Memory-learning impairments in progressive dementia and depression.
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aFGF injection s.c. once a week into SAMP8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. learning and memory and cellular immunological functions in the aFGF group were enhanced significantly, while those of the saline group deteriorated. 1. The number of cholinergic neurons was decreased by less than 20% and ChAT activity in individual neurons in the medial septum which send monosyonaptic terminals to the hippocampus was significantly decreased in the saline group, but not so much in the aFGF group. 2. The respective densities of muscarinic and aFGF receptors, on the hippocampal neurons were significantly higher in the aFGF group than in the saline group. 3. The LTP in hippocampal slice preparations was significantly facilitated in the aFGF group, but not in the saline group. 4. The DTH, (T cell immune response) measured at the end of the 2nd and 7th months were reduced in the 7th month as compared with the 2nd month in the saline group, but aFGF group protected against this reduction. 5. These results show that aFGF provides protection against impairment of not only learning and memory but also the DTH immunoreactivity in SAMP8.
Treatment of adult rats with intracerebroventricularly (i.c.v.) injected streptozotocin (STZ) may provide a relevant animal model of chronic neuronal dysfunction that is characterized by a decrease in both the neuronal metabolism of glucose and the formation of energy. The present study was designed to evaluate whether or not rats treated with triplicate i.c.v. STZ injection would show long-term effects in learning and memory behavior as measured by means of a holeboard test, closed field activity, and passive avoidance behavior over a period of 6 weeks. For this purpose, animals with good performance were discriminated from those with poor performance by the holeboard test before i.c.v. administration of STZ. After a 1-week training period with the holeboard all animals improved their abilities in learning and memory, and the improvement was maintained over the investigation period of 6 weeks in the control group. After i.c.v. STZ working memory (WM), reference memory (RM), as well passive avoidance (PA) behavior decreased, deteriorating progressively during the investigation period. The latter were accompanied by a permanent deficit in cerebral energy metabolism. The ongoing deterioration in behavior and the sustained deficit in cerebral energy metabolism occurring after a triplicate i.c.v. STZ administration lead us to assume that this animal model may be appropriate for the investigation of mechanisms characteristic for sporadic Alzheimer disease. In this context, the effect of Estradiol-17beta (E2) on behavior and energy metabolism was studied. We found that E2 slowed down the i.c.v. STZ-induced deterioration in memory functions, partially compensated the learning deficit, and improved the disturbances in cerebral energy metabolism to the extent that it was almost completely normal again. These findings underscore the beneficial effect of E2 in dementia disorders.
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Zinc-enriched (ZEN) neurons are distributed widely throughout the brain and spinal cord. Synaptic vesicle zinc in these neurons is thought to function as a neuromodulator upon its release into the synaptic cleft. Consistent with this possibility, zinc or zinc chelators can alter spatial learning, working memory, and nociception in rodents. Here we use zinc transporter-3 (ZnT3) knockout mice, which are depleted of synaptic vesicle zinc, to assess the consequences of removing this potential neuromodulator on the behavior of adult mice. ZnT3 knockout mice performed equally as well as wild-type mice in the rotarod, pole, and cagetop tests of motor coordination. They exhibited normal thermal nociception in the hot-plate and tail-flick tests, and had similar olfactory, auditory and sensorimotor gating capabilities as wild-type mice. ZnT3 knockout mice behaved similarly as wild-type mice in the open field test and in the elevated plus maze test of anxiety. They exhibited normal learning and memory in the passive avoidance, Morris water maze, and fear conditioning tasks, and normal working and reference memory in a water version of the radial arm maze. We conclude that synaptic vesicle zinc is not essential for mice to be able to perform these tasks, despite the abundance of ZEN neurons in the relevant regions of the CNS. Either the neuromodulatory effects of zinc are not relevant for the tasks tested here, or mice are able to compensate easily for the absence of synaptic vesicle zinc.
Studies have been made on the effect of an immunostimulator - the complete Freund's adjuvant - upon the learning ability in Wistar rats for visual discrimination using food-obtaining and avoidance of the electric shock techniques. Injection of the adjuvant significantly increases learning ability provided negative reinforcement technique is used, but inhibits the former under the conditions of positive reinforcement. Analysis of the extinction of the conditioned reflexes yielded similar results. Possible relation of immunogenesis to the formation of memory is discussed.
Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with free radical generation in the brain of rats. Melatonin is a potent free radical scavenger and antioxidant. In the present study, the effect of melatonin was investigated against ICV STZ induced cognitive impairment and oxidative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The rats were treated with STZ twice, on days 1 and 3. The learning and memory behavior was assessed using passive avoidance paradigms, elevated plus maze and the closed field activity while the parameters of oxidative stress assessed were malondialdehyde (MDA) and glutathione. The rats were treated chronically with melatonin for 21 days starting from day 1 of STZ injection. The learning and memory behavior was evaluated on days 17, 18 and 19 and the rats were sacrificed on day 21 for estimation of MDA and glutathione. The rats treated with melatonin showed significantly less cognitive impairment. There was also insignificant increase in brain MDA and decrease in glutathione levels in melatonin-treated ICV STZ rats as compared to the vehicle-treated ICV STZ animals. The study demonstrates the effectiveness of melatonin in preventing the cognitive deficits as well as the oxidative stress caused by ICV STZ in rats and suggests it's potential in age and age-related neurodegenerative disorders where oxidative stress and cognitive impairment are involved.
Marijuana and its psychoactive constituents induce a multitude of effects on brain function. These include deficits in memory formation, but care needs to be exercised since many human studies are flawed by multiple drug abuse, small sample sizes, sample selection and sensitivity of psychological tests for subtle differences. The most robust finding with respect to memory is a deficit in working and short-term memory. This requires intact hippocampus and prefrontal cortex, two brain regions richly expressing CB1 receptors. Animal studies, which enable a more controlled drug regime and more constant behavioural testing, have confirmed human results and suggest, with respect to hippocampus, that exogenous cannabinoid treatment selectively affects encoding processes. This may be different in other brain areas, for instance the amygdala, where a predominant involvement in memory consolidation and forgetting has been firmly established. While cannabinoid receptor agonists impair memory formation, antagonists reverse these deficits or act as memory enhancers. These results are in good agreement with data obtained from electrophysiological recordings, which reveal reduction in neural plasticity following cannabinoid treatment, and increased plasticity following antagonist exposure. The mixed receptor properties of the pharmacological tool, however, make it difficult to define the exact role of any CB1 receptor population in memory processes with any certainty. This makes it all the more important that behavioural studies use selective administration of drugs to specific brain areas, rather than global administration to whole animals. The emerging role of the endogenous cannabinoid system in the hippocampus may be to facilitate the induction of long-term potentiation/the encoding of information. Administration of exogenous selective CB1 agonists may therefore disrupt hippocampus-dependent learning and memory by 'increasing the noise', rather than 'decreasing the signal' at potentiated inputs.
SAMP8 (P8) mice are characterized by impaired learning and memory relatively early in their life, while CD-1 mice show impairment later in life. A series of paternal backcross strains were developed from a CD-1 dame and P8 sire. Siblings from each backcross were bred to establish strains with 50% to 97% P8 genes. F4 mice, 4 or 12 mo of age, were trained to avoid foot shock in a T-maze with retention tested 1 wk later. After testing, brain sections were examined for lipofuscin autofluorescence. At 4 mo of age, all strains, including the CD-1 and P8 strains, showed no significant differences in learning, retention or lipofuscin deposits. At 12 mo of age, groups with 94%, 97% P8 genes or P8 mice (100%) required significantly more trials to learn the task or relearn the task 1 wk later than groups with 88% or fewer P8 genes. Lipofuscin deposits increased in the hippocampus as the percentage of P8 genes increased suggesting that many genes control aging of the brain. However, the sudden appearance of impaired learning in the 94% strain suggests that the mechanism(s) responsible for the impairment involves a few recessive genes and are independent of the mechanisms controlling the general aging of the brain.
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The present investigation has shown that Ginseng root saponins (ig, 50mg/kg x 7d) facilitate the learning and memory of normal male Wistar rats, while the effect of Ginseng stem-leaf saponins (ig, 50mg/kg x 7d) on antielectrconvulsive shock-induced impairment of memory consolidation in rats is more intensive than that of root saponins. Both Ginseng root and stem-leaf saponins can significantly raise the levels of biogenic monoamines in normal rat's brain.
Human and non-human animals acquire information about the world through the process of learning, and store that information as memory. Yet central as the storage process is to adaptive behaviour, progress in understanding its neural bases has been slow and only recently efforts have shown clear signs of being successful. The knowledge that comes from this progress strongly suggests that different kinds of learning involve different neural circuits and accordingly involve different memory systems. Indeed, it is becoming increasingly clear that multiple memory systems may be a fundamental part of the design of the vertebrate brain. It has long been supposed that learning leads to the formation, or to the strengthening of particular pathways in the brain. Once formed, or strengthened in this way a pathway was viewed as a 'trace' or 'engram' 'representing' the particular experience or relationship which had been learned. There is substantial evidence that neural pathways, especially synaptic connectivity, can be modified by experience-as by rearing rats in an 'enriched' environment with other rats rather than rearing them in isolation--as well as by modifying the diet or by depriving young rats of their thyroid gland. This evidence demonstrates that the central nervous system is plastic, but provides no hint that such plasticity is involved in learning. The evidence that synaptic plasticity is indeed involved in learning and memory is relatively recent.
Twenty-four healthy male and female subjects, who participated in this randomized, double-blind, crossover study, received single nighttime doses of zaleplon 10 mg (therapeutic dose), zaleplon 20 mg, zolpidem 10 mg (therapeutic dose), zolpidem 20 mg, triazolam 0.25 mg (positive control), and placebo. Subjective behavioral ratings and psychomotor tests were completed before and 1.25 and 8.25 hours after administration of the study drug. The Immediate and Delayed Word Recall tests and the Digit Span Test were used to assess memory. The Digit-Symbol Substitution Test, Paired Associates Learning Test, and Divided Attention Test were used to assess other cognitive skills. Zaleplon 10 mg did not produce any significant changes in memory or learning compared with placebo. All other active treatments, including zolpidem 10 mg, caused psychomotor impairment at the 1.25-hour test battery. Zolpidem 20 mg (twice the therapeutic dose) produced more psychomotor impairment at the 1.25-hour assessment than did any of the other active treatments, including zaleplon 20 mg. At the 8.25-hour time point, test scores for subjects who received zaleplon 10 mg and 20 mg did not differ from the test scores for those who received placebo. However, cognitive impairment persisted up to the 8.25-hour observation for subjects who were administered triazolam 0.25 mg and zolpidem 20 mg. Adverse events associated with the use of zaleplon were transient and mild-to-moderate in severity. Overall, this study shows that zaleplon is a safe hypnotic that does not affect memory, learning, or psychomotor skills associated with vigilance.
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Memory, the ability to store and retrieve information, is essential for learning in children. Modern neurobiology research is revealing some of the fundamental steps that encode memories within networks of neuronal synaptic connections in the brain. Somewhat different networks store verbal declarative memories and habit or procedural memories. Several biochemical steps convert short-term memories into permanent memories. These changes include activation of neurotransmitter and growth factor receptors, intracellular protein kinases, and nuclear transcription factors that stimulate gene expression of memory proteins. The proteins strengthen synaptic connections and stabilize long-term memories. Genetic defects in those pathways appear to be responsible for several human retardation and learning disability syndromes, including Coffin-Lowry syndrome and neurofibromatosis.
A range of neuropsychological deficits have been identified in individuals with obstructive sleep apnea syndrome (OSAS) and have been related to disruptions in function of the frontal cortex of the brain. We hypothesized that impairments in the use of strategic, frontally-mediated processes that facilitate learning and memory would be associated with deficits in the long-term episodic memory of verbal material (i.e., word lists). We evaluated 28 adults with OSAS and 24 controls (ranging from 28 to 60 years of age) using the California Verbal Learning Test. General executive abilities were assessed using the Wisconsin Card Sorting Test, Letter fluency, and Category fluency. Individuals with OSAS exhibited poorer recall across learning trials, less efficient use of semantic clustering, and poorer use of semantic cues. Retention of previously encoded information and recognition, however, were intact. With the exception of letter fluency, deficits were not observed in general executive control. Results are discussed within the context of disruptions in the interactions between long-term memory and executive abilities that are subserved by frontal and distal brain regions.