Diphenylhydantoin extension of short-term and intermediate stages of memory
Abstract
Diphenylhydantoin was shown to extend the duration of maximum availability of both short-term and intermediate memory in day-old chicks following a single trial passive avoidance learning task. Diphenylhydantoin also extended the time of susceptibility of long-term memory to inhibition by cyloheximide, suggesting that the extention of the life of intermediate memory was accompanied by a delay in long-term memory formation. Furthermore, while diphenylhydantoin counteracted amnesia induced by cycloheximide given 5 min before or immediately after learning, it had no effect on amnesia induced by cycloheximide administered 5 min or later after learning. For the latter, a second injection of diphenylhydantoin was necessary. This is consistent with the argument that the first injection of diphenylhydantoin extended the life of intermediate memory and delayed the formation of long-term memory.
... Thus each group of chicks should contribute one red-bead point and one blue-bead point in Figure 1 At some TTIs (eg, 15 mm), the number of red-bead points (one) differs from the number of blue-bead points (two) This is because coincident points were not distinguished (K. T Ng, personal communication, March 18, 1985) At a TTI of 15 mm, for example, this means that two groups were tested and produced different results with the blue bead but the same results with the red bead According to Ng, the lines summarizing the redbead data were drawn in an unusual way-rather than through the average of the red-bead points-"to indicate more clearly the effects of replication and to show that replication was not earned out on all TTIs" (K T Ng, personal communication, March 18, 1985) Three papers (Gibbs & Ng, 1979, 1984a, 1984b) contain a total of 11 graphs that resemble Figure 1 Two of the papers (Gibbs & Ng, 1979, 1984b contain no other graphs, the other paper (Gibbs & Ng,I984a) contains three other graphs that differ in many ways from Figure 1 If trials with different chicks were independent, then all of the graphs resembling Figure 1 show variability that is less than what is expected due to chance alone. When the dips in the function are excluded, the rest of the red-bead points are remarkably constant, and the blue-bead points are also unusually constant ...
... The expected chi-square is 37; the actual chi-square is 20 4 The probability of a value as low as this happening by chance is 03 Table 1 shows the result of analyzing all 11 graphs in this way. Two graphs ( Figure 3 of Gibbs & Ng, 1979, and Figure 2 of Gibbs & Ng, 1984a) contain a dip that is at a minimum for two TTIs, in these two cases, the data from both TTIs were excluded, along with the data from the two neighboring TTIs. In two cases ( Figure 1 of Gibbs & Ng, 1984a, and Figure 1 of Gibbs & Ng, 1984b), differences in the number of redbead points and blue-bead points at a single TTI meant that there were some coincident points, but it was impossible to determine exactly what the coincident points were, in these cases, values were chosen that maximized the chi-square Combining the analyses over graphs for each combination of bead (two beads) and paper (three papers) gives six overall This document is copyrighted by the American Psychological Association or one of its allied publishers. ...
... Two graphs ( Figure 3 of Gibbs & Ng, 1979, and Figure 2 of Gibbs & Ng, 1984a) contain a dip that is at a minimum for two TTIs, in these two cases, the data from both TTIs were excluded, along with the data from the two neighboring TTIs. In two cases ( Figure 1 of Gibbs & Ng, 1984a, and Figure 1 of Gibbs & Ng, 1984b), differences in the number of redbead points and blue-bead points at a single TTI meant that there were some coincident points, but it was impossible to determine exactly what the coincident points were, in these cases, values were chosen that maximized the chi-square Combining the analyses over graphs for each combination of bead (two beads) and paper (three papers) gives six overall This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. ...
Gibbs and Ng (1976, 1977) proposed a three-stage model of long-term memory formation on the basis of results from a one-trial-learning passive-avoidance procedure using chicks. Chi-square tests show that much of the evidence for this model (Gibbs & Ng, 1976, 1977, 1979, 1984a, 1984b), involving transient drops in retention and drug effects, is less variable than would be expected by chance. This should reduce belief in the model.
Gibbs and Ng (1976, 1977) proposed a three-stage model of long-term memory formation on the basis of results from a one-trial-learning passive-avoidance procedure using chicks. Chi-square tests show that much of the evidence for this model (Gibbs & Ng, 1976, 1977, 1979, 1984a, 1984b), involving transient drops in retention and drug effects, is less variable than would be expected by chance. This should reduce belief in the model.
Roberts's (1987, this issue) argument that the observed less-than-expected variability should reduce belief in our three-stage model is rejected. Experimenter bias, intentional or otherwise, does not account for the lack of variability. The reduced variability can be explained by an effective binomial p greater than that estimated from the data and arising within the experimental paradigm used. There appears to be evidence for a natural retention ceiling of 80–85% for chicks trained under this paradigm. The explanation for this is not immediately apparent.
The material in this chapter represents one component of a more global approach to the discovery of drugs to treat a variety of cognitive disorders. The broader plan, which is described in greater detail elsewhere (1), is based on a pragmatic behavioral approach to the search for agents to treat cognitive disease states that may range from attention deficit disorders (or hyperkinesis) and dyslexia in children to forget-fulness and Alzheimer’s disease in the aged. This overall broad-based approach requires examination of many types of behaviors representing a number of processes and is functional in nature. Although such a behavioral program can exist on its own, it is usually employed in conjunction with one or more specific biochemical or chemical hypotheses.
This chapter discusses the historical perspective pertaining to the neurobiology of learning and memory. Formal research on learning and memory began in the late 19th century. In 1885, empirical research on human learning and memory was initiated. However, laboratory research on learning in animal subjects began independently in 1898 by on the basis of planned experiments and unexpected observations during research on alimentary secretions. This research was followed up rapidly by other investigators. Although an extensive program of research on conditioning was conducted, few other laboratories took up this research until the late 1920s. Training and differential experience were demonstrated by the early 1960s to cause measurable changes in neurochemistry and neuroanatomy of weanling rats. An experiment also involved littermates that were either trained on a difficult problem or left untrained. The trained rats developed significantly higher total cortical enzyme acetylcholinesterase (AChE) activity than their untrained littermates. However, later on instead of continuing to train rats in problem-solving tests, a time-consuming and expensive procedure, the animals in different environments were housed that provided differential opportunities for informal learning. Formation of long-term memory was demonstrated in the early 1970s that required synthesis of proteins in the hours following training. The chapter also illustrates the changing concepts of learning and memory formation and discusses the distinction between direct and modulatory processes in memory formation. Formation of short-term, intermediate-term, and long-term memories require a cascade of neurochemical events, and rather similar sequences have been found in birds, mammals, and invertebrates. Newer biomedical and behavioral techniques are adding to the knowledge of the neural mechanisms of learning and memory.
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.
Presents a broad survey of more than a century of research on learning and memory and their biological mechanisms. This examination reveals anticipations of current thinking and also many sidetracks and errors. Such a survey provides insights about factors that favor discovery and also pitfalls that lie in the path of research. A historical review is necessarily selective; to help avoid selection that is either arbitrary or made to justify the present, the author draws upon some major reviews made at key points in time. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Roberts's (1987, this issue) argument that the observed less-than-expected variability should reduce belief in our three-stage model is rejected. Experimenter bias, intentional or otherwise, does not account for the lack of variability. The reduced variability can be explained by an effective binomial
p greater than that estimated from the data and arising within the experimental paradigm used. There appears to be evidence for a natural retention ceiling of 80–85% for chicks trained under this paradigm. The explanation for this is not immediately apparent. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The memorial effects of glutamate, LaCl3, ouabain, or anisomycin injection around the time of active avoidance training in mice were assessed in this study. Based on the Gibbs and Ng hypothesis of memory formation in chicks (Biobehav. Rev., 1 [1977] 113–136), it was predicted that these pharmacological agents would not only induce significant amnesia but, more specifically, short duration memory should be selectively impaired by glutamate and LaCl3, intermediate duration memory should be impaired by ouabain, and anisomycin should affect only long-lasting memories. Results of the experiments described below indicate these drugs are potent inhibitors of memory formation in rodents. In addition, LaCl3-induced amnesia was fully prevented by CaCl2. However, the mechanism by which glutamate and ouabain affected memory may not be exactly as described by Gibbs and Ng: γ-d-glutamylglycine and diphenylhydantoin did not completely prevent glutamate- and ouabain-induced amnesias, respectively. Finally, all amnestic agents induced amnesia that developed within minutes of training, and the time course of development of amnesia for each drug could not be distinguished from one another. These data are discussed in terms of their implications for the Gibbs and Ng model of memory formation.
Evidence from the use of inhibitory drugs and antagonists to these drugs suggest a three phase model of memory formation, with phases sequentially dependent. Hyperpolarization due to potassium conductance changes following learning are postulated to underlie the formation of a short-term memory phase. Hyperpolarization associated with sodium pump activity appears to be involved in the formation of the succeeding labile phase. Long-term memory formation appears to involve sodium pump associated amino acid uptake occuring during labile phase formation. Protein synthesis is accepted as underlying the formation of long-term memory. Although reference is made to available evidence in the literature, this review deals in detail with evidence from our laboratories.
Diphenylhydantoin (DPH 10(-4)M) administered subcutaneously to chicks 5 min after a one-trial passive avoidance learning task successfully counteracted amnesia induced by pretreatment 5 min before learning with ouabain or cycloheximide (CXM). Biochemical assays confirmed that in chick forebrain homogenate DPH at concentrations of 1 and 5 X 10(-4)M enhanced Na+/K+ ATP'ase activity. Since both DPH and ouabain inhibit post-tetanic potentiation, the results support the hypothesis of an initial labile phase of memory based on sodium pump (Na+/K+ ATP'ase) activity. DPH was less effective in counteracting ouabain-induced amnesia if administered later than 10 min after learning and CXM-induced amnesia if administered later than 30 min after learning. This suggests that the effect of DPH on CXM-induced amnesia is through enhancement of Na+/K+ ATP'ase activity. It was suggested that the possible hyperpolarization of membrane potential associated with sodium pump activity may serve to mark the labile memory trace, enabling formation of a more permanent trace through protein synthesis.
Day-old chickens trained in pairs on an aversive discrimination task yielded a retention function with two points of reduced retention, at 15 and 55 min after learning. These points of temporary reduction in retention were interpreted as reflecting change-over of recall from three successive phases in memory formation. Chicks trained in isolation showed the same retention function as paired chicks except that the second point of reduced retention occurred at 70 min after learning. It was suggested that isolation prolonged the availability for recall of the second phase of memory formation. The findings are consistent with and support a three phase, behaviourally sequentially dependent, model of memory formation previously postulated on the basis of pharmacological studies.
Psychobiology of memory: towards a model of memory formation
- Gibbs