Synaptic plasticity. The role of NMDA receptors in learning and memory.
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[Overview: molecular mechanisms for learning and memory].
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[Synaptic plasticity and mechanisms of learning and memory].
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Animals↗
Role of sleep in the regulation of learning and memory.
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Animals↗
Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks.
From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.
Animals↗
Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory.
Much of the research on long-term potentiation (LTP) is motivated by the question of whether changes in synaptic strength similar to LTP underlie learning and memory. Here we discuss findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing this question. We first review the evidence suggesting that fear conditioning is mediated by changes in synaptic strength at sensory inputs to the lateral nucleus of the amygdala. We then discuss several outstanding questions that will be important for future research on the role of synaptic plasticity in fear learning. The results gained from these studies may shed light not only on fear conditioning, but may also help unravel more general cellular mechanisms of learning and memory.
Amygdala↗
Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats.
A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.
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Identification of linotte, a new gene affecting learning and memory in Drosophila melanogaster.
We describe the identification of linotte, a new autosomal gene in Drosophila involved with learning and memory. The linotte mutant was derived from a PlacW transposon mutagenesis and was screened for three-hour memory deficits after classical conditioning of an olfactory avoidance response. Sensory and motor systems (olfactory acuity and shock reactivity) required for the classical conditioning experiments were normal in mutant linotte flies--indicating that the mutation disrupts learning/memory specifically. A chromosomal deficiency of the 37D region, where the linotte P insert was localized in situ, failed to complement linotte's memory defect, and flies from two lines homozygous for independent PlacW excisions show normal memory--indicating that the P insertion is responsible for the mutant phenotype. Additional behavior-genetic data suggest that linotte gene is non-vital.
Animals↗
A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat.
Two experiments were conducted to compare the effects of radiofrequency lesions of thalamus and frontal cortex on three measures of spatial learning and memory: delayed non-matching to sample (DNMTS), radial arm maze with imposed delays, and serial reversal learning. Thalamic lesions were aimed at the lateral internal medullary lamina (L-IML) and cortical lesions at the projection areas of the mediodorsal nucleus along the medial wall (MW) and dorsal to the rhinal sulcus (RS) in frontal cortex. In Experiment 1 rats were trained on DNMTS prior to surgery. After recovery, rats with MW lesions showed persistent deficits on DNMTS that were significantly greater than for RS lesions. The deficits observed in MW lesioned animals were comparable to the effects of L-IML lesions on this task that have been described in previous studies. In Experiment 2 animals were trained to perform the radial arm maze task prior to treatment. After recovery, animals with L-IML lesions were impaired on the radial arm maze and on subsequent acquisition of the serial reversal task. Rats with RS and MW lesions showed transient impairments on the radial arm maze task, but otherwise performed as well as controls on both these tasks.
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[Effects of lithium on rat hippocampus cholecystokinin protein expression and learning and memory].
OBJECTIVE: To investigate the effects of lithium on brain development, leaning and memory, we observed the effects of lithium chloride on rat body weight, learning ability and memory capacity. METHODS: Wistar rats were randomly divided into control group and four lithium chloride (LiCl) groups. Four LiCl groups were feed with food containing 3, 30, 300, 3000 mg/kg LiCl respectively. Control group was feed with normal food. By means of measuring the body weight, using Y-maze test and ABC immunohistochemistry, we observed the difference of the body weight gains and Y-maze training times of different groups, and the changes of CCK positive neurons in hippocampus. RESULTS: Compared with control group, 3, 30 mg/kg LiCl groups could increase the body weight and improve the ability of learning and memory of rats(P < 0.01), however, these of the rats of 300, 3000 mg/kg group were lower (P < 0.05). The numbers of CCK positive neurons in hippocampus of 3, 30, 300 mg/kg groups were significantly increased compared with control group (P < 0.05), that of 3000mg/kg group was lower than control group (P < 0.05). CONCLUSION: Low dose of lithium can improve the growth, the learning ability and the memory capacity obviously, but high dose of lithium could result in harmful effects.
Animals↗
The effects of natal anoxia upon learning and memory at maturity.
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Humans↗
Influence of dietary triacylglycerol structure and level of n-3 fatty acids administered during development on brain phospholipids and memory and learning ability of rats.
OBJECTIVE: The objective of this study was to examine the effects of triacylglycerol (TAG) structure and level of n-3 fatty acids on fatty acid profile of brain phospholipids (PL) of dams and offspring, and the memory and learning ability of the offspring, when administered during initial development of the nervous system. METHODS: Pregnant rats were fed experimental diets from the 8th day of pregnancy throughout lactation. After weaning and until 13 weeks of age, the pups were fed the same diet as their dams. The experimental diets contained either a structured oil, a linseed oil, or a fish oil. In the structured oil, alpha-linolenic acid (18:3n-3) was predominantly located in the SN-2 position of the triacylglycerols and the level of 18:3n-3 was 2 mol or 10 mol%. In the linseed oil diets the level of 18:3n-3 was 2 mol or 10 mol% as well. Finally, the fish oil diet contained 18:3n-3 as well as 20:5n-3 and 22:6n-3 adding up to a total of 2 mol% n-3 fatty acids. The effects of the experimental diets were compared to the effect of a chow diet. RESULTS: The amount of 22:6n-3 in brain phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS) of dams and offspring (3 and 13 weeks of age) was not affected by the six different diets. 18:2n-6, but not 18:3n-3, was detected in brain PL, suggesting a specificity of the tissues in the metabolism of n-3 and n-6 fatty acids. The level of monounsaturated fatty acids (MUFA) increased with increasing age of the pups, indicating an enhanced myelinization. No considerable differences between groups were found when memory or learning was tested in the Morris water maze. CONCLUSION: The results suggest that extreme diet modifications are needed in order to observe significant effects on the memory and learning ability in rats.
Animals↗
A role for immediate-early transcription factors in learning and memory.
This article summarizes recent studies from the long-term potentiation (LTP), long-term depression (LTD), and behavioral learning literature, indicating that immediate-early genes (IEGs) may play an important role in learning and memory. The LTP studies suggest that synaptic modifications occurring during NMDA-receptor-mediated hippocampal LTP and LTD are stabilized by the protein products of the krox family of IEGs (as well as by brain-derived neurotrophic factor, BDNF). Activation of muscarinic receptors also induces members of the krox as well as the fos and jun family (jun-B but not c-jun) IEGs in hippocampal neurons and this action may be involved in the facilitatory effects of muscarinic receptor activation on both hippocampal LTP and learning. The possible role of IEGs in the learning-enhancing effects of cholinergically mediated hippocampal theta is also discussed. Finally, I review a number of recent studies showing IEG expression in brain neurons after behavioral learning. Together these results suggest some role for select IEGs (e.g., Krox 24) in learning and memory, although definitive studies using antisense DNA technology are required to establish any causal links. In particular, IEGs may be critical components of the signal transduction cascade that links NMDA and muscarinic receptors to the neuronal genome and ultimately to the generation of permanent modifications in neuronal biochemistry that provides the substrate for learning.
Acetylcholine↗
[Effect of chronic Toxoplasma infection on the spatial learning and memory capability in mice].
OBJECTIVE: To investigate the effect of chronic infection of Toxoplasma gondii on the spatial learning and memory capability in mice. METHODS: Toxoplasma tachyzoites (RH strain) were reanimated at 37 degrees C after 15 days' storage at -20 degrees C, and injected intraperitoneally to mice of the experimental group each with 7.7 x 10(5). Normal saline was given to the control group, 0.5 ml per mouse. Two months later, all mice were tested in the Morris Water Maze. Smears of the mice brain homogenate and pathological sections were examined. RESULTS: (1) The density of cysts in the brain homogenate was 15/HP, and there was no evident pathological change in the hippocampus and adjacent areas of mice in the brain in the experimental mice. (2) Latency to platform, cumulative distance to the platform, total distance traveled in both experimental and control groups decreased significantly with the increase of training days (P < 0.01). The latency and cumulative distance in experimental group were significantly longer than that of the control group (P < 0.01). (3) The searching strategy of mice in the experimental group was significantly different from that of the control group. CONCLUSION: Toxoplasma tachyzoites can induce chronic infection in mice and the infection can damage at some extent the spatial learning and memory capability of mice.
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Protective effect of acidic fibroblast growth factor against ischemia-induced learning and memory deficits in two tasks in gerbils.
The influence of transient forebrain ischemia on behavioral performance, and the effect of intracerebroventricular (i.c.v.) injection of acidic fibroblast growth factor (aFGF) on such ischemia-induced deficits were examined in Mongolian gerbils by assessing learning and memory in two tasks: passive avoidance and Morris water maze. A 5-min period of forebrain ischemia led to learning and memory deficits in both tasks, and also to neuronal death in the hippocampal CA1 region. Continuous i.c.v. infusion of aFGF bilaterally into the lateral ventricules by osmotic minipumps over 2 days before, and 5 days after the ischemia (a total of 3.6 microg/gerbil) largely prevented both the ischemia-induced behavioral deficits and the neuronal death in the hippocampus. These observations suggest that the hippocampus is a critical site for the performance of the two tasks, and that aFGF has a protective effect against such ischemia-induced learning and memory deficits in gerbils.
Amnesia↗
The negative cell cycle regulator, Tob (transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory.
Tob (transducer of ErbB2) is a negative cell cycle regulator with anti-proliferative activity in the periphery. Using a behavioral screening paradigm to look for novel gene functions in the brain, we identified Tob as a brain-expressed protein involved in learning and memory. Behavioral training of fear-conditioning triggered a transient elevation of Tob protein, which preceded the formation of long-term memory. Functional perturbation of Tob by intra-CA1 infusion of antisense oligonucleotides in rats impaired spatial learning and memory in the Morris water maze and long-term memory for contextual fear conditioning, two behavioral paradigms that require the hippocampus. Furthermore, long-term potentiation was suppressed by Tob antisense infusion into the CA1 region. Together, these results indicate that the negative cell cycle regulator Tob is a multifunctional protein involved in hippocampus-dependent learning and memory.
Amino Acid Sequence↗
Blockade of cannabinoid CB1 receptors alters contextual learning and memory.
The endocannabinoid system appears to have an important role in specific aspects of learning and memory, yet there has been no systematic study of the role of cannabinoid receptors in contextual fear conditioning. The present study examined the effects of cannabinoid CB(1) receptor blockade on the acquisition, consolidation, and expression of contextual fear using the selective cannabinoid CB(1) receptor antagonist AM251. AM251 produced a decrease in the expression of contextual fear when administered prior to training, testing, or both. This effect was observed when footshock was signaled by an auditory cue but not in an unsignaled shock version of the task. Moreover, blocking cannabinoid CB(1) receptors had no effect on consolidation of contextual memory regardless of the conditioning paradigm. These data indicate that inhibition of cannabinoid CB(1) receptors produces specific deficits in processing contextual information and that the effects of CB(1) antagonists on contextual learning may differ from effects on other types of learning.
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Pentoxifylline improves learning and memory in glutamate-lesioned rats.
The present work shows the effects of pentoxifylline (ptx), on learning and memory in rats with hippocampal lesions induced by glutamate (glu). Immediately after stereotaxic procedures and in the absence or presence of glu lesions, animals were treated with ptx (50, 100, or 200 mg/kg, IP) for 6 days. Twenty-four hours after the last injection, behavior and memory tests were performed, animals were sacrificed, and hippocampi dissected for cAMP determination or histopathological studies. Results from the T-maze task showed a less learning ability in the glu-lesioned group compared to other ones. Ptx alone or associated with glu significantly improved memory acquisition, but not memory consolidation compared to glu-lesioned rats. Except for the increased locomotor activity observed in the ptx100+glu-treated group compared to saline, no other difference was detected in the open-field test. A significant impairment in avoidance performance was observed in glu-lesioned group as compared to saline or to other groups in the short as well as in the late phase of memory. All groups showed an improved water-maze performance over time with similar performances on the final day of acquisition. The impairment in memory retention observed in glu-lesioned rats was reversed by the pretreatment with ptx200. Glu induced hippocampal lesion and reduced cAMP levels. Both effects were blocked by ptx, suggesting that its action may be the result of increased cAMP levels and/or inhibition of adenosine A1 receptors.
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