Kim T. Ng

Psychobiology of memory: Towards a model of memory formation

Abstract 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.

Behavioural stages in memory formation

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.

Both non-NMDA and NMDA glutamate receptors are necessary for memory consolidation in the day-old chick

Day-old chicks (black Australorp-white Leghorn) trained to avoid an aversive stimulus will usually retain memory for this event indefinitely. The passive avoidance task used involves a period of pretraining where chicks peck freely at two differently colored glass beads, a single training trial where one of the beads is coated in a chemical aversant eliciting typical disgust reactions from the chicks, and a test trial where both beads are presented dry, and discrimination memory is demonstrated by avoidance of the previously aversive bead with continued pecking of the nonaversive bead. Intracranial administration of a N-methyl-D-aspartate glutamate receptor antagonist (50 microM 2-amino-5-phosphopentanoate) immediately after or prior to learning, or a non-N-methyl-D-aspartate glutamate receptor antagonist (100 microM 6,7-dinitro-quinoxaline-2,3-dione) between 10 and 25 min after learning, resulted in amnesia for this task at 80 to 90 min post-training. These data indicate that processes dependent on N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptor activation are necessary for memory consolidation of a passive avoidance task in the day-old chick. Since these agents must be administered during the earlier stages of memory formation to cause amnesia, the receptors are probably activated close to the time of learning. The delayed effect of these antagonists, however, suggests that memory is independent of these receptors until quite late in the memory consolidation process.

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 Ngs 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.

Astrocytic glycogenolysis energizes memory processes in neonate chicks

In previous pharmaco-behavioural experiments, we have shown that three sequential stages can be distinguished in discrimination memory for a single trial passive avoidance experience in neonate chicks: a short-term (STM) stage, available for 10 min following learning; an intermediate (ITM) stage, operating between 20 and 50 min (ITMB) post-learning; and a long-term (LTM) stage formed by 60 min after learning. The ITM stage can be divided into two parts: a first phase (ITMA) which is susceptible to inhibition by the uncoupler of oxidative phosphorylation (and thus of oxidative metabolism), 2,4-dinitrophenol (DNP), and a second DNP-insensitive phase (ITMB). ITMA occurs between 20 and 30 min post-training and ITMB between 30 and 50 min. In the present study we have shown: (1) that day-old chicks trained in the passive avoidance task and immediately thereafter injected with the glycolytic inhibitor iodoacetate show retention deficits that are first evident 30 min post-training, and (2) that glycogenolysis, i.e. breakdown of glycogen, a high-molecular carbohydrate energy store localized in astrocytes, occurs in the forebrains of trained, but otherwise untreated birds, between 35 and 55 min after learning. These findings strongly suggest that glycolysis, including astrocytically localized glycogenolysis, is essential to provide energy for active processes occurring during ITMB and that these processes are indispensable for subsequent development of long-term memory.

Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod.

The present series of experiments were conducted to discover whether rats would self-administer acetaldehyde (AcH) intravenously. The first study establishes the basic parameters for AcH self-injection in rats at 80% reduced body weight on a fixed-time 1 min (FT-1) food delivery schedule tested in the dark phase of a 12:12 light/dark cycle. The results show a dose-dependent effect with 1.3% AcH being the preferred dose as measured by the number of infusions. In the second experiment rats were on 100% free-feeding and at 80% reduced body weight, both conditions either with or without the influence of a FT-1 min schedule. The findings indicate that an interaction between dose, food deprivation and a FT-1 min schedule appears to initiate and maintain high levels of AcH self-injection in the dark. In a further experiment using 1.3% AcH the self-injection rates of animals at 80% body weight with a FT-1 min schedule reveal that the time of day of testing may be an important variable for inducing AcH intake. The results suggest that under altered environmental conditions AcH may have both an aversive and reinforcing effect.

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.

Alteration of alcohol drinking in the rat by peripherally self-administered acetaldehyde

The effects of intravenous acetaldehyde or saline self-injection and feeding regimes on oral alcohol consumption in rats was examined. The alcohol solutions offered to the animals was increased systematically in concentrations from 3 to 30%, according to a three-bottle, two-choice technique. Results suggest that (1) acetaldehyde pre-treatment using a self-injection procedure induces increased consumption of alcohol, the effect being particularly marked when coupled with conditions of food-deprivation (2) food-deprivation alone may be capable of inducing increased alcohol intake and this effect may persist even when deprivation is terminated (3) the combination of acetaldehyde and food-deprivation is most effective when food-deprivation follows a period of free-feeding. These findings provide support for an involvement of acetaldehyde in the development of an animals preference for alcohol.

Salsolinol and dopamine in rat medial basal hypothalamus after chronic ethanol exposure

Endogenous levels of salsolinol and dopamine were measured by a gas chromatography/mass spectrometry (GC/MS) - selected ion monitoring technique using deuterated internal standards in Long Evans rats chronically exposed to ethanol for ten months. Chronic ethanol exposure produced significant increases of dopamine and salsolinol concentrations in the medial basal hypothalamus but not striatum. The data suggest that the occurrence of salsolinol in rat brain tissue is a consequence of an in vivo Pictet-Spengler cyclization.

Dual action of cycloheximide on memory formation in day-old chicks

Amnesia for a single trial discriminated passive avoidance learning task in day-old chicks, resulting from the antibiotic cycloheximide, is shown to begin after 30 min following learning when cycloheximide is given immediately after or before learning. However, amnesia does not begin until after 50 min following learning when cycloheximide is given 5 min or later after learning. The results are interpreted in the context of a 3 stage model of memory formation. It is suggested that the second or intermediate stage involves two phases: phase A which lasts up to 30 min following learning, is energy dependent, and is susceptible to inhibition by 2,4-dinitrophenol; phase B which occurs after phase A, lasts up to 50 min following learning, is energy independent, and is not susceptible to inhibition by 2,4-dinitrophenol. It is concluded that cycloheximide given immediately after or before learning inhibits expression of phase B of intermediate memory as well as formation of long-term memory, while cycloheximide given 5 min or later after learning only inhibits formation of long-term memory. Another antibiotic, anisomycin, is shown to have no effect on intermediate memory, independent of time of administration.