Effects of lipopolysaccharide on consolidation of partial learning in the Y-maze

Research on consolidation of long-term memory suggests that acute immune system activation induced by endotoxin lipopolysaccharide (LPS) may disrupt consolidation of newly acquired learning. Adult male Sprague-Dawley rats were trained to perform a simple Y-maze task and were immediately afterwards administered LPS (15 μg/kg) or saline. After a seven-day interval, subjects were returned to the Y-maze and were retrained to criterion. It was found that subjects treated with saline required significantly fewer trials to relearn the task relative to the LPS group and a no-partial-learning control group, which themselves did not differ. These results are most readily explained in terms of a disruptive effect of acute immune system activation on consolidation of newly induced acquired memories.     

脂多糖免疫激活对强迫游泳应激导致的抑郁样行为的影响

应激导致抑郁样行为的同时导致免疫激活敏感化, 但是免疫激活对应激导致的抑郁样行为的影响目前并不清楚。研究目的：利用脂多糖(Lipopolysaccharide, LPS)作为外周免疫激活启动剂, 强迫游泳应激(forced swim stress)作为应激模式, 考察免疫激活背景是否影响应激导致的抑郁样行为。方法：42只SD雄性大鼠随机分为四组：LS组(LPS + swim, n=12), LC组(LPS +空白, n=10), AS组(生理盐水+swim, n=10), AC组(生理盐水+空白, n=10)。在实验期第一天根据分组分别注射脂多糖(LPS, 50 μg/kg, 腹腔注射)或生理盐水一次, LS组和AS组大鼠于注射后2小时进行第一次游泳应激, 此后持续应激2周。分别在应激一次后, 应激2周, 应激结束后1周和应激结束后2周测定大鼠的糖精水偏爱、旷场行为和高架十字迷宫行为。结果显示：应激一次后, 应激2周, 应激后1周LS组大鼠与AC组相比较, 糖精水偏爱分数, 旷场中的水平活动显著下降; 应激2周, AS组大鼠相对于AC组大鼠的糖精水偏爱分数以及旷场中的水平活动都显著下降, 结论：慢性强迫性游泳应激导致抑郁样行为, 应激前LPS免疫激活能够促使应激导致的抑郁样行为更容易出现, 症状加剧, 并持续较长的时间。     

Agmatine facilitates memory of an inhibitory avoidance task in adult rats

Agmatine is a new putative neurotransmitter; however, the physiological role(s) of this endogenous released polyamine is still to be determined. We investigated its cognitive effect in an inhibitory avoidance task in adult rats. Agmatine (0.1, 1, 10, and 20 mg/kg) or saline was administered ip immediately after training or 1 h before testing. Posttraining injection of agmatine facilitated (p < 0.05) memory consolidation in this task; however pretest treatment showed no effect on retrieval (p > 0.05). We suggest that the facilitatory effect of agmatine on memory consolidation in inhibitory avoidance task might be mediated through the activation of the locus coeruleus.     

脂多糖免疫激活导致抑郁性行为的动物研究：剂量和时程效应

“抑郁症细胞因子假说”的提出为抑郁障碍的病因学研究提供了一个新的方向,为了探讨脂多糖（lipopolyaccharide,LPS）诱导的免疫激活与抑郁性行为产生之间的关系,本研究采用50只SD大鼠随机分为五组LPS400,LPS200,LPS50,LPS10,LPS0,分别于实验期第0天和第3天注入LPS400ug/kg,,200ug/kg,50ug/kg,10ug/kg和生理盐水。以糖精水偏爱,旷场行为和高架十字迷宫评定大鼠LPS注射后2小时,24小时,48小时的行为变化。结果显示一次LPS注射后2小时,LPS50,LPS200,LPS400组动物与生理盐水组动物相比较,其糖精水偏爱分数（p<0.01）,旷场中的水平活动距离(p<0.01)和直立行为(p<0.01)以及高架十字迷宫中的闭合臂进入次数(p<0.01)和开放臂进入次数显著下降(p<0.01);重复注射后2小时LPS注射组动物的闭合臂进入次数显著降低（p<0.01）;但LPS10组与生理盐水组动物在行为上没有差异,50ug/kg,200ug/kg和400ug/kg剂量的各组之间没有差异。LPS注射后24小时和48小时以及重复注射后大鼠的行为没有发现显著变化。提示LPS诱导的免疫激活对抑郁行为产生有一定的作用。免疫激活的细胞因子能够导致动物出现明显的抑郁性行为,但是这种行为缺乏长时程效应,因此LPS诱导的抑郁障碍的动物模型应用是非常有限的。免疫激活的前炎性细胞因子可能是导致抑郁障碍产生的其中一个原因而不是唯一原因。     

Adrenergic enhancement of consolidation of object recognition memory

Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects. However, previous studies have not examined the effects of EPI on consolidation of recognition memory. Here we report that systemic administration of EPI enhances consolidation of memory for a novel object recognition (NOR) task under different training conditions. Control male rats given a systemic injection of saline (0.9% NaCl) immediately after NOR training showed significant memory retention when tested at 1.5 or 24, but not 96h after training. In contrast, rats given a post-training injection of EPI showed significant retention of NOR at all delays. In a second experiment using a different training condition, rats treated with EPI, but not SAL-treated animals, showed significant NOR retention at both 1.5 and 24-h delays. We next showed that the EPI-induced enhancement of retention tested at 96h after training was prevented by pretraining systemic administration of the beta-adrenoceptor antagonist propranolol. The findings suggest that, as previously observed in experiments using aversively motivated tasks, epinephrine modulates consolidation of recognition memory and that the effects require activation of beta-adrenoceptors.     

脂多糖激活所致大鼠抑郁样行为及对海马神经细胞钾电流变化的影响

采用细胞因子刺激剂脂多糖(lipopolysaccharide, LPS)为免疫激活手段, 研究LPS诱导的免疫激活产生的抑郁样行为及对海马神经细胞电压依赖钾电流变化的影响。应用膜片钳技术对海马神经细胞钾电流进行全细胞记录, 比较抑郁样行为大鼠与正常大鼠钾离子通道电流密度和激活特性的变化。结果发现, 与生理盐水对照组相比, 一次LPS注射后2 hr, 实验组动物产生抑郁样行为, 同时急性观察的海马神经细胞的钾离子通道的电流密度呈现显著升高(p<0.01); 而一次LPS注射后24 hr, 动物的抑郁样行为消失, 且急性观察的海马神经细胞的钾离子通道与对照组相比较, 其电流密度和激活曲线没有显著性变化。结论：LPS诱导的抑郁样行为, 与LPS诱导的海马神经细胞电压依赖钾电流的上调在时程上同步, 提示钾离子通道可能参与免疫激活所致的抑郁样行为。     

The role of the primary motor cortex during skill acquisition on a two-degrees-of-freedom movement task

One can partially eliminate motor skills acquired through practice in the hours immediately following practice by applying repetitive transcranial stimulation (rTMS) over the primary motor cortex. The disruption of acquired levels of performance has been demonstrated on tasks that are ballistic in nature. The authors investigated whether motor recall on a discrete aiming task is degraded following a disruption of the primary motor cortex induced via rTMS. Participants (N = 16) maintained acquired performance levels and patterns of muscle activity following the application of rTMS, despite a reduction in corticospinal excitability. Disruption of the primary motor cortex during a consolidation period did not influence the retention of acquired skill in this type of discrete visuomotor task.     

一个中枢炎性免疫诱发长时程抑郁样行为的新模型

脂多糖(lipopolysaccharide, LPS)免疫激活模型是研究抑郁症细胞因子假说的重要动物模型, 目前国际上常用外周单次LPS注射诱发抑郁样行为, 但该模型中抑郁样行为持续仅有数小时。为建立诱发较长时程抑郁样行为的免疫激活动物模型, 本研究尝试侧脑室注射LPS激活大鼠中枢免疫炎性反应, 考察单次以及重复中枢LPS注射诱发抑郁样行为的效果, 以及中枢炎性免疫诱发行为改变的时程。结果显示：单次中枢LPS注射后24 h只能诱发旷场自发活动和探索行为下降等部分抑郁样行为, 未能诱导糖水偏好下降和悬尾不动时间增加; 3次重复注射则在末次LPS注射后24 h表现出显著的糖水偏好下降, 自发活动和探索行为减少, 悬尾不动时间增加等行为。且自发活动、探索行为减少和悬尾不动时间增加能够延续至末次LPS注射后72 h。这些结果表明脑室重复LPS注射可诱发较长时程的抑郁样行为, 这种新的中枢炎性免疫激活诱发的抑郁症模型, 为研究抑郁症炎性免疫机制提供了更为有效的动物模型, 有助于深入探讨行为和免疫功能间的复杂关系。     

Suppression of restraint-induced plasma cytokines in mice pretreated with LPS

A previous exposure to an inflammatory reaction is known to increase or decrease the activation of the hypothalamic-pituitary-adrenal (HPA) axis induced by a psychological/physical stress. Beside HPA activation, the non- specific responses to these two kinds of stresses involve the immune system including the production of cytokines. Therefore, they could interfere in cytokine production. In order to test this hypothesis, female C3H mice were first injected i.p. with 5 microg of lipopolysaccharide (LPS) or not (C). Eight days later, half of them were submitted to a 4 h-restraint (R) applied during the nocturnal part of the dark-light cycle and sacrificed immediately after (groups LPS-R and C-R), while the non restrained mice stayed in their home cages (groups LPS-C and C-C). Restraint induced an increase in corticosterone production that was not altered by the previous administration of LPS. It had no effect on mitogen-induced lymphoproliferation. However, restraint induced an augmentation of plasma concentrations of interleukin (IL)-1 and IL-6 that was not observed in animals previously exposed to LPS. These results show that restraint, which represents a psychological stress is able to induce the production of plasma cytokines in mice. They also suggest that LPS may induce a long lasting suppression of plasma cytokines through mechanisms that remain to be elucidated.     

Paradoxical Sleep Deprivation and Sleep Recording Following Training in a Brightness Discrimination Avoidance Task in Sprague–Dawley Rats: Paradoxical Effects

Previously, we reported that posttraining paradoxical sleep deprivation (PSD) resulted in an enhancement of the subsequent avoidance performance for rats trained for 15 trials in a Y-maze brightness avoidance discrimination task. A series of experiments were conducted to try to further understand the reasons for results which were contrary to those of the bulk of the sleep-learning literature. Experiment 1 investigated the effectiveness of the PSD technique. Rats (N= 4) were sleep recorded while residing on a “swimming pool” apparatus for 24 h. Compared to their baseline values, all animals showed a very large reduction in paradoxical sleep and spent significantly more time awake. Slow-wave sleep was unchanged. In Experiment 2, proactive motor effects were tested. Rats were deprived of PS for 24 h and then tested in a hole board motor activity task. There was a slight effect of PS deprivation on the day following the PSD and no effect when the rats were retested 1 week later. Experiment 3 investigated possible proactive effects of PSD on avoidance performance. Rats exposed to PSD in the 24 h before training in the Y-maze task did not demonstrate any facilitative effect on the subsequent avoidance performance. Experiment 4 investigated the possibility that the PSD facilitative effect could be due to partial training. Rats were given 75 acquisition trials in the brightness discrimination Y-maze avoidance before being subjected to 24 h of PSD. PS-deprived animals showed superior avoidance scores compared to non-PSD controls when retested 24 h later. In Experiment 5, the same strain of rats (N= 11) were sleep recorded after exposure to a partial acquisition in a Y-maze brightness avoidance discrimination task. They were then continuously monitored for 4 consecutive days. The percent PS for the Trained rats was significantly lower than that for the Control animals. This drop in percent PS was not confined to any particular time period in the 24-h day. None of the other sleep parameters reached significance. Analyses of the present results suggest that PSD exerts its facilitative effects on posttraining consolidation processes. We present arguments suggesting that PSD can have effects opposite to those generally reported, in animals demonstrating poor avoidance abilities, in an avoidance task.     

Mental relaxation improves long-term incidental visual memory

Experimental evidence has linked increased arousal to enhanced memory retention. There is also evidence that procedures reducing arousal, i.e., mental relaxation, might improve memory, but conflicting results have been reported. To clarify this issue, we studied the effects of a single session of relaxation training on incidental visual long-term memory. Thirty-two relaxation-naive subjects viewed 280 slides without being told that there would be subsequent memory testing. Afterwards, subjects listened to a 12 min relaxation tape; 16 subjects relaxed by following the instructions (relaxation group), and the other 16 subjects pressed a button whenever a body part was mentioned (control group). While listening to the relaxation tape, high frequency heart rate variability (HRV) was greater and low frequency HRV was lower in the relaxation group, implying effective relaxation and increasing parasympathetic activation. The relaxation group had superior memory retention 4 weeks later (p = .004), indicating enhancement of long-term memory performance. This effect could not be explained by retroactive interference experienced in the control group because short-term memory performance immediately after the tape was slightly better in the control group. Retention of materials acquired after the relaxation session remained unaffected, suggesting relaxation has retrograde effects on memory consolidation. Our data demonstrate a favorable influence of relaxation on at least this aspect of learning. Our data also extend previous knowledge on the beneficial effects of ascending parasympathetic stimulation on memory retention in that enhanced long-term memory consolidation may also occur in the presence of central and descending parasympathetic activation triggered by willful psychomotor activity.     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Perceived self-efficacy in coping with cognitive stressors and opioid activation

This experiment tested the hypothesis that perceived self-inefficacy in exercising control over cognitive stressors activates endogenous opioid systems. Subjects performed mathematical operations under conditions in which they could exercise full control over the cognitive task demands or in which the cognitive demands strained or exceeded their cognitive capabilities. Subjects with induced high perceived self-efficacy exhibited little stress, whereas those with induced low perceived self-efficacy experienced a high level of stress and autonomic arousal. Subjects were then administered either an inert saline solution or naloxone, an opiate antagonist that blocks the analgesic effects of endogenous opiates, whereupon their level of pain tolerance was measured. The self-efficacious nonstressed subjects gave no evidence of opioid activation. The self-inefficacious stressed subjects were able to withstand increasing amounts of pain stimulation under saline conditions. However, when endogenous opioid mechanisms that control pain were blocked by naloxone, the subjects were unable to bear much pain stimulation. This pattern of changes suggests that the stress-induced analgesia found under the saline condition was mediated by endogenous opioid mechanisms and counteracted by the opiate antagonist.     

Slow wave sleep during a daytime nap is necessary for protection from subsequent interference and long-term retention

While it is now generally accepted that sleep facilitates the processing of newly acquired declarative information, questions still remain as to the type and length of sleep necessary to best benefit declarative memories. A better understanding could lend support in one direction or another as to the much-debated role of sleep, be it passive, permissive, or active, in memory processing. The present study employed a napping paradigm and compared performance on a bimodal paired-associates task of those who obtained a 10-min nap, containing only Stages 1 and 2 sleep, to those whose nap contained slow-wave sleep (SWS) and rapid eye movement (REM) sleep (60-min nap), as well as to subjects who remained awake. Measurements were obtained for baseline performance at training, after a sleep/no sleep interval for short-term retention, after a subsequent stimulus-related interference task, and again after a weeklong retention period. While all groups learned the information similarly, both nap groups performed better than the Wake group when examining short-term retention, approximately 1.5h after training (10-min p=.052, 60-min p=.002). However, performance benefits seen in the 10-min nap group proved to be temporary. Performance after a stimulus-related interference task revealed significantly better memory retention in the 60-min nap group, with interference disrupting the memory trace far less than both the Wake and 10-min nap groups (p<.001, p=.006, respectively). After a weeklong retention period, sleep's benefit to memory persisted in the 60-min nap group, with performance significantly greater than both the Wake and 10-min nap groups (p<.001, p=.004, respectively). It is our conclusion that SWS, obtained only by those in the 60-min nap group, served to actively facilitate the consolidation of learned bimodal paired-associates, supported by theories such as the Standard Theory of Consolidation as well as the Synaptic Homeostasis Hypothesis.     

Persistent impairments in hippocampal function following a brief series of photoperiod shifts in rats

The impact of an acute circadian disruption on learning and memory in male and female rats was examined. Circadian disruption was elicited using a brief series of photoperiod shifts. Previous research using male rats showed that acute circadian disruption during acquisition of a spatial navigation task impaired long-term retention and that chronic circadian disruption impaired acquisition of the same task. However, the long-term effects of acute circadian disruption following circadian re-entrainment and whether sex differences in response to circadian disruption exist are still unknown. For the present study, rats were trained on the standard, spatial version of the Morris water task (MWT) and a visual discrimination task developed for the eight-arm radial maze. After reaching asymptotic performance, behavioural training was terminated and the experimental group experienced a series of photoperiod shifts followed by circadian re-entrainment. Following circadian re-entrainment, the subjects were given retention tests on the MWT and visual discrimination task. Following retention testing, an extra-dimensional shift using the eight-arm radial maze was also performed. An acute episode of circadian disruption elicited via photoperiod shifts negatively impacted retention of spatial memory in male and female rats. Retention of the visual discrimination task and the ability to detect extra-dimensional shifts were not impaired. The observed impairments on the MWT indicate that hippocampal representations are susceptible to a small number of photoperiod shifts even if the association is acquired prior to rhythm manipulation and retention is assessed following rhythm stabilization. Effects were limited to a hippocampus-dependent task, indicating that impairments are specific, not global.     

Amnesia produced by anisomycin in an appetitive task is not due to conditioned aversion

Two experiments investigated the effects of lithium chloride (LiCl) and anisomycin (ANI) in a water reward Y-maze task. In Experiment 1, male CD-1 mice given weak or strong training were injected post-training with either saline or LiCl (150 mg/kg), which has been reported to produce conditioned aversion in mice. One day after training, both LiCl groups avoided the rewarded arm of the maze and drank less water than saline-injected controls. Two days after training, the strongly trained LiCl mice showed avoidance, while both LiCl groups drank less water. In Experiment 2, weakly trained mice given pre- and post-training ANI (30 mg/kg) were amnesic on the second test day compared to mice that received post-trial saline. However, water consumption was increased on the test day for both groups. LiCl produced a different pattern of results than ANI in this task. On the basis of these results, it is suggested that amnesia produced by ANI is due to impaired memory formation and not to conditioned aversion.     

Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions

Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the ipsilateral NAc shell or core in male Sprague-Dawley rats ( approximately 300 g). One week later, the rats were trained on an inhibitory avoidance (IA) task and, 48 h later, they were tested for retention. Drugs were infused into the BLA and NAc shell or core immediately after training. Post-training intra-BLA infusions of DA enhanced retention, as assessed by latencies to enter the shock compartment on the retention test. Infusions of the general DA receptor antagonist cis-Flupenthixol (Flu) into the NAc shell (but not the core) blocked the memory enhancement induced by the BLA infusions of DA. In the reverse experiment, post-training intra-NAc shell infusions of DA enhanced retention and Flu infusions into the BLA blocked the enhancement. These findings indicate that BLA modulation of memory consolidation requires concurrent DA receptor activation in the NAc shell but not the core. Similarly, NAc shell modulation of memory consolidation requires concurrent DA receptor activation in the BLA. Together with previous findings, these results suggest that the dopaminergic innervation of the BLA and NAc shell is critically involved in the modulation of memory consolidation.     

Neural correlates of acquired color category effects

Category training can induce category effects, whereby color discrimination of stimuli spanning a newly learned category boundary is enhanced relative to equivalently spaced stimuli from within the newly learned category (e.g., categorical perception). However, the underlying mechanisms of these acquired category effects are not fully understood. In the current study, Event-Related Potentials (ERPs) were recorded during a visual oddball task where standard and deviant colored stimuli from the same or different novel categories were presented. ERPs were recorded for a test group who were trained on these novel categories, and for an untrained control group. Category effects were only found for the test group on the trained region of color space, and only occurred during post-perceptual stages of processing. These findings provide new evidence for the involvement of cognitive mechanisms in acquired category effects and suggest that category effects of this kind can exist independent of early perceptual processes.     

Teaching adults new words: the role of practice and consolidation

Semantic and orthographic learning of new words was investigated with the help of the picture-word interference (PWI) task. In this version of the Stroop task, picture naming is delayed by the simultaneous presentation of a semantically related as opposed to an unrelated distractor word (a specific PWI effect), as well as by an unrelated word compared with a nonword (a general PWI effect). This interference is taken to reflect automatic orthographic and semantic processing. The authors observed that participants showed both types of PWI effects for newly learned words following a single study session. Interestingly, specific PWI effects were not obtained immediately after testing but did emerge a week later without additional practice. This suggests that a period of consolidation is involved in the establishment of word representations. In addition, identical PWI effects were obtained when the study and test words were presented in either the same or different letter case. This provides evidence that the newly acquired orthographic representations are coded in an abstract format.     

Post-training intra-basolateral amygdala infusions of norepinephrine block sevoflurane-induced impairment of memory consolidation and activity-regulated cytoskeletal protein expression inhibition in rat hippocampus

Considerable evidence indicates that the noradrenergic system of the basolateral amygdala (BLA) participates in the consolidation of various types of emotionally arousing memories. We previously reported that administration of an anesthetic-dose of sevoflurane immediately after continuous multiple-trail inhibition avoidance (CMIA) training impaired memory consolidation. This experiment investigated whether posttraining noradrenergic activation of the BLA is sufficient to reverse the memory impairing effect of sevoflurane. Adult male Sprague-Dawley rats received bilateral injections of norepinephrine (NE 0.3, 1.0, or 3.0 μg/0.5 μl) or normal saline (NS 0.5 μl) immediately after training in a CMIA paradigm. Subsequently, the rats were exposed to sevoflurane (2% inspired) or air for 2h. Norepinephrine produced a dose-dependent enhancement of memory consolidation on a 24-h retention test. The highest dose of NE tested (3.0 μg/0.5 μl) blocked sevoflurane-induced impairment of memory consolidation and reversed the inhibitory effect of sevoflurane on activity-regulated cytoskeletal protein (Arc) expression in the hippocampus 2h after training. These findings provide evidence that the mechanism mediating the memory-impairing effect of sevoflurane involves a network interaction between the BLA noradrenergic system and modulation of Arc protein expression in the hippocampus.