Reversed Memory Impairment Research Articles

Exposure to hypomagnetic field space for multiple generations causes amnesia in Drosophila melanogaster

This is the introduction of Drosophila into the study of learning and memory affected by removal of the geomagnetic field (GMF) for successive generations. Using the operant visual learning/memory paradigm at a flight simulator, the present study revealed that wild-type flies raised in a hypomagnetic field environment continuously for 10 successive generations were gradually impaired in visual conditioning learning and memory formation and finally the 10th generation flies became morphs of nonlearners and completely amnesiac. The control experiments show that the impairment could not be ascribed to any apparent sensorimotor problems in Drosophila. The reverse shift from hypomagnetic field (HMF) to natural GMF restored the GMF-free induced amnesia fully after six consecutive generations. Thus, our findings demonstrate conclusively that some serious, but reversible learning and memory impairment may occur for living organisms in a prolonged separation from GMF over many consecutive generations. And Drosophila has the potential to develop into a new model organism for the study of the neurobiology of magnetism for multiple generations.

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice.

Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Mechanisms of HIV type 1-induced cognitive impairment: evidence for hippocampal cholinergic involvement with overstimulation of the VIPergic system by the viral coat protein core.

HIV-1 is associated with a neuroAIDS syndrome that includes cognitive impairment. Several components of HIV-1 are capable of affecting cognition, but which of these is the major mediator is unknown. We injected into the lateral cerebral ventricle of mice HIV-1 pseudoviruses expressing the full viral genome with or without the viral coat glycoproteins, gp120/gp41. Only virus possessing gp120/gp41 induced defects in memory as assessed in an active avoidance T-maze footshock paradigm. By itself, gp120 also induced impairments that were reversed by hippocampal cholinergic stimulation. Paradoxically, low doses of gp120 could improve memory. Such low-dose, paradoxic improvement is a characteristic of substances that impair memory by overstimulating pathways that normally sustain memory. Consistent with this, a low, but not a high, dose of gp120 reversed memory impairment induced by overstimulation of the VIPergic system, a memory-sustaining pathway. Further characterization showed that two strains of gp120 (SF and MN) were equally effective at improving memory and that, unlike other actions of gp120, glycation was not required. We conclude that (1) the predominant cognitive-impairing component of HIV-1 is its viral coat glycoproteins, (2) gp120 impairs memory by overstimulating pathways that normally sustain memory, (3) the cognitive effect of gp120 is mediated by its protein core, and (4) gp120 likely impairs memory by affecting the cholinergic/VIPergic system.

Age‐related decline in neurogenesis: Old cells or old environment?

Age‐related decline in neurogenesis: Old cells or old environment?

Involvement of κ-opioid and σ receptors in short-term memory in mice

κ-Opioid receptor agonists, trans-(±)-3,4-dichloro- N-methyl- N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate (U-50,488H) and dynorphin A-(1–13), improve impairments of learning and memory in mice and rats. σ Receptor agonists, (+)- N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), also reverse learning and memory impairment in various animal models. However, the mechanisms underlying these effects are not well understood. In the present study, the effect of coadministration of U-50,488H and (+)-SKF10,047 on scopolamine-induced memory impairment was investigated in mice using spontaneous alternation performance in a Y-maze. U-50,488H (0.21–2.15 μmol/kg, subcutaneously (s.c.)) and (+)-SKF10,047 (0.10–1.02 μmol/kg, s.c.) 25 min before the Y-maze test improved the impairment of spontaneous alternation induced by scopolamine (1.65 μmol/kg, s.c.). When U-50,488H and (+)-SKF10,047 were coadministered, no additive effect was observed. Furthermore, the ameliorating effects of U-50,488H and (+)-SKF10,047 were not antagonized by a selective σ receptor antagonist, N, N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride (NE-100), and a selective κ-opioid receptor antagonist, nor-binaltorphimine, respectively. These results suggest that the mechanisms underlying the ameliorating effects on memory impairment are independent and no direct modulation exists in κ-opioid and σ receptors-mediated mechanisms.

Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model.

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.

Opioid blockade improves human recognition memory following physiological arousal

Rationale: States of heightened emotion and arousal, such as those that may occur during crimes or traumatic accidents, can impair human memory. Animal models suggest that such memory alterations may be mediated by opioid neuropeptides. In some experimental paradigms, opioid blockade reverses memory impairments related to arousal. Objectives: The present study evaluated the hypothesis that, under conditions of heightened arousal, opioid blockade would enhance memory in human subjects. Methods: Memory for story information was evaluated among subjects randomized to one of four study groups (two orthogonal study conditions): (1) no arousal+no opioid blockade, (2) no arousal+opioid blockade, (3) arousal+no opioid blockade, and (4) arousal+opioid blockade. Both free recall and recognition memory were assessed. Opioid receptor blockade was achieved using a single oral dose of naltrexone. Results: With heightened arousal, subjects receiving naltrexone performed better than those receiving placebo on tests of total and incidental recognition memory. In contrast, with emotionally neutral stimuli, naltrexone subjects performed worse than placebo subjects. Conclusions: These findings demonstrate that opioid peptides mediate alterations in specific aspects of human memory during heightened emotional states, and help to explain why memories may be selectively deficient under conditions of stress.

Conditionally immortal neuroepithelial stem cell grafts reverse age-associated memory impairments in rats

In order to investigate the effects of stem cell grafts on water maze deficits in aged (22-month-old) rats, three groups of aged rats, assigned by pre-training latency scores to unimpaired, impaired control and impaired grafted groups, were compared with young (five-month-old) controls, six to eight weeks after implantation of cells from the conditionally immortal Maudsley hippocampal stem cell line, clone 36 (MHP36 stem cell line), in the cortex, striatum and hippocampus. Grafted rats were substantially superior to their matched impaired aged controls, and learned to find the platform as rapidly as unimpaired aged rats, although young controls were more efficient than all aged groups in several measures of spatial search during training. On the probe trial, however, aged rats with grafts showed significantly better recall of the precise position of the platform than any other group, including young controls, possibly indicating some perseveration. A further comparison found that groups of unimpaired and moderately impaired aged rats showed far less improvement from water maze pre-training to acquisition phases than young controls, indicative of progressive deficits over time. Histological investigation showed that β-galactosidase-positive MHP36 cells migrated widely from the implantation sites to infiltrate the striatal matrix, all hippocampal fields and areas of the cortex. Grafted cells showed both astrocytic and neuronal morphologies, with cells of pyramidal and granular appearance in appropriate hippocampal strata. Taken together, these results indicate that neuroepithelial stem cell grafts extensively colonize the aged rat brain and substantially reverse progressive cognitive decline associated with ageing.

Course of objective memory impairment in non-demented subjects attending a memory clinic and predictors of outcome.

The aim of the study was to investigate the course of objective memory impairment in non-demented subjects who attended a memory clinic and to test predictors of outcome. Non-demented subjects (N=74) were included when they were older than 40 years and had a baseline score on the delayed recall of a word learning test below the tenth percentile. Subjects with memory impairment due to known somatic or neurological causes were excluded. The subjects were reassessed after 2 and 5 years. At the 5-year follow-up, 42% of the subjects had no memory impairment, 19% of the subjects had memory impairment without dementia, and 39% of the subjects had Alzheimer type dementia (AD). Predictors at baseline of reversible memory impairment in a multivariate analysis were age, scores on the MMSE and delayed recall, and the degree of functional impairment. Predictors at baseline of AD in a multivariate analysis were age and the score on the MMSE. The apolipoprotein E genotype and the presence of depression at baseline were not predictors of outcome. The positive predictive value was 72% for reversible memory impairment and 81% for AD. Memory impairment is often reversible and therefore its presence alone is not sufficient to consider subjects as preclinically demented. Predictive accuracy can be increased by including simple measures such as age, the scores on the MMSE and delayed recall, and the degree of functional impairment.

Dissociative detachment and memory impairment: Reversible amnesia or encoding failure?

The authors propose that clinicians endeavor to differentiate between reversible and irreversible memory failures in patients with dissociative symptoms who report “memory gaps” and “lost time”. The classic dissociative disorders, such as dissociative amnesia and dissociative identity disorder, entail reversible memory failures associated with encoding experience in altered states. The authors propose another realm of memory failures associated with severe dissociative detachment that may preclude the level of encoding of ongoing experience needed to support durable autobiographical memories. They describe how dissociative detachment may be intertwined with neurobiological factors that impair memory, and they spell out the significance of distinguishing reversible and irreversible memory impairment for diagnosis, patient education, psychotherapy, and research.

Nicotinic agonist and antagonist effects on memory

Nicotine has been found by a variety of investigators to improve memory in rats, monkeys, and humans. Recent studies have helped to determine the behavioral and pharmacological nature of critical nicotine effects on memory function. Other nicotinic agonists, including ABT-418, GTS-21, or lobeline, can also significantly improve memory performance. Conversely, nicotinic antagonists, such as mecamylamine, can impair memory. Nicotine can reverse memory impairments caused by aging or by lesions to hippocampal connections. The observation that nicotine improves memory performance when it is administered by chronic infusion is potentially important for the development of treatments of cognitive impairment. Nicotinic agonists show promise for the development of novel treatments for cognitive disorders. Some characteristics of nicotine, nicotinic receptors, and the nature of the disorders to be treated, however, present challenges to the development of nicotinic-based treatments. Drug Dev. Res. 38:188–195 © 1996 Wiley-Liss, Inc.

Inhibitory avoidance impairments induced by intra-amygdala propranolol are reversed by glutamate but not glucose.

Both systemic and central injections of glucose can enhance memory. For example, glucose reverses impairments on inhibitory avoidance resulting from intra-amygdala injections of morphine. The present experiment investigated the ability of glucose to reverse memory impairments resulting from intra-amygdala injections of propranolol, a beta-noradrenergic antagonist. Pretraining administration of 10 microg propranolol significantly reduced inhibitory avoidance retention latencies but had no effect on performance in a spontaneous alternation task. Coadministration of glucose into the amygdala at 3 doses (1.5, 3.0, and 6.0 microg) did not reverse the propranolol-induced inhibitory avoidance deficits. However, coadministration of 2.5 microg of glutamate with the propranolol did reverse these deficits. The ability of glucose to reverse impairments following intra-amygdala injections of morphine but not propranolol may reflect the neurotransmitter system or systems through which glucose exerts its effects.

Inhibitory avoidance impairments induced by intra-amygdala propranolol are reversed by glutamate but not glucose.'

Both systemic and central injections of glucose can enhance memory. For example, glucose reverses impairments on inhibitory avoidance resulting from intra-amygdala injections of morphine. The present experiment investigated the ability of glucose to reverse memory impairments resulting from intra-amygdala injections of propranolol, a beta-noradrenergic antagonist. Pretraining administration of 10 microg propranolol significantly reduced inhibitory avoidance retention latencies but had no effect on performance in a spontaneous alternation task. Coadministration of glucose into the amygdala at 3 doses (1.5, 3.0, and 6.0 microg) did not reverse the propranolol-induced inhibitory avoidance deficits. However, coadministration of 2.5 microg of glutamate with the propranolol did reverse these deficits. The ability of glucose to reverse impairments following intra-amygdala injections of morphine but not propranolol may reflect the neurotransmitter system or systems through which glucose exerts its effects.

Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil

The effects of flumazenil, a benzodiazepine receptor antagonist, on triazolam- and zolpidem-induced memory impairment were investigated. Sixty subjects received oral triazolam 0.5 mg, zolpidem 20.0 mg, or placebo at 10 a.m. (n = 20 per drug). Ninety minutes later, half of the subjects (n = 10) in each oral drug group were administered flumazenil 1.0 mg, while the remaining half received placebo (normal saline), through indwelling venous catheters. Learning/memory tests (including Simulated Escape, Restricted Reminding, Paired-Associates, and Repeated Acquisition) were administered at that time, and at 1.5-h intervals over the next 6 h. Triazolam/placebo and zolpidem/placebo drug combinations impaired memory on all tests (all Ps < 0.05). However, the triazolam/flumazenil and zolpidem/flumazenil groups showed no evidence of impairment during any test session. These results demonstrate that flumazenil 1.0 mg rapidly and lastingly reverses memory impairment caused by agonists of the benzodiazepine receptor. Furthermore, nonsignificant trends suggested that performance of the placebo/flumazenil group was consistently better than that of the placebo/placebo group, denoting a possible role of endogenous benzodiazepine agonists in natural sleep/wake processes.

Aniracetam reverses memory impairment in rats

The pyrrolidinone derivative aniracetam given orally immediately after acquisition of an inhibitory avoidance response reproducibly ameliorated scopolamine-induced amnesia in female rats in an extensive series of test sessions conducted over a 1-year period. In a dose-response experiment it was demonstrated that 50 mg kg −1 was the lowest oral dose of aniracetam to significantly ameliorate scopolamine-induced amnesia. Combined results from these numerous test sessions demonstrated that 50 mg kg' aniracetam administered to scopolamine-treated rats resulted in 53% of the animals exhibiting correct passive avoidance responding in the retention evaluation versus 9% of the scopolamine-treated rats given vehicle (in comparison, 64% of the rats injected with vehicle rather than scopolamine in this experimental situation exhibited correct responding in the retention test). There was minimal variation in this pattern of results over the successive 1-month blocks constituting the complete experimental period. Thus, the nootropic compound aniracetam replicably exhibited memory enhancing effects in this animal model of reduced cholinergic function.

Partial M1 but not M3 muscarinic agonists reverse scopolamine-induced memory impairment in rats : J. Blosser, D.V. Widzowski, P. Bialobok, K. Kucera, S. Sitar, S. McCreedy, A. Machulskis, G. Mullen, E. Wu, R. Murray, J. Gordon. Depts. Biology and Chemistry, Fisons Pharmaceuticals, Rochester, NY 14623

Partial M1 but not M3 muscarinic agonists reverse scopolamine-induced memory impairment in rats : J. Blosser, D.V. Widzowski, P. Bialobok, K. Kucera, S. Sitar, S. McCreedy, A. Machulskis, G. Mullen, E. Wu, R. Murray, J. Gordon. Depts. Biology and Chemistry, Fisons Pharmaceuticals, Rochester, NY 14623

State dependent and/or direct memory retrieval by morphine in mice

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.