Effects of early postnatal alcohol exposure on learning in the developing rat: replication with intubation method of delivery.

Early postnatal exposure to alcohol during early development produces deficits in learned persistence, as reflected in the partial reinforcement extinction effect (PREE) in weanling rats, and deficits memory-based learning, as shown by patterned single alternation (PSA) discrimination learning in preweanling rats. We report a partial replication of these effects using the intubation method instead of artificial rearing. Rat pups were intubated once per day with 4.5 g/kg/day alcohol in a milk-based diet or control diet on postnatal days (PNDs) 4 to 9, and then assessed for the PREE on PNDs 20 and 21 or PSA learning on PNDs 17 and 18. Compared with previous artificial rearing reports, the intubation method produced healthier and heavier pups, and yielded a consistently lower and less variable blood alcohol levels. Even with the lower alcohol levels, intubation with alcohol eliminated the PREE. Intubation with alcohol had a weaker but still detrimental effect on PSA learning. These results suggest that alcohol exposure during development can produce behavioral deficits in the absence of the more severe effects on brain and body growth typically associated with fetal alcohol syndrome.

Reversal of a postnatal alcohol-induced deficit in learned persistence in the rat by d-amphetamine.

Periodic (high peak) exposure to alcohol during early infancy in the rat has been shown to disrupt the partial reinforcement extinction effect (PREE), a measure of persistence learning, when rats were tested at weaning age. The current study examined the effects of d-amphetamine (0.3 mg/kg, i.p.) on the PREE after early postnatal exposure to alcohol (4.5 mg/kg) delivered in a milk-based diet or an isocaloric control diet via oral intubation once a day on postnatal days 4 to 9. On postnatal days 20 and 21, rats were trained on either a continuously reinforced or partially reinforced schedule of food reward, followed by extinction. Rats were randomly assigned to eight conditions, depending on diet, drug, and reward schedule. The results were (1) a replication of the finding that periodic (high peak) exposure to alcohol diminishes the PREE, and (2) that amphetamine restores the PREE to normal levels in alcohol-treated animals, and may reduce the PREE in control subjects. The possible role of noradrenergic and dopaminergic systems in situations of extinction and nonreward are discussed.

Extinction after regular and irregular reward schedules in the infant rat: influence of age and training duration.

Greater persistence in extinction is observed following inconsistent reward compared to that observed following consistent reward, an effect termed the partial reinforcement extinction effect (PREE). We report three experiments in which the extinction rates of random partially reinforced (PRF) or continuously reinforced (CRF) infant rat pups were compared to the extinction rate of pups trained with an alternative and regular schedule of partial reinforcement, known as patterned single alternation (PSA). In PSA, subjects learn to alternate speed of responding in anticipation of the regular alternation of reward and nonreward trials in the straight alley runway. In Experiment 1, 17-day-old PSA subjects showed CRF-like extinction rates; whereas in Experiment 2, in which extinction was initiated early in training prior to the onset of the PSA discrimination, PSA subjects showed prolonged, PRF-like extinction curves. In contrast, 12-day-old pups in Experiment 3 showed no reward-schedule-related differences in extinction, despite differences in behavior during acquisition. These results prompt a modification of Amsel's (1962) model of discrimination learning, and suggest the existence of a dissociation between different types of reward-related expectancies in the younger subjects.

Effects of MK-801 on vicarious trial-and-error and reversal of olfactory discrimination learning in weanling rats.

The effects of dizocilpine maleate (MK-801) on vicarious trial-and-error (VTE), and on simultaneous olfactory discrimination learning and its reversal, were observed in weanling rats. The term VTE was used by Tolman (The determiners of behavior at a choice point. Psychol. Rev. 1938;46:318-336), who described it as conflict-like behavior at a choice-point in simultaneous discrimination learning. It takes the form of head movements from one stimulus to the other, and has recently been proposed by Amsel (Hippocampal function in the rat: cognitive mapping or vicarious trial-and-error? Hippocampus, 1993;3:251-256) as related to hippocampal, nonspatial function during this learning. Weanling male rats received systemic MK-801 either 30 min before the onset of olfactory discrimination training and its reversal, or only before its reversal. The MK-801-treated animals needed significantly more sessions to acquire the discrimination and showed significantly fewer VTEs in the acquisition phase of learning. Impaired reversal learning was shown only when MK-801 was administered during the reversal-learning phase, itself, and not when it was administered throughout both phases.

Immediate and long-term effects of neonatal MK-801 treatment on nonspatial learning.

These experiments observed the immediate and long-term effects of neonatal treatment with MK-801 on patterned single alternation (PSA), a form of nonspatial, memory-based learning. Rat pups were injected daily on postnatal days (PND) 7-19, with MK-801 (MK+) or the less active isomer of MK-801 (MK-) (0.25 mg/kg), and trained at either PND 22 or 60. Rats treated with MK+ or MK- and trained on PND 22 were significantly impaired in PSA when compared with the saline control. Beyond the learning impairment, MK+ rats showed an overall decreased running speed during training. They also presented an array of abnormal behaviors and significant weight loss. These nonassociative variables were determined for several doses (0.025, 0. 05, 0.1, 0.15, and 0.20 mg/kg) through PND days 22-25. Rats that received the threshold dose for secondary effects (0.025 mg/kg) also showed an overall decrease in running speed, but failed to show a significant nonspatial learning impairment on PSA. The PSA learning impairment was found to be not long lasting; rats trained at PND 60, after neonatally receiving the original high dose of MK-801, did not differ from controls.

Alleviation of x-irradiation-based deficit in memory-based learning by D-amphetamine: suggestions for attention deficit-hyperactivity disorder.

Selective exposure to x-irradiation during infancy, from postnatal days (PND) 2-11 in the rat, results in severe hippocampal granule cell hypoplasia. Preweanling (PND 17-18) rats, which suffer such hippocampal granule-cell agenesis, show deficits in patterned single alternation (PSA), a form of memory-based learning. Deficits in short-term memory along with increased arousal have been suggested as characteristic of children diagnosed with attention deficit-hyperactivity disorder (ADHD). We report here on the ameliorating effects of D-amphetamine, a drug commonly used in the treatment of ADHD, before Ritalin, on PSA, after infantile (PND 2-15) exposure to x-irradiation. After i.p. injections of 0.3 mg/kg D-amphetamine, the onset and magnitude of the PSA memory-based discrimination in the x-irradiated preweanling rats was restored to about the level of controls. These results, showing alleviation of x-irradiation-related deficits in short-term memory by D-amphetamine injections, along with our earlier and present results, showing substantial deficits after x-irradiation alone, encourage the hypothesis that hippocampal granule-cell hypoplasia, which would occur in humans prenatally and is Altman's model of "minimal brain dysfunction" [Altman, J. (1986) in Learning Disabilities and Prenatal Risk, ed. Lewis, M. (Univ. of Illinois Press, Urbana), pp. 241-304], may be a factor in at least some forms of ADHD and may provide a basis for an animal model of the disease.

Effects of prenatal and early postnatal ethanol exposure on [3H]MK-801 binding in rat cortex and hippocampus.

The effects of prenatal and/or early postnatal exposure to ethanol at high concentrations on N-methyl-D-aspartate (NMDA) receptor number and functioning in the weanling rat were examined. The binge-like exposure protocol was used in an animal model of acute ethanol effects at two critical periods of development. [3H]MK-801 binding parameters for the internal channel phencyclidine site were assessed in the presence of 10 microM glutamate and 10 microM glycine activation. Four treatment groups were included: (1) animals exposed to ethanol both prenatal and postnatal; (2) animals exposed only prenatal; (3) animals exposed early postnatal only; and (4) control animals with no exposure to ethanol. The results of the [3H]MK-801 binding experiments showed that both prenatal and postnatal exposure to ethanol resulted in a significant decrease in the density of NMDA receptors. In addition, data indicated an apparent increase in the percentage of high-affinity state (open channel state) relative to low-affinity state (close channel state) receptors in the ethanol-treated groups. These results show that both prenatal and postnatal ethanol exposure decrease NMDA receptor density in the cortex and hippocampus. The findings are consistent with previous observations by our laboratory and others that NMDA-mediated calcium influx is reduced in these regions, as well as in whole brain by prenatal ethanol exposure. It is suggested that after ethanol exposure, the remaining functional NMDA receptors might have altered sensitivity to coagonist activation with an increased probability of channel opening.

Development of vicarious trial-and-error behavior in odor discrimination learning in the rat: relation to hippocampal function?

Previous work from our laboratory has suggested that hippocampal electrolytic lesions result in a deficit in simultaneous, black-white discrimination learning and reduce the frequency of vicarious trial-and-error (VTE) at a choice-point. VTE is a term Tolman used to describe the rat's conflict-like behavior, moving its head from one stimulus to the other at a choice point, and has been proposed as a major nonspatial feature of hippocampal function in both visual and olfactory discrimination learning. Simultaneous odor discrimination and VTE behavior were examined at three different ages. The results were that 16-day-old pups made fewer VTEs and learned much more slowly than 30- and 60-day-olds, a finding in accord with levels of hippocampal maturity in the rat.

The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

The N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor has been implicated in several kinds of learning and memory, as well as in long-term potentiation (LTP), a putative cellular mechanism for learning and memory. This experiment examined the role of the NMDA receptor in patterned single-alternation (PSA) learning in preweanling rats following intraperitoneal injections of 0.05 mg/kg MK-801, a selective NMDA antagonist. MK-801 significantly inhibited PSA at both 60-s and 30-s intertrial intervals (ITIs), and attenuated, but did not block, learning at 8-s ITI. These results are compared with effects on PSA, a form of nonspatial, memory-based learning, observed after early postnatal exposure to alcohol, infant hippocampal lesions, and infant exposure to X-irradiation, and they add strongly to these earlier demonstrations of the role of the hippocampus in learning and memory that is clearly nonspatial and non-cognitive-map-related.

A simple test of the vicarious trial-and-error hypothesis of hippocampal function.

Vicarious trial-and-error (VTE) is a term that Muenzinger and Tolman used to describe the rat's conflict-like behavior before responding to choice. Recently, VTE was proposed as a mechanism alternative to the concept of "cognitive map" in accounts of hippocampal function. That is, many phenomena of impaired learning and memory related to hippocampal interventions may be explained by behavioral first principles: reduced conflicting, incipient, pre-choice tendencies to approach and avoid. The nonspatial black-white discrimination learning and VTE behavior of the rat were investigated. Hippocampal-lesioned and sham-lesioned animals were trained for 25 days (20 trials per day) starting at 60 days of age. Each movement of the head from one discriminative stimulus to the other was counted as a VTE instance. Lesioned rats had fewer VTEs than sham controls, and the former learned much more slowly or never learned. After learning, VTE frequency declined. Male and female rats showed no significant differences in VTE behavior or discrimination learning.

Age and dose-related effects of hippocampal ibotenic acid on lesion size, mortality, and nonspatial working memory in infant rats.

Three experiments are presented in which the neural and behavioral consequences of multiple ibotenic acid (IBO) injections into the hippocampus were examined in Sprague-Dawley rat pups. Rat pups were 11 or 15 days of age at the time of surgery (SURG11, SURG15), the dose of IBO was either 1 microgram in 1 microliter, 2.5 micrograms in 0.5 microliters, or 5 micrograms in 1 microliter for each of four injections, and pups were allowed to survive for 3 or 7 days after the lesion was made. The Fink-Heimer silver stain was used in Experiment 1 to examine the extent of neural damage following unilateral lesions and showed that the degeneration was primarily located in the hippocampus. The magnitude of the damage was greatest in younger pups and in those which received the higher of the two concentrations (injection volume was not a factor). Degenerating fibers were seen in the columns of the fornix as well as precommissural fornix fibers, but only in SURG15 animals when damage extended into the dorsal subiculum. Mortality rates following multiple IBO injections were very high in infant rats, in some cases as high as 60%. Experiments 2 and 3 examined the effects of bilateral lesions on neuroanatomy and behavior. Bilateral lesions were somewhat smaller than unilateral lesions, and as for unilateral lesions, degeneration in pre- and postcommissural fornix was seen only in SURG15 animals. The behavioral task used in Experiments 2 and 3 was patterned single alteration, a memory-based appetitive learning discrimination. Earlier work has shown that damage to the infant hippocampus results in moderate deficits in this task at 30-s intervals and more substantial deficits at 60-s intertrial intervals. This was not the case in the present studies: regardless of age at surgery or time postlesion, all infant rats tested learned this discrimination at the two intertrial intervals. As has been recently reported for adult rats, excitotoxic lesions of the hippocampus in infant rats do not produce the same patterns of behavioral deficits as electrolytic lesions.

Selective activity enhancement and persistence in weanling rats after hippocampal X-irradiation in infancy: possible relevance for ADHD.

We examined the effects of focal X-irradiation of the hippocampus in infancy on the partial reinforcement extinction effect (PREE) in weanling rats in a runway and on running wheel activity at 40 days of age. Our results show a dose-dependent X-irradiation-related reduction in granule cell neurogenesis. Weanling rats showed a corresponding increase in running speed in both acquisition and extinction and a dose-dependent reduction in the PREE--an increase in persistence after CRF and a decrease in persistence after PRF training. The same degree of hippocampal granule cell agenesis had no effect on running wheel activity. These results suggest that the enhanced speeds in the runway are incentive-related and do not reflect simple hyperactivity but rather hyperreactivity. The discussion of these results is in part a speculation regarding their possible relation to some explanations of attention deficit-hyperactivity disorder in children.

Postnatal high-peak blood ethanol concentration and external cue-based discrimination learning and reversal in the preweanling rat: comparison with memory-based discrimination learning.

Postnatal exposure to ethanol that produces high-peak blood ethanol concentrations (HP-BEC) in artificially reared infant rats affects hippocampal neuroanatomy and discrimination learning based on memorial cues from a patterned (single) alternation (PA) schedule in preweanling rats (P. L. Greene, J. L. Diaz-Granados, & A. Amsel, 1992). In the present experiments, discrimination by preweanling rats exposed to ethanol in the same way was tested with nonmemorial, external cues. In this external cue-based discrimination and in its reversal, ethanol-exposed rats were not different from normal or artificially reared controls whether the cues were presented in a PA or random manner, although there was some evidence that the memorial cues from the PA schedule contributed to learning a discrimination based on external cues, suggesting that the deficit reported earlier in ethanol-exposed rats is a memorial deficit and not a general discrimination deficit.

Précis ofFrustration Theory: An Analysis of Dispositional Learning and Memory.

This is a précis of a book on frustration theory, whose explanatory domain includes a family of phenomena that have been summarized by the terms dispositional learning and memory-systems that ordinarily have a long-term historical etiology, and in which the learning is relatively reflexive and the memory implicit and not strongly episodic. The book is an attempt, in the context of stimulus-response learning theory, to present in some detail an animal-based model of frustration as it is applied to a limited-but still large-number of these experimentally established phenomena (perhaps the largest number organized by any one such theory). These bear some resemblance to equivalent phenomena in humans, to which the descriptive terms arousal, suppression, persistence, and regression have been applied. An explicit caveat is that this is a book on one particular theory of frustration and not a book on frustrationtheories. Whereas it does address other theories of frustration, its main purpose is to review a line of theorizing and experimental research that has evolved over some 40 years: an analysis of the status of the concept of frustration in learning theory.

Mitigating effects of combined prenatal and postnatal exposure to ethanol on learned persistence in the weanling rat: a replication under high-peak conditions.

Replicating an earlier report under low-peak blood ethanol concentration (BEC) conditions, weanling rats, exposed in utero or postnatally to levels of ethanol that resulted in high-peak BECs, showed an attenuated partial reinforcement extinction effect, whereas pups exposed both pre- and postnatally did not differ from controls. Also supporting earlier work, postnatal exposure resulted in significantly reduced brain weight and had effects on hippocampal measures. These results from the combined-exposure group, along with earlier work, point to a possible mitigating influence in the rat of prenatal exposure to ethanol on the behavioral effects of postnatal exposure. They suggest that a protective factor may be operating, akin to the proactive immunoreactive effects of heat shock proteins shown in recent work at the cellular and hippocampal levels.

Hippocampal function in the rat: cognitive mapping or vicarious trial and error?

The most prominent hypothesis of hippocampal function likens the hippocampus to a "cognitive map," a term used by a famous learning theorist, E. C. Tolman, to explain maze learning. The usual application of this concept of cognitive map, as it applies to the hippocampus, is to what is called spatial learning, mainly in the radial-arm maze of Olton and the Morris water maze. In a recent Hippocampus Forum, evidence for the cognitive map hypothesis was reviewed in a lead article by Nadel, followed by a series of commentaries by leading investigators of hippocampal function. This speculative commentary offers an alternative not represented in the forum--that the function of the hippocampus in spatial learning is not as a cognitive map, but that it subserves another function proposed by Tolman in his work on simple discrimination learning, vicarious trial and error, based on incipient, conflicting dispositions to approach and avoid.

Age-dependent effects of hippocampal muscarinic receptor blockade on memory-based learning in the developing rat.

The effects of ventral intrahippocampal injections of atropine sulfate on patterned single alternation (PSA), a discrimination task that requires intact short-to-intermediate-term memory, were examined in the developing rat at 16-17 and 28-32 days of age. Atropine treatment disrupted simple acquisition in some 16- to 17-day-old pups by interfering with approach to the goal, but did not eliminate PSA at either 8- or 15-s intertrial intervals when approach was normal. In the older rats, atropine treatment delayed the onset and reduced the magnitude of PSA, indicating a reduced memory-based discrimination. These results provide additional support for an increasing role of muscarinic receptors in learning and memory as this system matures in the developing rat, and suggest different mechanisms for PSA at the two ages.

Memory-based learning in preweanling and adult rats after infantile x-irradiation-induced hippocampal granule cell hypoplasia.

Infantile exposure to x-irradiation induced severe hippocampal granule cell hypoplasia in preweanling and young adult rats. Hippocampally damaged pups, tested at 16 days of age, showed deficits in a memory-based discrimination based on single alternations of reward and nonreward when training was conducted at a 60-s intertrial interval (ITI) but not when conducted at a 30-s ITI. This deficit was still present at the 60-s ITI in animals x-irradiated in infancy and tested at 60-65 days of age. These data provide further support for the role of the hippocampus in intermediate-term memory and demonstrate, in a developmental context, the importance of an intact hippocampus in learning that depends on nonspatial memory.