Ion involvement in memory formation: the potential role of astrocytes.
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Biomedical subjects
M E Gibbs
Publications and source records attributed to M E Gibbs.
Behavioral and pharmacological unravelling of memory formation.
A brief description of how a passive avoidance task, using one day-old chicks, has been used to test for memory formation is given. Chicks will peck at bright shiny beads but if a bead is painted with a bitter tasting chemical, after tasting it once, the chicks will refuse to peck on subsequent presentation of that bead. The chick associates the bitter taste with the particular characteristics of the bead. These experiments have led to the development of a model of memory. The basic model is made of short-term memory, which lasts 10 minutes, intermediate memory that has two phases A and B and lasts for 30 minutes and finally long-term memory. The use of certain classes of drugs to prolong, delay or abolish the various phases is described and then it is shown that many hormones and certain behavioral manipulations can modulate memory. Experiments are described which examine not only the temporal storage but delineate spatial storage within the brain. A brief discussion of current methodologies for looking at the exact spatial location of memory traces is given. The article concludes by emphasizing how even minor differences in protocols across laboratories can have large effects on the memory traces and stresses the significance of the narrow temporal windows, around the training trial, when memory can be modulated.
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Molecular mechanisms of memory formation.
Studies with neonate chicks, trained on a passive avoidance task, suggest that at least two shorter-term memory stages precede long-term, protein synthesis-dependent memory consolidation. Posttetanic neuronal hyperpolarization arising from two distinct mechanisms is postulated to underlie formation of these two early memory stages. Maintenance of the second of these stages may involve a prolonged period of hyperpolarization brought about by phosphorylation of particular proteins. A triggering mechanism for long-term consolidation is postulated to occur at a specific time during the second stage, and may involve reinforcement-contingent release of neuronal noradrenaline stimulating cAMP-dependent intracellular processes. The possibility that astroglia may have a critical role to play in these early stages of memory processing is raised.
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Brain metabolic activity associated with long-term memory consolidation.
The use of day-old chickens trained on a single-trial passive avoidance task provides a useful paradigm for investigations into cellular mechanisms underlying memory formation. Pharmacological intervention studies indicate that there are three temporally identifiable stages of memory processing leading to the consolidation of information for this task. These stages, designated as short-term (STM; up to 15 min), intermediate-term (ITM; 15-55 min), and long-term (LTM; more than 55 min) memory, have been found to be sequentially dependent (Ng and Gibbs, 1989). In addition, ITM appears to consist of two physiologically distinguishable phases, A and B. Evidence in this laboratory suggests that the crossover between these ITM phases (at 30 min after training) represents a critical time-point for the triggering of LTM.
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Possible noradrenergic involvement in training stimulus intensity.
Day-old chicks trained on a single trial passive discrimination avoidance task using a concentrated chemical aversant, methyl anthranilate (MeA), have been shown to exhibit three stages of memory processing: short, intermediate and long term. A similar learning task with the aversant diluted to 20% in ethanol leads to short- and intermediate-term memory only, but not to long-term memory. The emergence of long-term memory has been shown to be associated with the production of a nonenergy-dependent phase of the intermediate memory stage. Subcutaneous administration of propranolol proved capable of inhibiting this nonenergy-dependent phase of memory under a number of training regimes: strongly reinforced training, and with weakly reinforced training presented twice or coupled with a selected dose of the stress-related hormone ACTH. This study supports the notion that there is a phase of memory that occurs prior to the protein synthesis-dependent phase of memory which is susceptible to interference by drugs affecting noradrenergic processes and which may be associated with the intensity of the training stimulus.
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Forebrain noradrenaline concentration following weakly reinforced training.
Day-old chicks trained on a single-trial discriminated passive avoidance task using a concentrated taste aversant, methyl anthranilate, have been shown to exhibit three stages of memory processing; short-, intermediate-, and long-term memory. If the aversant is diluted to 20% v/v methyl anthranilate in absolute ethanol, only the short-term and some of the intermediate stage are observed. In this study we investigated the whole forebrain levels of noradrenaline in response to differing intensities of the training experience. The results show a profound difference in the level of whole forebrain NA at all training-sacrifice intervals for the trained as compared to the untrained controls, except at 15- and 20-minute posttraining, when a substantial reduction in the level of NA was achieved under all training conditions. Furthermore, subjects which received treatments which resulted in the emergence of behavioural evidence of long-term memory tended to have higher levels of whole-forebrain NA at 30 minutes after initial training. This is the time when we have postulated that triggering of protein synthesis associated with long-term memory formation takes place.
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Memory consolidation of weak training experiences by hormonal treatments.
Day-old chicks trained on a single-trial passive discrimination avoidance task using a concentrated chemical aversant, methyl anthranilate (MeA), have been shown to exhibit three stages of memory processing; short-, intermediate- and long-term. A similar learning task with the aversant diluted to 20% in ethanol leads to short-and intermediate-term memory, but no long-term memory. Subcutaneous administration of selected doses of the stress-related hormones, noradrenaline, ACTH and vasopressin in close temporal proximity to the training trial, produced long-term memory in chicks trained on the weakly reinforced task, mimicking the outcome of strongly reinforced learning and of retraining with the weakly reinforced task reported previously. These effects are shown to be associated with the production of a nonenergy-dependent phase of the intermediate memory stage, postulated to be necessary for long-term memory consolidation.
2,4-Dinitrophenol↗
Memory formation processes in weakly reinforced learning.
Day-old chicks trained on a single-trail passive avoidance learning task, with varying concentrations of the aversive stimulus (methyl anthranilate), truncated retention functions for low concentrations. The retention function for a 20% v/v dilution of methyl anthranilate in absolute ethanol yielded high retention levels until approximately 40 to 45 minutes following learning. This retention function appears to consist of only the short-term and intermediate (phase A) memory stages of Gibbs and Ng's three-stage model of memory formation, with the short-term stage susceptible to inhibition by monosodium glutamate, and the intermediate stage by ouabain and dinitrophenol. The results suggest that processing of memory into the relatively permanent long-term stage may depend on the strength of the reinforcer in aversive learning.
2,4-Dinitrophenol↗
Effect of retraining trials on memory consolidation in weakly reinforced learning.
Day-old chicks given a single weakly reinforced (20% v/v methyl anthranilate in absolute ethanol) passive avoidance learning trial showed no evidence of long-term memory. A second learning trial given at 15 minutes after initial resulted in consolidation of the learning experience into long-term memory. The retention function resulting from two learning trials is similar to that observed with a single strongly reinforced learning trial, and consists of the stages postulated by Gibbs and Ng. With a dilution of 10% methyl anthranilate in ethanol, four training trials were needed to yield unequivocal evidence of long-term memory consolidation.
2,4-Dinitrophenol↗
Inhibition of memory in the chick using a monoclonal anti-Thy-1 antibody.
One-day-old chicks trained on a single trial passive avoidance task were administered a monoclonal anti-chick Thy-1 antibody, either intracranially or subcutaneously, at various times before and after learning and retention tested at various times post-learning. This procedure resulted in profound amnesia when anti-Thy-1 antibody was administered immediately before learning (5 min) in the case of the subcutaneous injections or 5 min before until 5 min after the learning process with intracranial injections. Antibody administered at other times, either before or after learning had little or no effect on retention. Retention levels were normal until 50 min post-learning, then declined sharply and remained at control levels for the duration of the test period. Chicks injected with anti-chick cerebellum or anti-rat Thy-1 antibodies showed no evidence of amnesia for the concentration of the antibodies used.
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Effect of excess intracranial amino acids on memory: a behavioural survey.
Nineteen naturally occurring amino acids were administered intracranially to day-old chicks at various times before and after a single trial passive avoidance learning task. The results suggest a consistent and simple difference between essential and non-essential amino acids. Except for arginine, phenylalanine, tryptophan and tyrosine, the essential amino acids had no effect on memory formation when administered 5 min before or immediately after learning. However, arginine, phenylalanine and tryptophan yielded amnesia after 60 min following learning, when given between 5 min before and 2.5 min after learning. In the case of tryptophan, amnesia was only temporary, lasting from 60 min to 240 min post-learning. All non-essential amino acids, when administered between 5 min before and 5 min after learning yielded amnesia by 60 min post-learning, with no evidence of recovery by 24 hr post-learning. Alanine-, asparagine-, cysteine- and glutamate-treated chicks, however, showed signs of generalized avoidance shortly after administration. The retention time courses after injection of glutamine, proline, serine and taurine were similar to that obtained with the non-metabolizable amino acid alpha-amino-isobutyric acid, and amnesia arising from administration of these amino acids was counteracted by diphenylhydantoin, as was amnesia induced by phenylalanine and tyrosine. The retention function obtained with tryptophan was similar to that obtained with 5-hydroxytryptamine, and DPH had no effect on the action of tryptophan or the actions of arginine, alanine or asparagine. The findings were interpreted in the context of a three-stage model of memory formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Effect of testosterone on intermediate memory in day-old chicks.
Day-old chicks trained on a single trial passive avoidance discrimination task show three well-defined behavioural stages in memory formation: short-term, intermediate and long-term memory. Testosterone (2 mg), given subcutaneously, yielded results which may be tentatively interpreted as an extension of the time of availability of recall from the intermediate stage by between 20 and 50 min, provided the hormone is administered no earlier than 90 min before learning. A higher dose (12.5 mg) of testosterone administered 30 min before learning had a similar effect. The findings with testosterone are comparable to those reported for pituitary-adrenal hormones.
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Effect of stress-related hormones on short term memory.
Adrenocorticotropic hormone (ACTH)1-24, ACTH4-10, corticosterone (CS) or arginine vasopressin (AVP) was administered subcutaneously to one day-old chicks immediately after learning a single trial passive avoidance task. Chicks were pretreated with 2 mM KC1 or 4 mM monosodium glutamate 5 min before learning. With KC1 or monosodium glutamate alone, no evidence of memory was observed on retention tests carried out as early as 5 min and as late as 24 h postlearning. However, the addition of ACTH1-24, ACTH4-10 or AVP to KC1-pretreated animals yielded normal retention levels up till 10 min, 10 min and 20 min after learning, respectively. Similar results were obtained with ACTH1-24 and AVP given to glutamate-pretreated birds. CS had no effect on KC1- or glutamate-induced amnesia. The calcium channel blocker, lanthanum chloride, also inhibited the formation of short-term memory, with amnesia still present as late as 24 h following learning. ACTH1-24, but not CS or AVP, yielded normal retention levels until 10 min postlearning in the presence of lanthanum chloride. Thus ACTH1-24 and AVP can overcome KC1 or glutamate inhibition of STM formation but will not prevent subsequent amnesia. The mechanisms underlying this action of ACTH1-24 and AVP are different. The possibility that the effect of ACTH1-24 is related to the role of calcium in STM formation is explored.
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Saccharin aversion memory in rats: inhibition of cycloheximide-resistant memory by ouabain.
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Neuronal depolarization and the inhibition of short-term memory formation.
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Biochemical aspects of protein synthesis inhibition by cycloheximide in one or both hemispheres of the chick brain.
Instracrnial administration of cycloheximide into one hemisphere of the chick brain resulted in inhibition of 14C-leucine incorporation into protein only in that hemisphere when the labelled amino acid was administered intracranially. With pericardial injections of labelled amino acid, inhibition of 14C-leucine incorporation was obtained in both the CXM-treated and the untreated hemisphere, when compared with bilateral saline-treated controls. The levels of inhibition were comparable to those obtained with bilateral administration of CXM. There was, however, a slight but significantly higher level of inhibition in the CXM-treated hemisphere. The results were interpreted as supporting the conclusion that monocular learning in chicks resulted in the formation of an engram only in the trained hemisphere.
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Similar effects of a monoamine oxidase inhibitor and a sympathomimetic amine on memory formation.
Amnesia resulting from inhibition of cerebral protein synthesis by cycloheximide can be prevented by subcutaneous injection of the monoamine oxidase inhibitor pargyline (25 mg/kg) or the sympathomimetic amine metaraminol (3.0 mg/kg) administered up to 30 min following learning of a single trial passive avoidance task in day-old chickens. The injection has to be made during the life time of labile memory for the prevention of cycloheximide-induced amnesia. On the other hand, amnesia induced by the Na/K ATP'ase inhibitor ouabain can only be prevented if these two agents are administered up to 5 min after learning, i.e. during the life time of short-term memory. In addition, both agents produce a retrieval deficit 90 min after the injection, but only when memory is in long-term storage. These results are compared to those obtained with administration of norepinephrine, d-amphetamine and diphenylhydantoin.
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Interhemispheric engram transfer in chick.
Monocular training on a one-trial passive avoidance task in the young chick has been shown to establish an engram in the forebrain hemisphere contralateral to the trained eye, and hence interocular transfer of this task must involve the naive hemisphere making access to the engram in the opposite hemisphere. We have studied the consequences for the untrained hemisphere of accessing a unilateral engram during two short term stages of its consolidation, by conducting interocular transfer tests at 7.5 min and 30 min after learning, prior to onset of amnesia induced by intracranial injection of ouabain or cycloheximide. Testing the naive hemisphere 24 h later indicated that engram transfer had occurred in chicks receiving one access trial at 7.5 min, during the first stage of consolidation of the unilateral engram. At 30 min, during second consolidation stage, five access trials were required to achieve engram transfer. These experiments confirm the findings from the rat that engram transfer can follow from making access to the unilateral engram. However, it has not previously been recognised that interhemispheric memory transfer depends on the recency of formation of the unilateral engram.
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