RELATIVE EFFECT OF OVERLEARNING ON REVERSAL AND NONREVERSAL SHIFTS WITH TWO AND FOUR SORTING CATEGORIES.
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Concept Formation↗
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Aged neuropeptide Y transgenic rats are resistant to acute stress but maintain spatial and non-spatial learning.
The behavioral phenotype of five-month-old rats overexpressing neuropeptide Y (NPY) has previously been described [Proc Natl Acad Sci USA 97 (2000) 12852]. In this transgenic rat model, there is central overexpression of prepro-NPY mRNA and NPY peptide in the hippocampus and hypothalamus and decreased Y1 binding sites within the hippocampus. These molecular and neurochemical events led to altered anxiety profile and learning abilities in NPY-overexpressing rats. In the present study, anxiety and learning/memory related behaviors were examined in one-year-old NPY-transgenic rats in order to assess any behavioral changes that may have occurred during the aging process. As observed in 5-month-old overexpressing rats, aged NPY-transgenic animals are resistant to acute physical restraint stress measured by the elevated-plus maze and demonstrate anxiolytic-like activity in the open field. However, in contrast to data in young rats, there was no significant difference between aged wildtype and NPY-transgenic animals in relation to spatial and non-spatial memory as indicated by the (allo- and ego-centric) Morris water maze and object recognition test. It would thus appear that the anxiolytic-like profile observed in young NPY-overexpressing rats is maintained in older animals providing further evidence for a role for NPY in anxious behaviors. However, the cognitive deficits observed in young rats do not appear to occur in older animals suggesting the existence of compensatory mechanisms leading to a reversal of the learning deficits noted in younger animals. These results also provide additional evidence for the mechanistic dissociation between anxiety and cognition-related behaviors modulated by NPY.
Adaptation, Psychological↗
POSITION REVERSAL VS. DIMENSION REVERSAL IN NORMAL AND RETARDED CHILDREN.
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Child↗
Mecamylamine interactions with galantamine and donepezil: effects on learning, acetylcholinesterase, and nicotinic acetylcholine receptors.
Patch-clamp recordings of single ion channel activity demonstrated that donepezil, but not galantamine, could be blocked by the nicotinic cholinergic antagonist mecamylamine, suggesting that galantamine acted at a separate (allosteric) site. The aim of this experiment was to demonstrate at a whole organism, behavioral level that galantamine, but not donepezil, could reverse mecamylamine-induced learning impairment. Forty-four young female rabbits received 15 sessions in the 750-ms delay eyeblink classical conditioning procedure, after one of five drug treatments: 0.5 mg/kg mecamylamine, 3.0 mg/kg donepezil, 0.5 mg/kg mecamylamine plus 3.0 mg/kg galantamine, 0.5 mg/kg mecamylamine plus 3.0 mg/kg donepezil, or sterile saline vehicle. An additional 24 young female rabbits were tested in the explicitly unpaired condition after treatment with the same mecamylamine plus galantamine or donepezil combinations or with vehicle. In a previous study we demonstrated that 3.0 mg/kg galantamine facilitated learning in young rabbits. Donepezil (3.0 mg/kg) did not facilitate learning in this experiment. However, both galantamine and donepezil reversed the deleterious effects of mecamylamine on learning. Significant differences in plasma and brain acetylcholinesterase levels were detected among the drug treatment groups. Fifteen daily injections did not produce statistically significant changes in nicotinic receptor binding in any of the five treatment groups. One possible interpretation of these results is that donepezil affected nicotinic acetylcholine receptors by raising the synaptic level of acetylcholine and hence, the probability of receptor activation, whereas galantamine bound to distinct allosteric sites not blocked by mecamylamine.
Acetylcholinesterase↗
Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine.
The role of the cholinergic nucleus basalis magnocellularis in spatial learning and memory was studied in the rat. Animals received bilateral injections of ibotenic acid (5 micrograms/microliters) into the region of the nucleus basalis magnocellularis. Six weeks postoperatively they were deprived of food and trained for 5 weeks in a 16-arm radial maze in which 9 of the arms were baited with food. The nucleus basalis magnocellularis-lesioned animals showed significant deficits in the acquisition of the task. Further analysis of the data indicated that this was due primarily to a deficit in reference (long-term) as opposed to working (short-term) memory. After the 5-week training period the nucleus basalis magnocellularis-lesioned animals received intraperitoneal injections of physostigmine sulphate (0.5 mg/kg) 30 min before each daily trial for 1 week. This treatment resulted in a significant improvement in the performance of the spatial memory task on all three measures. The ibotenate lesions reduced the activity of choline acetyltransferase by about 40% in the anterior cortex and by 15% in the posterior cortex. Hippocampal choline acetyltransferase activity was not affected, indicating that the septohippocampal cholinergic projection was spared by the lesions. The activity of glutamate decarboxylase was not affected in any of these regions. These results suggest that the cholinergic projections of the nucleus basalis magnocellularis play an important role in the acquisition of a spatial memory task.
Animals↗
Reversal set formation in the visually decorticate rat.
Rats given large visual cortex lesions demonstrated a simultaneous task reversal deficit previously reported to follow more extensive cortical ablation. However, no deficit appeared in an operant discrimination that deemphasized visuospatial cues, and the simultaneous task deficit vanished when translucent eye occluders were applied to eliminate spatial, but not intensity, cue use. Because the lesion subjects showed an impairment only when visuospatial cues were available and relevant to correct reversal performance, they seemed hindered by their incompetent processing of visuospatial information. The results are interpreted as support for spatial rather than learning approaches to visual cortex function.
Animals↗
Dose-related effects of metrazol on retention and EEG.
The effects of various dose levels of Metrazol on retention and electrocorticogram (ECoG) were investigated. Mice given a subconvulsive 30 mg/kg or a convulsive 50 mg/kg dose of Metrazol 15 min before reversal training in a discriminated escape learning task showed retention impairment of reversal training retention. Lower dose levels (5 or 10 mg/kg) had no effect. The 30 mg/kg dose produced asymmetrical dissociation. The convulsive dose (50 mg/kg), previously reported to result in symmetrical dissociation, produced ECoG changes that were still evident 15 min following the injection, i.e. at the time when training or testing usually took place. With lower doses (10 or 30 mg/kg), no apparent ECoG effects were observed at this interval. The implications of the findings were discussed with respect to the state-dependent hypothesis.
Animals↗
Assessment of a cholinergic contribution to chlordiazepoxide-induced deficits of place learning in the Morris water maze.
This investigation sought to characterize the interaction between benzodiazepine and cholinergic systems in place learning in the Morris water maze. In the first experiment, rats were treated with scopolamine (1 mg/kg) alone or concomitantly with one of two doses of flumazenil (15 and 30 mg/kg) or with chlordiazepoxide (5 mg/kg) alone or concomitantly with flumazenil (15 mg/kg). Chlordiazepoxide and scopolamine severely impaired place learning but not cue learning. The low dose of flumazenil completely reversed the impairment produced by chlordiazepoxide and both high and low doses of flumazenil attenuated the place learning deficit produced by scopolamine. Neither dose of flumazenil affected place learning when administered alone. In the second experiment, rats were administered chlordiazepoxide (5 mg/kg) or scopolamine (1 mg/kg) alone or concomitantly with one of four doses of physostigmine (0.05, 0.10, 0.25, and 0.5 mg/kg). Once again, both chlordiazepoxide and scopolamine impaired place but not cue learning. Physostigmine reversed the impairment produced by scopolamine in a dose-dependent manner but failed at every dose to attenuate the impairment produced by chlordiazepoxide. The higher doses of physostigmine impaired place learning when administered alone. None of the drug treatments impaired cue learning. Together, these results suggest that the scopolamine-induced impairment of place learning is due to an increase in benzodiazepine/GABA activity, and contradict the notion that benzodiazepines impair memory by cholinergic mechanisms.
Acetylcholine↗
Pseudolearners in discrimination reversal.
This research investigated the shape of the acquisition and reversal functions in retardates' discrimination learning, with safeguards against suspected artifacts in other studies. A modified Wisconsin General Test Apparatus was used with 60 retardates in a 2 X 2 factorial design. Another 11 were classified as pseudolearners. The variables were the prereversal criteria and the number of irrelevant dimensions. After meeting criterion subjects were given 30 more trials for the detection of pseudolearners, but all received reversal training. Performance was stationary in both acquisition and reversal, suggesting all-or-none learning. For learners, differences of midreversal plateaus appeared which were opposite to predictions of the Zeaman and House (1963) theory. When pseudolearners were included, however, the plateau effect partially conformed to the theory.
Adolescent↗
Influence of treatment with L-deprenyl on the structure of the cerebellar cortex of aged rats.
Treatment with L-deprenyl increases mean and maximum life span in the rat and reverses memory and learning deficits associated with old age. Since only sparse information is available concerning the influence of L-deprenyl administration on the aging brain microanatomy, we have investigated the effect of long-term treatment with L-deprenyl on the structure of the cerebellar cortex in the aged rat. The cerebellar cortex was used since it represents a useful model for assessing age-related changes in nervous system anatomy and function. Male Sprague-Dawley rats were treated from the 19th to the 24th month of age with a daily oral dose of 1.25 mg/kg or 5 mg/kg L-deprenyl. Age-matched rats were left untreated and used as a control group. Eleven-month-old untreated rats were used as an adult reference group. The density of Purkinje and granule neuron profiles as well as the intensity of Nissl's staining within the cytoplasm of Purkinje neurons were reduced in 24-month in comparison with 11-month rats. Moreover, an increased accumulation of lipofuscin was noticeable in the cytoplasm of Purkinje neurons of old rats as well as an increase in MAO-B activity in the molecular layer of the cerebellar cortex. The two doses of L-deprenyl increased the density of both Purkinje and granule neuron profiles and the intensity of Nissl's staining in the cytoplasm of Purkinje neurons and reduced lipofuscin deposition within Purkinje neurons. The lower dose of L-deprenyl caused only a slight decrease in MAO-B activity, whereas the 5-mg/kg/day dose remarkably reduced it. These results suggest that long-term treatment with L-deprenyl counters the expression of some age-related microanatomical changes in the rat cerebellar cortex. The possible independence of the effects of the compound on age-related microanatomical changes of the cerebellar cortex and on MAO-B inhibitory activity is discussed.
Aging↗
Lead neurotoxicity: from exposure to molecular effects.
The effects of lead (Pb(2+)) on human health have been recognized since antiquity. However, it was not until the 1970s that seminal epidemiological studies provided evidence on the effects of Pb(2+) intoxication on cognitive function in children. During the last two decades, advances in behavioral, cellular and molecular neuroscience have provided the necessary experimental tools to begin deciphering the many and complex effects of Pb(2+) on neuronal processes and cell types that are essential for synaptic plasticity and learning and memory in the mammalian brain. In this review, we concentrate our efforts on the effects of Pb(2+) on glutamatergic synapses and specifically on the accumulating evidence that the N-methyl-D-aspartate type of excitatory amino acid receptor (NMDAR) is a direct target for Pb(2+) effects in the brain. Our working hypothesis is that disruption of the ontogenetically defined pattern of NMDAR subunit expression and NMDAR-mediated calcium signaling in glutamatergic synapses is a principal mechanism for Pb(2+)-induced deficits in synaptic plasticity and in learning and memory documented in animal models of Pb(2+) neurotoxicity. We provide an introductory overview of the magnitude of the problem of Pb(2+) exposure to bring forth the reality that childhood Pb(2+) intoxication remains a major public health problem not only in the United States but worldwide. Finally, the latest research offers some hope that the devastating effects of childhood Pb(2+) intoxication in a child's ability to learn may be reversible if the appropriate stimulatory environment is provided.
Animals↗
PermaVision intracorneal lens for the correction of hyperopia.
PURPOSE: To evaluate the safety, predictability, and efficacy of sutureless synthetic keratophakia (SSK) with PermaVision intracorneal lens (Anamed) implantation. SETTING: Ophthalmic Hospital, Rome, Italy. METHODS: This retrospective study analyzed the refractive outcomes in 10 eyes of 6 patients who had SSK with PermaVision lens implantation for spherical hyperopia (cylinder less than 1.0 diopter [D]). Preoperatively, the mean spherical equivalent (SE) refraction was +4.33 D +/- 1.52 (SD) (range +3.00 to +6.37 D). All procedures were performed using the Hansatome microkeratome (Bausch & Lomb) with a superior hinge except in 1 eye in which the flap was cut using the Amadeus microkeratome (Allergan) with a nasal hinge. RESULTS: Six months after PermaVision lens insertion, the mean SE refraction was +0.03 +/- 0.36 D (range -0.50 to +0.38 D), the mean uncorrected visual acuity was 0.85 +/- 0.13 (range 0.63 to 1.00), and the mean best corrected visual acuity was 0.99 +/- 0.19 (range 0.63 to 1.25). No eye lost lines of visual acuity. In 1 eye, the lens was acutely decentered and had to be explanted. CONCLUSIONS: Sutureless synthetic keratophakia with the PermaVision intracorneal lens is a new technique for the correction of hyperopia. It is easy to perform as well as reversible, and the learning curve of the experienced laser in situ keratomileusis surgeon is short. The technique was safe and effective for spherical hyperopia, but longer follow-up and additional cases are needed to draw conclusions about the efficacy of the technique.
Adult↗
Human neocortical oscillations exhibit theta phase differences between encoding and retrieval.
We analyzed intracranial brain activity recorded from human participants during the performance of a working-memory task. We show that 6-13 Hz activity exhibits consistent phase across trials following experimental stimuli, and that this phase significantly differs between study and test stimuli. These findings suggest that oscillatory phase reflects the encoding-retrieval state of neural networks, supporting predictions of recent models of memory.[Hasselmo, M.E., Wyble, B.P., and Bodelon, C., 2002. A proposed function for hippocampal theta rhythm: Separate phases of encoding and retrieval enhance reversal of prior learning. Neural Comput. 14 793-817.; Judge, S.J., Hasselmo, M.E., 2004. Theta rhythmic stimulation of stratum lacunosum-moleculare in rat hippocampus contributes to associative LTP at a phase offset in stratum radiatum. J. Neurophys. 92 1516-1624.].
Adolescent↗
Hippocampal CA1 spiking during encoding and retrieval: relation to theta phase.
The hippocampal theta rhythm is a prominent oscillation in the field potential observed throughout the hippocampus as a rat investigates stimuli in the environment. A recent computational model [Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002a). A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Computation, 14, 793-817. Neuromodulation, theta rhythm and rat spatial navigation. Neural Networks, 15, 689-707] suggested that the theta rhythm allows the hippocampal formation to alternate rapidly between conditions that promote memory encoding (strong synaptic input from entorhinal cortex to areas CA3 and CA1) and conditions that promote memory retrieval (strong synaptic input from CA3 to CA1). That model predicted that the preferred theta phase of CA1 spiking should differ for information being encoded versus information being retrieved. In the present study, the spiking activity of CA1 pyramidal cells was recorded while rats performed either an odor-cued delayed nonmatch-to-sample recognition memory test or an object recognition memory task based on the animal's spontaneous preference for novelty. In the test period of both tasks, the preferred theta phase exhibited by CA1 pyramidal cells differed between moments when the rat inspected repeated (match) and non-repeated (nonmatch) items. Also in the present study, additional modeling work extended the previous model to address the mean phase of CA1 spiking associated with stimuli inducing varying levels of retrieval relative to encoding, ranging from novel nonmatch stimuli with no retrieval to highly familiar repeated stimuli with extensive retrieval. The modeling results obtained here demonstrated that the experimentally observed phase differences are consistent with different levels of CA3 synaptic input to CA1 during recognition of repeated items.
Animals↗
Acetylcholinesterase inhibitors activate septohippocampal GABAergic neurons via muscarinic but not nicotinic receptors.
Acetylcholinesterase (AChE) inhibitors, which increase synaptic levels of available acetylcholine (ACh) by preventing its degradation, are the most extensively prescribed drugs for the treatment of Alzheimer's disease. In animals, AChE inhibitors improve learning and memory, reverse scopolamine-induced amnesia, and produce hippocampal theta rhythm. The medial septum/diagonal band of Broca (MSDB), which maintains hippocampal theta rhythm and associated mnemonic functions via the septohippocampal pathway, is considered a critical locus for mediating the effects of AChE inhibitors. Using electrophysiological recordings and fluorescent labeling techniques to identify living septohippocampal neurons in rat brain slices, we report that AChE inhibitors, in the absence of exogenous ACh, produce a profound excitation in 94% of septohippocampal GABAergic neurons and an inhibition in 24% of septohippocampal cholinergic neurons. The inhibitory and excitatory effects of AChE inhibitors, presumably, occur due to accumulation of ACh that is released locally within the MSDB via axon collaterals of septohippocampal cholinergic neurons. The excitatory effects of AChE inhibitors on septohippocampal GABAergic neurons were blocked by muscarinic but not nicotinic receptor antagonists, especially by the M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine mustard, and not by M1 or M2/M4 muscarinic receptor antagonists. M3 muscarinic receptor mRNA colocalized with the calcium-binding protein, parvalbumin, a marker of septohippocampal GABAergic neurons. These findings may be useful in designing therapeutic strategies that do not depend on endogenous ACh and may therefore be effective in situations where AChE inhibitors cease to be effective, such as in progressive neurodegeneration.
Animals↗
Hormonal regulation of gene expression.
In this presentation, three facets of the topic will be addressed: signal specificity, receptor specificity and kinetics. First, both clinical and co-transfection studies show cortisol to be a potent mineralocorticoid agonist when it occupies Type I (mineralocorticoid) receptors. Cytosol Type I receptors from various tissues, and recombinant-derived human renal mineralocorticoid receptors, show equivalent affinity in vitro for aldosterone and for cortisol, which circulates at approximately 100-fold higher levels. In vivo, aldosterone specificity of Type I receptors in physiological mineralocorticoid target tissues reflects local metabolism of cortisol (but not of aldosterone), to receptor-inactive cortisone, by the microsomal enzyme 11 beta OH steroid dehydrogenase. Secondly, alpha-lactalbumin synthesis in the mid-pregnant rat mammary gland explant is stimulated by very low doses of glucocorticoids, but progressively inhibited at higher doses, and is exquisitely sensitive to progestin blockade. To reconcile these data, we have developed a model of transcriptional regulation involving multiple overlapping glucocorticoid and progesterone regulatory elements. Finally, in the Porsolt swimming rat model, the effect of adrenalectomy on a learned response is reversed by glucocorticoid administration up to an hour after the conditioning experiment.
Aldosterone↗
Stress-induced disturbances in Morris water-maze performance: interstrain variability.
Marked differences were observed across strains of mice (i.e., DBA/2J, C57BL/6J, BALB/cByJ and CD-1 mice) in acquisition, performance and reversal of a place learning response in a Morris water-maze. While DBA/2J, C57BL/6J and CD-1 mice typically learned the response readily, only 20% of BALB/cByJ mice acquired the response. Commensurate with the effects of hippocampal disturbances, the performance deficits in BALB/cByJ mice were not evident when the position of the platform in the water-maze was cued. Exposure to uncontrollable foot shock did not affect the acquisition or performance of this response in the former three strains, but provoked a modest disruption of reversal performance in DBA/2J mice and markedly impaired reversal performance in BALB/cByJ mice. It seemed, however, that the response strategies adopted in these strains could be distinguished from one another. In the reversal paradigm BALB/cByJ mice initially persisted in returning to the original training quadrant rather than to the new goal quadrant. Following 2 days of training the perseveration was no longer apparent and animals seemed to adopt a random search strategy. In contrast, DBA/2J mice, which exhibited a smaller stress-induced disturbance, did not display a perseverative response style. These data suggest that inescapable shock does not disturb response-outcome associations, but may result from the induction of a perseverative response style. However, it appears that the mechanisms responsible for an interference of performance may not be uniform across strains.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Therapeutic effect of THA on hemicholinium-3-induced learning impairment is independent of serotonergic and noradrenergic systems.
Tetrahydroaminoacridine (THA: Tacrine) has previously been shown to reverse deficits in spatial discrimination learning induced by hemicholinium-3 (HC-3). In the present experiments the effects of prior depletion of serotonin (5-HT) or noradrenaline (NA) on this reversal were examined. In the first experiment 5-HT lesions were made by injecting 5,7-DHT (2 x 50 micrograms/5 microliters) into the lateral ventricles of rats pretreated with desmethylimipramine (DMI 25 mg/kg IP). A permanently indwelling guide tube was then implanted over the right lateral ventricle. Subsequent testing under drug-free conditions, revealed no effect of the lesion on the number of trials needed to attain criterion (nine consecutive correct choices) in two-platform spatial discrimination learning in a watermaze. Using a latin square design rats were then tested for the effects of HC-3 and THA. HC-3 (5 micrograms/5 microliters ICV) or placebo (CSF) were injected 60 min before the start of a 30-trial training session. THA (4.6, 10 mg/kg SC) or placebo were then injected 15 min before training. Choice accuracy but not choice latency was significantly impaired by HC-3 and the effect was reversed by THA in both sham operated and 5-HT lesioned rats. In the second experiment two injections of DSP-4 (50 mg/kg IP) were given, following cannulation, to deplete forebrain NA. The lesion had no effect on spatial learning under drug-free conditions and failed to block the THA-induced reversal of spatial discrimination learning deficits following HC-3. These results confirm that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and that the deficit is reversed by THA.(ABSTRACT TRUNCATED AT 250 WORDS)
5,7-Dihydroxytryptamine↗