The Intra-Hippocampal Leucine Administration Impairs Memory Consolidation and LTP Generation in Rats

Leucine accumulates in fluids and tissues of patients affected by maple syrup urine disease, an inherited metabolic disorder, predominantly characterized by neurological dysfunction. Although, a variable degree of cognition/psychomotor delay/mental retardation is found in a considerable number of individuals affected by this deficieny, the mechanisms underlying the neuropathology of these alterations are still not defined. Therefore, the aim of this study was to investigate the effect of acute intra-hippocampal leucine administration in the step-down test in rats. In addition, the leucine effects on the electrophysiological parameter, long-term potentiation generation, and on the activities of the respiratory chain were also investigated. Male Wistar rats were bilaterally administrated with leucine (80 nmol/hippocampus; 160 nmol/rat) or artificial cerebrospinal fluid (controls) into the hippocampus immediately post-training in the behavioral task. Twenty-four hours after training in the step-down test, the latency time was evaluated and afterwards animals were sacrificed for assessing the ex vivo biochemical measurements. Leucine-treated animals showed impairment in memory consolidation and a complete inhibition of long-term potentiation generation at supramaximal stimulation. In addition, a significant increment in complex IV activity was observed in hippocampus from leucine-administered rats. These data strongly indicate that leucine compromise memory consolidation, and that impairment of long-term potentiation generation and unbalance of the respiratory chain may be plausible mechanisms underlying the deleterious leucine effect on cognition.     

莫达非尼对睡眠剥夺条件下工作记忆的影响

目的:观察在睡眠剥夺条件下莫达非尼对工作记忆的改善作用,为此药在我军的应用策略提供实验依据。方法:18名健康男性志愿者,在两次睡眠剥夺实验中交叉服用莫达非尼和安慰剂,睡眠剥夺时间从第一天的07:00到第3d的07:00,并于第二天的0:00、12:00和第三天的0:00分别服用莫达非尼100mg或安慰剂。采用随机双盲设计给药,并在第一天的07:00、第二天的02:00和14:00以及第三天的02:00和07:00安排工作记忆测验。结果:工作记忆测验中,两组的反应时和正确率均有统计学差异(P<0.01),莫达非尼组的反应时要快于安慰剂组,正确率也要高于安慰剂组。莫达非尼对工作记忆的改善效果随着睡眠剥夺时间的延长而更趋明显。结论:莫达非尼对睡眠剥夺条件下个体的工作记忆有改善作用,是较为理想的睡眠剥夺对抗药物。     

Blocking Dopaminergic Signaling Soon after Learning Impairs Memory Consolidation in Guinea Pigs

Formation of episodic memories (i.e. remembered experiences) requires a process called consolidation which involves communication between the neocortex and hippocampus. However, the neuromodulatory mechanisms underlying this neocortico-hippocampal communication are poorly understood. Here, we examined the involvement of dopamine D1 receptors (D1R) and D2 receptors (D2R) mediated signaling on memory consolidation using the Novel Object Recognition (NOR) test. We conducted the tests in male Hartley guinea pigs and cognitive behaviors were assessed in customized Phenotyper home cages utilizing Ethovision XT software from Noldus enabled for the 3-point detection system (nose, center of the body, and rear). We found that acute intraperitoneal injections of either 0.25 mg/kg SCH23390 to block D1Rs or 1.0 mg/kg sulpiride to block D2Rs soon after acquisition (which involved familiarization to two similar objects) attenuated subsequent discrimination for novel objects when tested after 5-hours in the NOR test. By contrast guinea pigs treated with saline showed robust discrimination for novel objects indicating normal operational processes undergirding memory consolidation. The data suggests that involvement of dopaminergic signaling is a key post-acquisition factor in modulating memory consolidation in guinea pigs.     

Sleep Deprivation Induces Changes in Immunity in Trichinella spiralis-Infected Rats

Sleep is considered an important predictor of immunity. A lack of sleep may reduce immunity, which increases susceptibility to any type of infection. Moreover, sleep deprivation in humans produces changes in both, the percent of circulating immune cells (T cells and NK cells) and cytokine levels (IL-1, IFNγ, TNΦ-αα, IL-6 and IL-17). The aim of our study was to investigate whether sleep deprivation produces deregulation on immune variables during the immune response generated against the helminth parasite Trichinella spiralis. Because sleep deprivation is stressful per se, we designed another experiments to compared stress alone (consisting in movement restriction and single housing) with sleep deprivation, in both control (uninfected) and experimental (infected) rats. Our results demonstrate that the sleep deprivation and stress have a differential effect in mesenteric lymph nodes (MLN) and spleen. In uninfected rats sleep deprivation alone produces an increase in natural killer cells (NK+) and B cells (CD45+), accompanied by a decrease in cytotoxic T cells (CD3+CD8+) in spleen; while, in MLN, produces only an increase in natural killer cells (NK+). Both, SD and stress, produce an increased percentage of total T cells (CD3+) in spleen. In the MLN both are also associated to an increase in cytotoxic T cells (CD3+CD8+) and B cells (CD45+). In the spleens of parasitized rats, cell populations did not change. In spleens of both, sleep-deprived and stressed infected rats, we observed an increase in B cells (CD45+). In infected rats, sleep deprivation alone produced an increase in NK cells (NK+). In mesenteric node cell populations of parasitized rats, we observed a decrease in NK cells and an increase in T helper (CD4+) cells in both SD and stressed rats. Rats that were only subjected to stress showed a decrease in B cells (CD45+). These findings suggest that the immune response generated against infection caused by T. spiralis is affected when the sleep pattern is disrupted. These results support the notion that sleep is a fundamental process for an adequate and strong immune response generated against this parasite.     

The Consolidation of Implicit Sequence Memory in Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning.     

Sleep Deprivation Impairs Object-Selective Attention: A View from the Ventral Visual Cortex

Background

Most prior studies on selective attention in the setting of total sleep deprivation (SD) have focused on behavior or activation within fronto-parietal cognitive control areas. Here, we evaluated the effects of SD on the top-down biasing of activation of ventral visual cortex and on functional connectivity between cognitive control and other brain regions.

Methodology/Principal Findings

Twenty-three healthy young adult volunteers underwent fMRI after a normal night of sleep (RW) and after sleep deprivation in a counterbalanced manner while performing a selective attention task. During this task, pictures of houses or faces were randomly interleaved among scrambled images. Across different blocks, volunteers responded to house but not face pictures, face but not house pictures, or passively viewed pictures without responding. The appearance of task-relevant pictures was unpredictable in this paradigm. SD resulted in less accurate detection of target pictures without affecting the mean false alarm rate or response time. In addition to a reduction of fronto-parietal activation, attending to houses strongly modulated parahippocampal place area (PPA) activation during RW, but this attention-driven biasing of PPA activation was abolished following SD. Additionally, SD resulted in a significant decrement in functional connectivity between the PPA and two cognitive control areas, the left intraparietal sulcus and the left inferior frontal lobe.

Conclusions/Significance

SD impairs selective attention as evidenced by reduced selectivity in PPA activation. Further, reduction in fronto-parietal and ventral visual task-related activation suggests that it also affects sustained attention. Reductions in functional connectivity may be an important additional imaging parameter to consider in characterizing the effects of sleep deprivation on cognition.     

Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34–2.68 μmol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 μmol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients.     

Sleep Deprivation in the Dark Period Does Not Impair Memory in OF1 Mice

There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n?=?20) or by spontaneous wheel running (RW; n?=?20). Two control groups were used: one had no RW throughout the experiment (n?=?23), while the other group's wheel was blocked immediately after acquisition (n?=?16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at “dark offset” correlated positively (r?=?0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation.     

大鼠成年前异常生活环境对其成年后恐惧记忆的影响

为了探讨早期饲养环境对成年后大鼠条件化恐惧的影响,实验采用巴氏恐惧条件化的方法对不同饲养环境下的大鼠进行了行为检测.具体操作为:把断奶后的大鼠饲养在3个不同的人工控制的环境中(丰富环境、社群环境和贫瘠环境);8周后进行恐惧条件化训练和测试(指标为僵直百分比),以及检测不同饲养环境下的大鼠的体重、自发活动和足部电击敏感性.结果显示:与社群组相比,丰富组的大鼠条件化僵直水平明显增加,而贫瘠组的明显减少;丰富和贫瘠环境明显的影响了大鼠的体重;不同环境对自发活动和足部电击敏感性没有影响.这些结果说明幼年期的丰富环境能提高成年后大鼠的由声音诱发的条件化恐惧反应,而贫瘠环境则削弱了这种反应.     

Hippocampal Sharp Wave/Ripples during Sleep for Consolidation of Associative Memory

The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination.     

Apelin-13 Impaires Acquisition but Not Consolidation or Expression of Contextual Fear in Rats

Apelin-13, as an endogenous neuropeptide, is the ligand for the G-protein-coupled receptor, APJ, which has recently been demonstrated to be involved in the process that contributes to learning and memory. Previous studies showed that apelin may be required for certain forms of learning and memory. Up to date, the role of apelin in fear memory has not been explored. In the present study, we tested the effects of apelin-13 (1.0, 2.0 and 4.0 µg/rat) on contextual fear conditioning (experiment 1), consolidation (experiment 2) and expression (experiment 3) in rats. A well established fear conditioning protocol was used, which contained three training phases: habituation, fear conditioning and test. Apelin-13 was i.c.v injected 10 min before conditioning (experiment 1), immediately after conditioning (experiment 2) or 10 min before testing (experiment 3). The values of percent freezing were used to measure fear. We found that only 2.0 µg apelin-13 administrations produced a decrease freezing in experiment 1. The most effective dose of apelin-13 (2.0 µg) was selected, but it had no effect on freezing in experiment 2 and 3. Furthermore, the decreased freezing in experiment 1 was not attributed to the deficits of locomotor activity and foot-shock sensitivity. These results, for the first time, indicated that apelin-13 impaired fear acquisition but not fear consolidation or expression.     

Sleep-Related Declarative Memory Consolidation and Verbal Replay during Sleep Talking in Patients with REM Sleep Behavior Disorder

Objective

To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep.

Methods

Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges.

Results

Sleep-related verbal memory consolidation was maintained in patients with RBD (+24±36% words) as in controls (+9±18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post-sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9±19%) was worse than night-time consolidation (+29±45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep.

Conclusion

Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level.     

Short-Term Sleep Deprivation Stimulates Hippocampal Neurogenesis in Rats Following Global Cerebral Ischemia/Reperfusion

Background

Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR).

Methods

One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.

Results

The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.

Conclusions

Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.     

Comparing the Effects of Nocturnal Sleep and Daytime Napping on Declarative Memory Consolidation

Nocturnal sleep and daytime napping facilitate memory consolidation for semantically related and unrelated word pairs. We contrasted forgetting of both kinds of materials across a 12-hour interval involving either nocturnal sleep or daytime wakefulness (experiment 1) and a 2-hour interval involving either daytime napping or wakefulness (experiment 2). Beneficial effects of post-learning nocturnal sleep and daytime napping were greater for unrelated word pairs (Cohen’s d = 0.71 and 0.68) than for related ones (Cohen’s d = 0.58 and 0.15). While the size of nocturnal sleep and daytime napping effects was similar for unrelated word pairs, for related pairs, the effect of nocturnal sleep was more prominent. Together, these findings suggest that sleep preferentially facilitates offline memory processing of materials that are more susceptible to forgetting.     

Effects of Deprivation of the Quick-Wave Sleep in Rats with Inherited Predisposition to Audiogenic Convulsions

In experiments on rats of Krushinskii–Molodkina line (KM) with genetic predisposition to audiogenic convulsions, effects of the 3- and 6-h periods of the absence of the quick-wave sleep (QS) were studied in animals under natural conditions as well as of selective deprivations of QS on EEG spectral characteristics in the wakening–sleep cycle, on organization of the cycle, and on intensity of convulsive symptoms. The QS deprivation for 3, 6, 9, and 12 h was produced by the classic methods of small platforms or of soft awakening. The data are presented about changes of the cycle parameters in the course of natural and experimental deprivations as well as about the dynamics of restoration of the cycle structure for 12 h of the post-deprivation period. It was established that during and after the QS deprivations (by any duration), in EEG of the hippocampus, caudate nucleus, medial central nucleus of thalamus, somato-sensory, visual and auditory cortex of the KM rat brain, no appearance of the paroxysmal fires was revealed in any of the states of the wakening–sleep cycle. It was also found that the selective QS deprivation did not affect duration of the latent period and parameters of the generalized tonic-clonic audiogenic convulsions. It is stated that in rats of the KM line that have the hidden convulsive syndrome, the used kinds and methods of QS deprivation fail to activate the epileptiform manifestations.