Preclinical and clinical behavioral paradigms for testing drugs that affect learning and memory processes.
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Animals↗
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Rolipram and its optical isomers, phosphodiesterase 4 inhibitors, attenuated the scopolamine-induced impairments of learning and memory in rats.
We investigated the effects of (+/-)-rolipram, a phosphodiesterase (PDE) 4 inhibitor, and its isomers on scopolamine-induced deficits of learning and memory in rats using an 8-arm radial maze task and a passive avoidance task. 1) In the 8-arm radial maze task, (+/-)-rolipram (0.02-0.2 mg/kg, p.o.), (-)-rolipram (0.01-0.02 and 0.2-0.5 mg/kg, p.o.) and (+)-rolipram (20-50 mg/kg, p.o.) attenuated the scopolamine-induced deficits of spatial cognition. As for the minimum effective dose of each drug, (-)-rolipram was 2 and 2000 times as potent as (+/-)-rolipram and (+)-rolipram, respectively. (-)-Rolipram produced a biphasic dose-response and (+/-)-rolipram produced a broad dose-response. 2) (+/-)-Rolipram and its isomers also attenuated the scopolamine-induced deficits in the passive avoidance response. Also for the minimum effective dose, (-)-rolipram (0.01-0.02 mg/kg) was 2 and 200 times as potent as (+/-)-rolipram (0.02-0.1 mg/kg) and (+)-rolipram (2mg/kg). 3) The behaviorally effective doses of (+/-)-rolipram and its isomers also enhanced the oxotremorine-induced tremors in mice. Comparing these racemic isomers, (-)- and (+/-)-rolipram have more potent effects than (+)-rolipram on scopolamine-induced deficits in the 8-arm radial maze task and passive avoidance task. Especially (+/-)-rolipram has a wide dose range in these behavioral study. These results suggest that the ameliorating effects of rolipram might result from the indirect potentiation of various transmitters including cholinergic and noradrenergic systems by an increase in cAMP with the inhibition of PDE4.
Animals↗
Age and time-of-day effects on learning and memory in a non-matching-to-sample test.
This study provides further evidence that the time-of-day (TOD) when testing is conducted affects cognitive performance in old rats and, for the first time in an animal model, in young adult rats as well. Groups of young and old rats were entrained to a 12-h light-dark schedule and administered tests of learning and memory in a non-matching-to-sample (NMTS) task in a water maze. Testing was conducted at the beginning of the rats' activity cycle (AM) or at the end of the cycle (PM). In addition to age differences in performing the task, there were major findings with respect to time of testing: (1) young rats tested in the PM were better than young rats tested in the AM at learning the NMTS rule and in the delayed-NMTS (DNMTS) task; (2) old rats tested in the AM were better than PM-tested old rats on the DNMTS task, with the former attaining performance levels that approximated those of young rats; (3) the TOD effect in old rats extended to a DNMTS reversal (DNMTS-R) condition in which rats, originally tested in the AM, subsequently were administered the test in the PM, and vice versa; (4) the TOD effects in young and old rats in the DNMTS and DNMTS-R tests were strongest at relatively long delays, suggesting that hippocampal function may be particularly vulnerable to such effects; (5) there was evidence in the old rats of a relationship between diurnal drinking patterns and performance at the longest delay in the DNMTS test. These results, which parallel similar findings with human subjects, emphasize a linkage between circadian rhythmicity and cognitive performance throughout adulthood, and indicate the importance of circadian disruption in old age as a contributing factor to age differences in learning and memory performance.
Aging↗
Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice.
beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.
Age Factors↗
Oxybutynin disrupts learning and memory in the rat passive avoidance response.
BACKGROUND: oxybutynin, a drug for pollakisuria and urinary incontinence, has a potent antimuscarinic activity. This study was aimed to determine whether this drug disrupts learning and memory in rats, because antimuscarinic activity in the central nervous system is considered to cause amnesia in humans. METHODS: male Wistar rats were given oxybutynin or scopolamine as a reference drug, and subjected to the acquisition trial of step-through passive avoidance response (PAR). Twenty-four hours later the retention test for each rat was performed and the latency time in the PAR was measured. RESULTS: oral administration of oxybutynin at 30 mg/kg or higher and intraperitonial injection of scoplamine at 0.5 mg/kg caused a significant decrease in the latency time in the retention test. CONCLUSIONS: oxubutynin caused a decrease in the retention time of the PAR in a manner similar to scopolamine, indicating that oxybutynin may cause disruption of learning and memory.
Administration, Oral↗
Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats.
Sprague-Dawley rats were used to study the effects of ibotenic acid lesions of the anterior (A.Th.) and the dorsomedial (MD) thalamic nuclei on learning and memory. Memory was assessed by employing a temporal alternation task in a straight alley with varying intertrial intervals. In addition, spatial orientation and response flexibility were evaluated on a radial maze and on a spatial reversal task (SSDR). The results indicated that MD rats required more trials to learn the temporal alternation task and exhibited impaired performance compared to A.Th. and control groups at the shortest delay (15 s). In contrast, compared to the control group, A.Th. subjects which required less trials to master the task and exhibited normal performance at the 15-s delay were impaired when the intertrial interval was increased to 45 s. Whatever the lesion, no impairments were found in the SSDR or the radial maze while only MD lesions were found to result in a night hyperactivity associated with greater food and water consumptions. These findings indicate that A.Th. and MD are differentially involved in learning and memory processes. It is suggested that the MD is mostly involved in registering new information while the A.Th. plays a role in the maintenance of information over time.
Animals↗
Gender differences in memory and learning in children with insulin-dependent diabetes mellitus (IDDM) over a 4-year follow-up interval.
OBJECTIVE: To examine demographic and disease predictors of memory and learning performance for children with diabetes and controls. METHOD: Children with diabetes (N = 95) and demographically similar control children (N = 100) were administered the Rey Auditory Verbal Learning Test (RAVLT) initially and 4 years later. RESULTS: Unlike other groups, boys with diabetes did not make expected developmental gains on the learning trials of the RAVLT. Boys with diabetes showed a plateau in words learned from the primacy position, and girls with diabetes appeared to lose their relative gender advantage for verbal information. Longer disease duration predicted poorer learning over time. CONCLUSIONS: Subtle difficulties were found in learning related to longer disease duration for a predominantly middle-class group of children with diabetes over a 4-year follow-up interval. It will be important to monitor children's educational development to help avoid a cumulative toll on classroom performance.
Adolescent↗
[Progress of research on effects of ginsenoside Rg1 in promoting capability of learning and memory].
It is testified by long-standing traditional Chinese medicine clinical practice that ginseng was effective in treating dementia and promoting capability of learning and memory, for which ginsenoside Rg1 has been proved the main effective ingredient. Recently many researches have been carried out on the mechanism and action links of ginsenoside Rg1, and illustrated that it could exert the anti-dementia and nootropic effects through intervening multiple targets and links, thus to provide a theoretical basis for bettering the clinical use of ginsenoside Rg1.
Animals↗
The beta-amyloid precursor protein and its derivatives: from biology to learning and memory processes.
Intensive investigation towards the understanding of the biology and physiological functions of the beta-amyloid precursor protein (APP) have been supported since it is known that a 39-43 amino acid fragment of APP, called the beta-amyloid protein (Abeta), accumulates in the brain parenchyma to form the typical lesions associated with Alzheimer's disease (AD). It emerges from extensive data that APP and its derivatives show a wide range of contrasting physiological properties and therefore might be involved in distinct physiological functions. Abeta has been shown to disrupt neuronal activity and to demonstrate neurotoxic properties in a wide range of experimental procedures. In contrast, both in vitro and in vivo studies suggest that APP and/or its secreted forms are important factors involved in the viability, growth and morphological and functional plasticity of nerve cells. Furthermore, several recent studies suggest that APP and its derivatives have an important role in learning and memory processes. Memory impairments can be induced in animals by intracerebral treatment with Abeta. Altered expression of the APP gene in aged animals or in genetically-modified animals also leads to memory deficits. By contrast, secreted forms of APP have recently been shown to facilitate learning and memory processes in mice. These interesting findings open novel perspectives to understand the involvement of APP in the development of cognitive deficits associated with AD. In this review, we summarize the current data concerning the biology and the behavioral effects of APP and its derivatives which may be relevant to the roles of these proteins in memory and in AD pathology.
Alzheimer Disease↗
Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats.
Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca(2+) concentration ([Ca(2+)](i)) in CA1 neurons, and (5) the activity of Ca(2+)/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50mug/kg, but not of 500mug/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10(-12)M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10(-10)M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca(2+)](i) induced by 10(-10)M leptin was two times greater than that induced by 10(-12)M leptin. In addition, the facilitation (10(-12)M) and suppression (10(-10)M) of LTP by leptin was closely associated with an increase and decrease in Ca(2+)-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.
Animals↗
Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo.
Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.
Alzheimer Disease↗
Long-term flashbulb memory for learning of Princess Diana's death.
Flashbulb memories are unusually vivid recollections of the circumstances in which one first learns of a shocking and emotionally arousing event. In the present study we examined students' memories concerning the death of Diana. Princess of Wales. Participants completed a standard flashbulb memory questionnaire 1 week after her death, in which they reported the circumstances in which they first heard the news. Accuracy of these memories (defined by consistency of responses across delays) was investigated by either a single retest 18 months after the event, or two retests at 3 and 18 months after the event. Participants' descriptions remained accurate at both 3 and 18 months, and testing at 3 months had no effect on accuracy of the subsequent 18-month responses. Consistent with previous research, both emotional intensity and rehearsal were related to accuracy.
Emotions↗
Effects of prenatal zidovudine treatment on learning and memory capacities of preweanling and young adult mice.
The present study analyzed the short and long-term effects of prenatal zidovudine (AZT) exposure on learning and memory capacities of CD-1 mice. Two tasks normally used in rodents were used, namely a passive avoidance step-through task and a Morris navigation task. AZT (0, 0.4, and 0.8 mg/ml) was administered via drinking water to pregnant CD-1 females from day 10 of gestation to delivery. Data on reproductive performance, such as gestation length, litter size, and pup mortality were collected. Avoidance learning in the offspring was tested on postnatal day (PND) 15, while spatial learning performances in the Morris water maze were obtained on PND 45. Retention of the passive avoidance response was mildly impaired in the offspring exposed to the 0.8 mg/ml AZT solution, whereas spatial learning on PND 45 was unaffected.
Animals↗
Historical review of research on protein kinase C in learning and memory.
1. In 1977, the discovery of a new type of kinase was reported, which turned out to be a receptor for phorbol esters. Thereafter, several mechanisms regulating PKC activity and various PKC subtypes have been discovered. 2. A role for PKC in synaptic plasticity and information storage has been postulated in the mid-1980s. An important role for PKC has since been suggested in several learning and memory models, in which persistent changes in the activation of PKC outlasting the initial stimulating event are thought to be crucial. 3. A vast number of experiments have further substantiated a role of PKC in learning and memory using, molecular genetic, behavioral, pharmacological, electrophysiological or immunocytochemical approaches in the late 1980s and the 1990s. PKC research of the past decade or so of has shown some exciting aspects of the putative role of PKC in synaptic plasticity and information storage. 4. The authors have provided highlights (Table 1) on research on PKC.
Animals↗
Protective effect of Oren-gedoku-to (Huang-Lian-Jie-Du-Tang) against impairment of learning and memory induced by transient cerebral ischemia in mice.
The protective effect of Oren-gedoku-to (OGT; Huang-Lian-Jie-Du-Tang), a traditional Chinese medicine, against impairment of learning and memory induced by transient cerebral ischemia was investigated in mice. The cerebral ischemia caused a reduction of step-down latency and an increase of step-down errors in the passive avoidance task. Pretreatment with oral administration of OGT (2, 4 or 8 g of herbs per kg) once daily for 5 days prolonged the step-down latency significantly and decreased the step-down errors as compared with those of sham-operated controls. In the Morris water maze test, the cerebral ischemia caused an increase in the latency until finding the platform in the training trial and a decrease in the percentage of swimming in the quadrant of the former platform in the probe trial. Oren-gedoku-to (OGT; 2, 4 and 8 g/kg, p. o.) shortened the latency of escaping markedly onto the platform in the training trial and increased the percentage of crossing the former platform quadrant in the probe trial. A reference drug, tacrine (0.5 and 1.0 mg/kg, p.o.), prevented the reduction of step-down latency in the passive avoidance task and shortened the escape latency in the Morris water maze task. Furthermore, OGT significantly protected against cerebral ischemia-induced reduction in the acetylcholine (ACh) content of the cerebral cortex, hippocampus and striatum. These results indicate that the protective effects of OGT against the impairment of learning and memory induced by transient cerebral ischemia may be associated with preventing the decrease in the ACh content of the mouse brain.
Acetylcholine↗
Effects of repeated administration of (-)-nicotine on AF64A-induced learning and memory impairment in rats.
It has been reported that pretreatment with (-)-nicotine prevents glutamate- and amyloid beta protein (Abeta)-induced cytotoxicity in vitro. However, few studies on the neuroprotective effects of (-)-nicotine in vivo have been reported. We examined whether repeated administration of (-)-nicotine exhibits neuroprotective effects in AF64A-treated rats. (-)-Nicotine (0.1 and 0.2 mg/kg, s.c.) was administered once a day for 28 days. On day 14, AF64A (2.5 nmol/side) was injected bilaterally into the hippocampus. Intrahippocampal injection of AF64A showed severe impairment of learning and memory in rats in the water maze and passive avoidance tests. Repeated administration of (-)-nicotine (0.1 and 0.2 mg/kg, s.c.) did not reverse the impairment of memory induced by AF64A in the water maze test. Interestingly, the (-)-nicotine (0.1 and 0.2 mg/kg, s.c.)-treated group showed weak impairment of learning and memory after AF64A treatment compared to the (AF64A + saline)-treated group in the passive avoidance test. These results suggested that (-)-nicotine may have neuroprotective effects against the neurotoxicity induced by AF64A.
Acetylcholine↗
Lateralized learning and memory effects of angiotensin II microinjected into the rat CA1 hippocampal area.
The effects of angiotensin II (ANG II) microinjected unilaterally (left or right) and bilaterally (left and right) at a dose of 0.5 microg (0.5 nmol) into the CA1 hippocampal area of male Sprague Dowley rats on learning and memory (shuttle box) were studied. Bilateral microinjections of ANG II improved learning, i.e. increased the number of avoidances during the two training days as compared to the respective controls microinjected with saline. ANG II facilitated learning and memory, especially when microinjected into the left CA1 hippocampal area as compared to the respective controls microinjected with saline. Left-side microinjection of ANG II increased the number of avoidances on the first and second training day as compared to the right-side microinjection of ANG II. These findings suggest asymmetric effects of ANG II on cognitive processes in hippocampus.
Analysis of Variance↗
Cholinergic mechanisms in the learning and memory facilitating effect of caffeine.
Experiments are made to train rats in a maze involving memory tests 24 hours and 14 days after training. As it was established in previous studies of the authors, caffeine introduced in low doses (5 mg/kg) 5 min before training facilitates learning and memory. Applied immediately after training, caffeine even in higher doses (20 mg/kg) also improves the memory indices 24 hours and 14 days after the experiment. The anticholinergic agents spasmolytine and scopolamine in higher doses (20 and 2 mg/kg respectively) have a markedly deteriorating effect on learning, while scopolamine deteriorates retention as well. Introduced after training, both drugs deteriorate memory even in smaller doses - 2 and 0,25 mg/kg, respectively. On the background of the anticholinergic agents (especially in the higher doses), the learning and memory facilitating effects of caffeine are not manifested in any of the experimental setups (administration before and after train. The results obtained show that cholinergic mechanisms play an important role in the learning and memory facilitating effect of caffeine. A necessary condition for the manifestation of this effect is the optimum functional level of these cholinergic mechanisms in the central nervous system.
Animals↗