显示3月龄疫苗组比空载体组和空白对照组小鼠穿越目标象限的次数分别增加48%和44%（P〈0.05）。结论NGI重组DNA疫苗能够提高转基因AD小鼠的学习与记忆能力。     

Mouse knockout of guanylyl cyclase C: Recognition memory deficits in the absence of activity changes

Guanylyl cyclase C (GC‐C) is found in brain regions where dopamine is expressed. We characterized a mouse in which GC‐C was knocked out (KO) that was reported to be a model of attention deficit hyperactivity disorder (ADHD). We re‐examined this model and controlled for litter effects, used 16 to 23 mice per genotype per sex and assessed an array of behavioral and neurochemical outcomes. GC‐C KO mice showed no phenotypic differences from wild‐type mice on most behavioral tests, or on striatal or hippocampal monoamines, and notably no evidence of an ADHD‐like phenotype. KO mice were impaired on novel object recognition, had decreased tactile startle but not acoustic startle, and females had increased latency on cued training trials in the Morris water maze, but not hidden platform spatial learning trials. Open‐field activity showed small differences in females but not males. The data indicate that the GC‐C KO mouse with proper controls and sample sizes has a moderate cognitive and startle phenotype but has no ADHD‐like phenotype.     

Neuronal cell adhesion molecule deletion induces a cognitive and behavioral phenotype reflective of impulsivity

Cell adhesion molecules, such as neuronal cell adhesion molecule (Nr-CAM), mediate cell–cell interactions in both the developing and mature nervous system. Neuronal cell adhesion molecule is believed to play a critical role in cell adhesion and migration, axonal growth, guidance, target recognition and synapse formation. Here, wild-type, heterozygous and Nr-CAM null mice were assessed on a battery of five learning tasks (Lashley maze, odor discrimination, passive avoidance, spatial water maze and fear conditioning) previously developed to characterize the general learning abilities of laboratory mice. Additionally, all animals were tested on 10 measures of sensory/motor function, emotionality and stress reactivity. We report that the Nr-CAM deletion had no impact on four of the learning tasks (fear conditioning, spatial water maze, Lashley maze and odor discrimination). However, Nr-CAM null mice exhibited impaired performance on a task that required animals to suppress movement (passive avoidance). Although Nr-CAM mutants expressed normal levels of general activity and body weights, they did exhibit an increased propensity to enter stressful areas of novel environments (the center of an open field and the lighted side of a dark/light box), exhibited higher sensitivity to pain (hot plate) and were more sensitive to the aversive effects of foot shock (shock-induced freezing). This behavioral phenotype suggests that Nr-CAM does not play a central role in the regulation of general cognitive abilities but may have a critical function in regulating impulsivity and possibly an animal's susceptibility to drug abuse and addiction.     

柚皮苷及其与吴茱萸碱联合用药对APP~（swe）/PS~（ΔE9）转基因痴呆模型小鼠学习记忆能力的影响

目的探讨柚皮苷及柚皮苷与吴茱萸碱联合用药对APPswe/PSΔE9转基因痴呆模型小鼠学习记忆能力的影响,研究柚皮苷与吴茱萸碱联合使用是否具有协同或叠加作用。方法 APPswe/PSΔE9转基因痴呆模型小鼠随机分组,每组12只,雌雄各半,分别选择在3月龄和5月龄两个时间段开始进行治疗,各给药组按设定剂量分别单独或联合加入鼠粮中。3月龄给药16周、5月龄给药4周后进行水迷宫实验,以安理申作为阳性药对照,并与安慰剂组小鼠进行比较。Thioflavin-S荧光染色检测单独使用柚皮苷治疗转基因小鼠脑组织老年斑的形成。结果单独使用柚皮苷4周和16周,缩短寻找平台的潜伏期分别为22%、32%;单独使用吴茱萸碱4周和16周,缩短寻找平台的潜伏期分别为33%、10%。柚皮苷治疗16周减少海马老年斑26%。柚皮苷与吴茱萸碱联合应用能够显著缩短寻找平台的潜伏期47%。结论单独使用柚皮苷或吴茱萸碱均能改善痴呆模型小鼠的学习记忆能力,柚皮苷长期的使用优于短期的治疗效果,但是吴茱萸碱短期有效,长期作用反而下降;柚皮苷与吴茱萸碱联合应用能够显著改善APPswe/PSΔE9痴呆模型小鼠的学习记忆能力,但联合用药组并未表现出强于单独给药组的协同保护效应。     

Galanin attenuates retention of one-trial reward learning.

Galanin is a neuropeptide that coexists with acetylcholine in the septohippocampal pathway. Galanin appears to have a negative modulating influence on cholinergic transmission, suggesting that it might interfere with memory formation on a one-trial discriminative reward learning task. The apparatus was a starburst maze with five radiating alleys, one an ascending baited alley. The subjects were 38 two to three month old Sprague-Dawley rats cannulated in the body of the lateral ventricles and deprived to 80% of initial weight. Ten rats were infused i.c.v. over six mins. with 8 micrograms galanin in 24 microliters saline and 10 with saline alone. Twenty mins. after completion of infusion, each rat was placed in the maze and observed under "blind" conditions for number of errors (blind alleys entered) and latency to reach reward. Each rat's speed score was 100 sec./latency. One day later, each rat was retested in the maze. Each rat's retention scores were its decrease in errors and increase in speed between the single training trial and the retention trial. Galanin infused rats showed significantly less retention by both measures. In a second experiment, either the same dose of galanin or saline alone was infused 20 mins. before the retention trial. There was no significant effect, suggesting that galanin may interfere with memory formation rather than memory retrieval or task performance.     

Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits

Studies using the Morris water maze to assess hippocampal function in animals, in which adult hippocampal neurogenesis had been suppressed, have yielded seemingly contradictory results. Cyclin D2 knockout (Ccnd2^?/?) mice, for example, have constitutively suppressed adult hippocampal neurogenesis but had no overt phenotype in the water maze. In other paradigms, however, ablation of adult neurogenesis was associated with specific deficits in the water maze. Therefore, we hypothesized that the neurogenesis‐related phenotype might also become detectable in Ccnd2^?/? mice, if we used the exact setup and protocol that in our previous study had revealed deficits in mice with suppressed adult neurogenesis. Ccnd2^?/? mice indeed learned the task and developed a normal preference for the goal quadrant, but were significantly less precise for the exact goal position and were slower in acquiring efficient and spatially more precise search strategies. Upon goal reversal (when the hidden platform was moved to a new position) Ccnd2^?/? mice showed increased perseverance at the former platform location, implying that they were less flexible in updating the previously learned information. Both with respect to adult neurogenesis and behavioral performance, Ccnd2^+/? mice ranged between wild types and knockouts. Importantly, hippocampus‐dependent learning was not generally impaired by the mutation, but specifically functional aspects relying on precise and flexible encoding were affected. Whether ablation of adult neurogenesis causes a specific behavioral phenotype thus also depends on the actual task demands. The test parameters appear to be important variables influencing whether a task can pick up a contribution of adult neurogenesis to test performance.     

Transgenic expression of androgen receptors improves spatial memory retention in both sham-irradiated and 137Cs gamma-irradiated female mice

Using a water maze, it has been shown that both wild-type and apoE4-expressing female mice are at greater risk of developing age-related hippocampal-dependent impairments in spatial learning and memory than age-matched male mice of the same genotype. In addition, apoE4-expressing female mice were more sensitive to 137Cs gamma-radiation-induced impairment in spatial learning and memory than age-matched male mice of the same genotype. These findings imply that androgen receptors (ARs) contribute to spatial learning and memory, posing the question as to whether transgenic expression of AR in female mice might modulate hippocampal-dependent learning and memory under baseline conditions and after local brain irradiation. Hippocampal-dependent novel location recognition was comparable in wild-type and AR-Tg female mice. This function was impaired after irradiation in AR-Tg but not wild-type mice. In contrast, sham-irradiated wild-type and AR-Tg female mice showed hippocampal-independent novel location recognition, and this was not affected by radiation. After the second day of hidden platform training, in a water maze probe trial, sham-irradiated and irradiated AR-Tg female mice showed spatial memory retention but irradiated wild-type mice did not. After the third day of hidden platform training, only irradiated wild-type female mice did not show spatial memory retention in the water maze probe trial. Both sham-irradiated and irradiated wild-type and AR-Tg female mice showed passive avoidance learning and memory. These data support an important role for AR in spatial memory retention in water maze probe trials in female mice under baseline conditions and after cranial irradiation.     

Beneficial effects of pituitary grafts under the renal capsule on behavior of dwarf mutant mice

The effects of pituitary grafts under the kidney capsule were studied in "dwarf" mutant mice which because of anterohypophyseal deficiency, exhibit dwarfism, sterility and important behavioral deficits. One month after grafting, the body weight was 120% in the grafted mutants while only 11 and 8% respectively in normal and sham-grafted controls. At the behavioral level, the animals were examined on 2 tasks: spontaneous alteration in a T maze and passive avoidance (step-through). Grafted mutant mice, as well as sham-grafted normal controls, were able to alternate successfully, while the sham-grafted "dwarf" mice persevered. In the step-through task, grafted animals as well as sham-grafted normal mice, avoided, entering the dark compartment, 24 h after the shock trial. On contrast, sham-grafted dwarf mice did not show passive avoidance of the shock. According to the literature, pituitary grafts under the kidney capsule secrete high levels of prolactin and very little, if any, of other pituitary hormones. It is not yet clear how the presence of only prolactin can explain the body weight and the maintenance of the behaviors we investigated.     

Low-stress Route Learning Using the Lashley III Maze in Mice

Many behavior tests designed to assess learning and memory in rodents, particularly mice, rely on visual cues, food and/or water deprivation, or other aversive stimuli to motivate task acquisition. As animals age, sensory modalities deteriorate. For example, many strains of mice develop hearing deficits or cataracts. Changes in the sensory systems required to guide mice during task acquisition present potential confounds in interpreting learning changes in aging animals. Moreover, the use of aversive stimuli to motivate animals to learn tasks is potentially confounding when comparing mice with differential sensitivities to stress. To minimize these types of confounding effects, we have implemented a modified version of the Lashley III maze. This maze relies on route learning, whereby mice learn to navigate a maze via repeated exposure under low stress conditions, e.g. dark phase, no food/water deprivation, until they navigate a path from the start location to a pseudo-home cage with 0 or 1 error(s) on two consecutive trials. We classify this as a low-stress behavior test because it does not rely on aversive stimuli to encourage exploration of the maze and learning of the task. The apparatus consists of a modular start box, a 4-arm maze body, and a goal box. At the end of the goal box is a pseudo-home cage that contains bedding similar to that found in the animal’s home cage and is specific to each animal for the duration of maze testing. It has been demonstrated previously that this pseudo-home cage provides sufficient reward to motivate mice to learn to navigate the maze¹. Here, we present the visualization of the Lashley III maze procedure in the context of evaluating age-related differences in learning and memory in mice along with a comparison of learning behavior in two different background strains of mice. We hope that other investigators interested in evaluating the effects of aging or stress vulnerability in mice will consider this maze an attractive alternative to behavioral tests that involve more stressful learning tasks and/or visual cues.Download video file.^{(94M, mp4)}     

硫辛酸对卵巢切除小鼠学习记忆的影响

目的:探讨硫辛酸(Lipoic acid,LA)对卵巢切除(ovariectomized,OVX)小鼠学习记忆的影响。方法:2月龄雌性昆明小鼠随机分为4组:假手术(Sham)组、OVX组、OVX+LA组、OVX+LA+左旋硝基精氨酸甲酯(L-NAME)组。建立卵巢切除模型并给药,Morris水迷宫检测各组小鼠学习记忆能力。结果:前4天定位巡航实验中,OVX组与Sham组相比,逃避潜伏期明显延长(P0.05),第5天撤除平台后,OVX组在目的象限游泳距离及时间百分比较Sham组明显缩短(P0.05);OVX+LA组与OVX组相比,逃避潜伏期明显缩短(P0.05),撤除平台后,在目的象限游泳距离及时间百分比明显延长(P0.05);OVX+LA+L-NAME组与Sham组相比,逃避潜伏期明显延长(P0.05),撤除平台后,在目的象限游泳距离及时间百分比明显缩短(P0.05)。结论:OVX损伤小鼠的学习记忆,LA可改善这种损伤,内皮型一氧化氮合酶(e NOS)抑制剂L-NAME可削弱LA的这种保护作用。     

Complementary remedy of aged-related learning and memory deficits via exogenous choline acetyltransferase

The present study aimed to examine whether the aged mice with naturally occurring cognitive deficits in learning and memory would benefit from supplementation of choline acetyltransferase (ChAT), the biosynthetic enzyme for neurotransmitter acetylcholine. Delivered by protein transduction domain (PTD), ChAT could pass through the blood-brain barrier, enter the neurons, interact with heat shock protein 70kDa, and retain enzyme activity. In behavior tests, PTD-ChAT given to the aged and memory-deficient mice almost completely reversed the behavioral changes, such as impairment of memory retention in the step-through test (an index of long-term memory) and prolonged swimming time in water maze test (an index of spatial recognition memory). The results suggest a novel and potential therapeutic use of PTD-ChAT in the age-related cognitive deficits.     

Spatial memory and orientation strategies in the elasmobranch<Emphasis Type="Italic"> Potamotrygon motoro</Emphasis>

We investigated whether juvenile freshwater stingrays (Potamotrygon motoro) can solve spatial tasks by constructing a cognitive map of their environment. Two experimental conditions were run: allocentric and ego-allocentric. Rays were trained to locate food within a four-arm maze placed in a room with visual spatial cues. The feeding location (goal) within the maze (room) remained constant while the starting position varied for the allocentrically but not for the ego-allocentrically trained group. After training, all rays solved the experimental tasks; however, different orientation strategies were used within and between groups. Allocentrically trained rays reached the goal via novel routes starting from unfamiliar locations, while ego-allocentrically trained rays primarily solved the task on the basis of an egocentric turn response. Our data suggest that P. motoro orients by constructing a visual cognitive map of its environment, but also uses egocentric and/or other orientation strategies alone or in combination for spatial orientation, a choice which may be governed by the complexity of the problem. We conclude that spatial memory functions are a general feature of the vertebrate brain.     

两种水迷宫在测试拟阿尔茨海默病小鼠学习记忆能力中的比较

目的采用两种水迷宫对拟阿尔茨海默病小鼠学习记忆功能进行比较。方法将小鼠分为正常对照组、模型组及给药组。用Morris水迷宫和MS-2水迷宫自动控制仪分别测试各组小鼠的学习记忆能力。结果在Morris水迷宫测试中,模型组与对照组,给药组与模型组比较,逃避潜伏期均有显著性差异（P〈0.01）,在MS-2水迷宫自动控制仪测试中,模型组与对照组比较有明显差异（P〈0.05）,而给药组与模型组比较,游出水迷路的时间均有所减少,但没有显著性差异（P〉0.05）。结论Morris水迷宫和MS-2水迷宫自动控制仪测试方法均能反映动物学习和记忆功能,而前者能更敏感地反映出动物的学习记忆能力。因此,Morris水迷宫应为实验首选,当然在实验需要时,两种水迷宫最好结合使用,以得到客观的结果。     

Deficiency of aminopeptidase P1 causes behavioral hyperactivity,cognitive deficits,and hippocampal neurodegeneration

Metabolic diseases affect various organs including the brain. Accumulation or depletion of substrates frequently leads to brain injury and dysfunction. Deficiency of aminopeptidase P1, a cytosolic proline‐specific peptidase encoded by the Xpnpep1 gene, causes an inborn error of metabolism (IEM) characterized by peptiduria in humans. We previously reported that knockout of aminopeptidase P1 in mice causes neurodevelopmental disorders and peptiduria. However, little is known about the pathophysiological role of aminopeptidase P1 in the brain. Here, we show that loss of aminopeptidase P1 causes behavioral and neurological deficits in mice. Mice deficient in aminopeptidase P1 (Xpnpep1^?/?) display abnormally enhanced locomotor activities in both the home cage and open‐field box. The aminopeptidase P1 deficiency in mice also resulted in severe impairments in novel‐object recognition, the Morris water maze task, and contextual, but not cued, fear memory. These behavioral dysfunctions were accompanied by epileptiform electroencephalogram activity and neurodegeneration in the hippocampus. However, mice with a heterozygous mutation for aminopeptidase P1 (Xpnpep1^+/?) exhibited normal behaviors and brain structure. These results suggest that loss of aminopeptidase P1 leads to behavioral, cognitive and neurological deficits. This study may provide insight into new pathogenic mechanisms for brain dysfunction related to IEMs.