Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α₇- and α₄β₂-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ_1-40/Aβ_1-42 or Aβ_40-1 (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ_1-40 and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α₇- and α₄-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).     

Early antibiotic administration prevents cognitive impairment induced by meningitis in rats

Neurological deficit and alterations in the hippocampus still frequently occur following bacterial meningitis in children, despite the antibiotic treatment. We investigated the long-term outcomes using early versus late antibiotic therapy in experimental pneumococcal meningitis. To this aim, male Wistar rats underwent a basilar cistern tap receiving either sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension. Antibiotics were started 8 or 16 h after infection and the animals were followed for 10 days to the determination of long-term cognitive outcomes. The animals were submitted to the habituation of an open-field as an index of long-term cognitive function. Early antibiotic administration (8 h after inoculation) when compared to late antibiotic administration (16 h after inoculation) prevented cognitive impairment induced by pneumococcal meningitis in Wistar rats. The findings from this study suggest that early antibiotic administration is an effective strategy to prevent long-term cognitive impairment in a meningitis animal model.     

Chronic Caffeine Treatment Prevents Sleep Deprivation-Induced Impairment of Cognitive Function and Synaptic Plasticity

Study Objectives:

This study was undertaken to provide a detailed account of the effect of chronic treatment with a small dose of caffeine on the deleterious effects of sleep loss on brain function in rats.

Experimental Design:

We investigated the effects of chronic (4 weeks) caffeine treatment (0.3 g/L in drinking water) on memory impairment in acutely (24 h) sleep-deprived adult male Wistar rats. Sleep deprivation was induced using the modified multiple platform model. The effects of caffeine on sleep deprivation-induced hippocampus-dependent learning and memory deficits were studied by 3 approaches: learning and memory performance in the radial arm water maze task, electrophysiological recording of early long-term potentiation (E-LTP) in area CA1 of the hippocampus, and levels of memory- and synaptic plasticity-related signaling molecules after E-LTP induction.

Measurement and Results:

The results showed that chronic caffeine treatment prevented impairment of hippocampus-dependent learning, short-term memory and E-LTP of area CA1 in the sleep-deprived rats. In correlation, chronic caffeine treatment prevented sleep deprivation-associated decrease in the levels of phosphorylated calcium/calmodulin-dependent protein kinase II (P-CaMKII) during expression of E-LTP.

Conclusions:

The results suggest that long-term use of a low dose of caffeine prevents impairment of short-term memory and E-LTP in acutely sleep-deprived rats.

Citation:

Alhaider IA; Aleisa AM; Tran TT; Alzoubi KH; Alkadhi KA. Chronic caffeine treatment prevents sleep deprivation-induced impairment of cognitive function and synaptic plasticity. SLEEP 2010;33(4):437-444.     

Nicotine improves AF64A-induced spatial memory deficits in Morris water maze in rats

Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxic derivative of choline that produces not only long-term presynaptic cholinergic deficits, but also various memory deficits in rats similar to some characteristics observed in Alzheimer's disease patients. This study investigated whether nicotine (NCT) administration attenuated spatial learning deficits induced by intracerebroventricular AF64A treatment. AF64A (6 nmol/6 μl)-or saline (SAL)-treated rats were trained in Morris water maze task. NCT (0.025–0.25 mg/kg) was subcutaneously injected 5 min before the training every day. The results showed that moderate dose (0.10 mg/kg) of NCT attenuated AF64A-induced prolongation of escape latency. Furthermore, NCT dose-dependently recovered the AF64A-induced decrease of time spent in the target quadrant in the probe test. These results suggest that NCT improves AF64A-induced spatial memory deficits, and thus it is a potential therapeutic agent for the treatment of memory deficits in dementia.     

Effect of age on the radial arm water maze-a test of spatial learning and memory

Aged rats show decrements in performance on cognitive tasks that require the use of spatial learning and memory. We used the 8-arm radial water maze (RAWM) to measure spatial learning as a function of age in young (6 months) and old (21 months) male F344 rats. Rats were placed in the RAWM in different start arms with the same goal arm for 3 days (five trials/day); the goal arm was changed on day 4. Old rats demonstrated spatial impairment as evidenced by increased latencies to find the hidden platform on day 4. Old rats made significantly more errors, both reference and working memory errors, than young rats on all days. It is likely that the old rats utilized non-spatial strategies to solve the task, and therefore were impaired in learning a new platform location. The RAWM is a reliable, sensitive, and powerful additional test to assess age-related spatial learning and memory deficits, combining the advantages of the Morris water maze and the radial arm maze while minimizing the disadvantages.     

Differential effects of osmotic and SSR149415 challenges in maternally separated and control rats: The role of vasopressin on spatial learning

Maternal separation (MS) has been demonstrated to up-regulate the hypothalamic vasopressin (VP) system. Intracerebrally released VP has been demonstrated to affect several types of animal behaviour, such as active/passive avoidance, social recognition, and learning and memory. However, the role of VP in spatial learning remains unclear. In the present study, we investigated the effects of an osmotic challenge and a V1b receptor-specific (V1bR) antagonist, SSR149415, on spatial learning of maternally separated and animal facility reared (AFR) adult male Wistar rats. The osmotic challenge was applied by injecting a hypertonic saline solution, 1 h before the Morris water maze test (MWM). V1bR antagonist SSR149415 (5 mg/kg) was injected i.p. twice (1 h and 30 min) previous to the MWM. A combined treatment with both osmotic challenge and the SSR149415 was applied to the third group whereas rats for basal condition were injected with isotonic saline. Under basal condition no differences between AFR and MS groups were observed. MS rats showed severe impairment during the MWM after the osmotic challenge, but not after the administration of SSR149415. For AFR rats, the opposite phenomenon was observed. The joint application of SSR149415 and osmotic challenge restored the spatial learning ability for both groups. The differential impairment produced by osmotic stress-induced up-regulation and SSR149415 induced V1bR blockage in MS and control rats suggested that VP involvement in spatial learning depends on the individual intrinsic ligand-receptor functional state.     

Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze

Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus-the radial six-arm water maze (RAWM)-for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.     

Parietal and frontal object areas underlie perception of object orientation in depth

Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder of cognition. Behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. We investigated the effects of treadmill exercise and methylphenidate (MPH) on activity and spatial learning memory in relation to dopamine synthesis and brain-derived neurotrophic factor (BDNF) expression using spontaneously hypertensive adult male rats. The rats in the MPH-treated group received 1 mg/kg MPH orally once a day for 28 days. The rats in the treadmill exercise group were made to run on a treadmill for 30 min once a day, five times a week, for 28 days. Activity was determined by an open-field test and spatial learning memory was evaluated by an 8-arm maze test. Immunohistochemistry and Western blotting were conducted to examine the levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine, and BDNF. The rats in the ADHD group showed hyperactivity and spatial learning memory deficit. Reduction of TH in the striatum and substantia nigra and BDNF in the hippocampus was observed of the rats in the ADHD group. Treadmill exercise and MPH alleviated the ADHD-induced hyperactivity and spatial learning memory impairment. Expressions of TH and BDNF in the ADHD rats were also increased by both treadmill exercise and MPH. These findings provide a possibility that exercise may be used as an effective therapeutic intervention for ADHD patients as MPH treatment.     

Hippocampal heterogeneity in spatial memory revealed by cytochrome oxidase

The oxidative metabolism was assessed in the septal, intermediate and temporal hippocampus in Wistar rats that were trained following a working memory schedule in the Morris water maze. The cytochrome oxidase histochemistry was measured at 90 min, 6, 24 and 48 h post-training. We found an increase in the septal dentate gyrus at 90 min, at 6 h the increase was also found in CA3 and CA1 regions and returned to basal levels at 24 h. In contrast, the intermediate region showed lower increase, limited to the dentate gyrus and CA3 at 24 h post-training. No changes were found in the temporal hippocampus. These findings suggest that septal and intermediate hippocampal zones participate in this spatial learning and contribute at different moments to process this information.     

Inverse benzodiazepine agonist β-CCM does not reverse learning deficit induced by sleep deprivation

Increasing evidence indicates that sleep deprivation (SD) alters responses to pharmacological agents by affecting specific transmitter systems. The present work addressed deficits in passive avoidance (PA) performance that are seen after SD, and investigated whether treatment with the inverse benzodiazepine agonist β-CCM could prevent such deficits. Male Wistar rats were deprived of sleep for 96 h using the platform method (SD group), or were sleep deprived and then allowed to recover sleep for 24 h (SR group). Animals were treated with saline or 0.5 mg/kg β-CCM before PA training, and were tested 30 min or 24 h later. A separate set of animals was sacrificed for [³H]Ro 15-4513 binding analysis. β-CCM increased PA performance in control animals in both short and long term retention tests, whereas SD and SR animals were unaffected by the drug treatment. Interestingly, [³H]Ro 15-4513 binding was reduced in the entorhinal cortex in both SD and SR groups. These findings suggest that the lack of promnesic effects of β-CCM after SD and SR may be associated with benzodiazepine receptor downregulation in specific brain regions related to memory formation.     

Correlation of increased hippocampal Sumo3 with spatial learning ability in old C57BL/6 mice

Age-related impairment of learning and memory is a common phenomenon in humans and animals, yet the underlying mechanism remains unclear. We hypothesize that a small ubiquitin-related modifier (Sumo) might correlate with age-related loss of learning and memory. To test this hypothesis, the present study evaluated age-related spatial learning and memory in C57BL/6 mice (25 aged 7 months and 21 aged 25 months) using a radial six-arm water maze (RAWM). After the behavioral test, the protein expression of Sumo3 was determined in different brain regions using Western blotting. The results showed that the 25-month-old mice had longer latency and a higher number of errors in both learning and memory phases in the RAWM task than the 7-month-old mice. Compared to the latter, the former's level of Sumo3 protein was significantly increased in the dorsal and ventral hippocampus. For the 25-month-old mice, the number of errors and the latency in the learning phase negatively correlated with the Sumo3 level in the dorsal hippocampus. These results suggest that increased Sumo3 in the hippocampus may be correlated with spatial learning ability in old C57BL/6 mice.     

Association of stimuli at long intervals in conditioned odor aversion

Rats learn to avoid a tasteless odorized solution if they experience visceral malaise after consuming it. This phenomenon is referred as Conditioned Odor Aversion (COA). It is widely accepted that an odor can only be associated with illness if the inter-stimulus interval (ISI) is shorter than 15 min. However, this conclusion is based on long-term memory tests usually made 48 h after conditioning, thus precluding the possibility to discriminate between a specific failure to make the odor-malaise association rather than the failure to consolidate the short-term association into long-term memory. In the present study, we compared the short-term and long-term memories for COA in rats trained with long ISIs.Independent groups of male rats were conditioned using 5, 15, 30, 60 or 90 min ISIs and tested either 4 or 48 h after conditioning. We found a reliable odor aversion at 5, 15, 30 and 60 min, but not at 90 min ISIs, when tested 4 h after conditioning. In contrast, odor aversion was only found at 5 and 15 min ISIs in the groups tested 48 h after training. Our results show that COA can be acquired when malaise follows the odor CS by at least 60 min. This finding indicates that the lack of aversion at long ISIs is not due to an association failure, but rather to a limitation in consolidating short-term memory into long-term memory of COA.     

Electroacupuncture pretreatment ameliorates hypergravity-induced impairment of learning and memory and apoptosis of hippocampal neurons in rats

High-sustained positive acceleration (+Gz) exposures might lead to impairment in cognitive function. Our previous studies have shown that electroacupuncture (EA) pretreatment can attenuate transient focal cerebral ischemic injury in the rats. In this study we aimed to investigate whether EA pretreatment could ameliorate the impairment of learning and memory induced by a sustained +Gz exposure. Using the centrifuge model, rats of experimental groups were exposed to +10Gz for 5 min. Morris water maze was used for assessing the cognitive ability, and the apoptotic hippocampal CA1 pyramidal neuronal cells were evaluated by caspase-3 activity and TUNEL staining. Our results showed that +Gz exposure significantly caused pyramidal neuronal damage, increased neuronal apoptosis and caspase-3 activity in hippocampal CA1 region, as well as resulted in an impairment of spatial learning and memory, as compared to the sham group animals. Furthermore, the EA pretreatment significantly attenuated the neuronal apoptosis, preserved neuronal morphology and inhibited the caspase-3 activity in hippocampal CA1 region resulted from +Gz exposure. The EA pretreatment also ameliorated the learning and memory function in rats exposed to +Gz. These findings indicate that EA pretreatment provides a novel method to prevent the cognitive damage caused by +Gz, which could significantly protect neuronal damage and impairment of learning and memory.     

Nicotine enhances contextual fear memory reconsolidation in rats

There is increasing evidence that nicotine is involved in learning and memory. However, there remains no study that has explored the relationship between nicotine and memory reconsolidation. At present study, we tested the effects of nicotine on the reconsolidation of contextual fear memory in rats. Behavior procedure involved four training phases: habituation (Day 0), fear conditioning (Day 1), reactivation (Day 2) and test (Day 3). Rats were injected saline or nicotine (0.25, 0.5 and 1.0mg/kg) immediately after reactivation. Percent of time spent freezing was used to measure conditioned fear response. Results showed that compared with saline rats, rats with nicotine at 1.0mg/kg presented a significant increase of freezing response on Day 3. Nicotine at 1.0mg/kg was ineffective when injected 6h after reactivation. Further results showed that the enhancement of freezing response induced by nicotine at 1.0mg/kg was dependent on fear memory reconsolidation, and was not attributed to an enhancement of the nonspecific freezing response 24h after nicotine administration. The results suggest that nicotine administration immediately after reactivation enhances contextual fear memory reconsolidation. Our present finding extends previous research on the nicotinic effects on learning and memory.     

Effects of ethanol, Δ-tetrahydrocannabinol,or their combination on object recognition memory and object preference in adolescent and adult male rats

Recent advances have been made in our understanding of the deleterious effects of both ethanol and THC on adolescent behavior and brain development. However, very little is known about the combined effects of EtOH + THC during adolescence, a time in which these drugs are often used together. The purpose of this experiment was to: (1) determine whether EtOH and/or THC induced greater working memory impairment in adolescent than adult male rats using the novel object recognition (NOR) task and (2) determine whether the EtOH + THC combination would produce a more potent additive effect in adolescents than adults when compared to these drugs alone. NOR was performed with a 24 h delay under each of the four drug conditions: vehicle; 1.5 g/kg ethanol; 1.0 mg/kg THC; and 1.5 g/kg EtOH + 1.0 mg/kg THC, at 72 h intervals. The results show that there was an age effect on working memory in NOR after the EtOH + THC challenge. Specifically, adolescent animals showed a preference for the familiar object whereas adults showed no preference for the novel or familiar object, the latter being characteristic of a classic working memory deficit. These effects were not dependent on changes in exploration across session, global activity across drug condition, or total object exploration. These novel findings clearly indicate that further understanding of this age–drug interaction is crucial to elucidating the influence that adolescent EtOH + THC use may have on repeated drug use and abuse later in life.     

Antiamnestic Effects of Antibodies to Glutamate in Experimental Alzheimer’s Disease

Experiments on rats showed that neurodegenerative brain damage caused by administration of neurotoxic fragment of β-amyloid protein Aβ_25-35 in a dose of 2 μg into Meynert giant cell nucleus leads to long-term memory impairment in rats. Intranasal administration of antibodies to glutamate in a dose of 300 μg/kg 1 h after damage restores learning capacity of the experimental animals in the conditioned passive avoidance paradigm.     

Effect of nitric oxide synthase inhibitor and NMDA receptor antagonist on the development of nicotine sensitization of nucleus accumbens dopamine release: An in vivo microdialysis study

We have previously found that the neuronal nitric oxide synthase inhibitor N-nitro-l-arginine (l-NNA) and the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 prevent behavioral sensitization to nicotine. This study aimed to investigate the effect of l-NNA and MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drugs on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague–Dawley rats were pretreated with l-NNA (15 mg/kg, i.p.), MK-801 (0.3 mg/kg, i.p.), or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for seven consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens for 60 min and DA release was monitored using in vivo microdialysis. In rats treated with repeated nicotine, acute nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response = 969 ± 235% (mean ± S.E.M.) of basal level versus 520 ± 93%, p = 0.042). Co-administration of l-NNA or MK-801 with nicotine attenuated an increase of DA release elicited by acute nicotine challenge, compared with nicotine alone (maximal DA response = 293 ± 58% and 445 ± 90% of basal level, respectively versus 969 ± 235%, p = 0.004 and p = 0.013, respectively). These data demonstrate that l-NNA and MK-801 block the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of nitric oxide and NMDA receptors in the development of behavioral sensitization to nicotine.     

Dietary trans-fat combined with monosodium glutamate induces dyslipidemia and impairs spatial memory

Aims

Recent evidence suggests that intake of excessive dietary fat, particularly saturated fat and trans-hydrogenated oils (trans-fatty acids: TFA) can impair learning and memory. Central obesity, which can be induced by neonatal injections of monosodium Glutamate (MSG), also impairs learning and memory. To further clarify the effects of dietary fat and MSG, we treated C57BL/6 J mice with either a TFA-enriched diet, dietary MSG, or a combination of both and examined serum lipid profile and spatial memory compared to mice fed standard chow. Spatial learning was assessed at 6, 16 and 32 weeks of age in a Morris Water Maze (MWM). The subjects were given four days of training to find a hidden platform and a fifth day of reversal learning, in which the platform was moved to a new location.

Results

The TFA + MSG combination caused a central adiposity that was accompanied by impairment in locating the hidden platform in the MWM. Females in the TFA + MSG group showed a greater impairment compared to the other diet groups, and also showed elevated levels of fasting serum LDL-C and T-CHOL:HDL-C ratio, together with the lowest levels of HDL-C. Similarly, males in the TFA + MSG diet group were less successful than control mice at locating the hidden platform and had the highest level of abdominal adiposity and elevated levels of fasting serum LDL-C.

Conclusion

Dietary trans-fat combined with MSG increased central adiposity, promoted dyslipidemia and impaired spatial learning.     

Different types of avoidance behavior in rats produce dissociable post-training changes in sleep

Avoidance learning affects post-training sleep, and post-training sleep deprivation impairs performance. However, not all rats learn to make avoidance responses, and some rats fail to escape; a definitive behavior of learned helplessness, a model of depression. This study investigated the changes in sleep associated with different behaviors adopted following avoidance training. Rats (n = 53) were trained for 100 trials over 2 days (50 trials/day), followed by 23-24 h of post-training polysomnography, then re-tested (25 trials). At re-test, rats were categorized into: 1) Active Avoiders (AA; n = 22), 2), Non-learning (NL; n = 21), or 3) Escape Failures (EF; n = 10). AA rats increased avoidances over days, whereas the NL and EF groups did not. EF rats increased escape failures over days, whereas the NL and AA rats did not. EF rats had increased rapid eye movement (REM) sleep in the first 4 h on training day 1. They also had increased non-REM sleep in the first 4 h and last 4 h on both training days. AA rats had increased REM sleep 13-20 h post-training. The type of behavioral strategy adopted throughout training is associated with a unique pattern of changes in post-training sleep. Training-dependent changes in post-acquisition sleep may reflect distinct processes involved in the consolidation of these different memory traces.     

Alterations in fear response and spatial memory in pre- and post-natal zinc supplemented rats: Remediation by copper

The role of zinc in the nervous system is receiving increased attention. At a time when dietary fortification and supplementation have increased the amount of zinc being consumed, little work has been done on the effects of enhanced zinc on behavior. Both zinc and copper are essential trace minerals that are acquired from the diet; under normal conditions the body protects against zinc overload, but at excessive dosages, copper deficiency has been seen. In order to examine the effect of enhanced metal administration on learning and memory, Sprague Dawley rats were given water supplemented with 10 ppm Zn, 10 ppm Zn + 0.25 ppm Cu, or normal lab water, during pre- and post-natal development. Fear conditioning tests at 4 months showed significantly higher freezing rates during contextual retention and extinction and cued extinction for rats drinking water supplemented with zinc, suggesting increased anxiety compared to controls raised on lab water. During the MWM task at 9 months, zinc-enhanced rats had significantly longer latencies to reach the platform compared to controls. The addition of copper to the zinc supplemented water brought freezing and latency levels closer to that of controls. These data demonstrate the importance of maintaining appropriate intake of both metals simultaneously, and show that long-term supplementation with zinc may cause alterations in memory.