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Prenatal benzodiazepine effects in mice: postnatal behavioral development, response to drug challenges, and adult discrimination learning.

Oxazepam treatment of primiparous mouse dams on days 12-16 of pregnancy (15 mg/kg p.o. twice daily) produced a transient retardation of postnatal body growth and neurobehavioral development, a reduction of the hyperactivity response to amphetamine in open-field tests on postnatal days 14-16, and a selective impairment of adult active avoidance in four go-no go discrimination tasks. Equally important for understanding the nature of the prenatal benzodiazepine syndrome were several negative results, namely, the absence of changes in homing performance on postnatal day 10, an intact hyperactivity response to scopolamine on postnatal days 21-23, a lack of effects on adult activity, and a normal passive avoidance performance in the go-no go tasks. A modification in monoaminergic regulatory functions may account for the overall profile of prenatal drug effects. Based on the results of this experiment, of a preliminary multidose study (0-50 mg/kg), and of an additional cross-fostering experiment, several methodological issues are addressed. These include the choice of appropriate treatment schedules and of testing procedures adequate for each developmental stage, and the control for various confounding variables such as litter effects, postnatal maternal influences, and developmental history.

Amphetamine↗

Visuomotor strategies in pattern discrimination learning in rats.

Normal rats were trained on a series of visual tilt discriminations ordered from simple to difficult to measure their angular difference thresholds. The stereotyped visuomotor running pattern which the animal made was recorded for all angular differences binocularly and whilst the animal was monocularly patched. The results show that the running pattern does not reflect visual guidance strategies and can produce a visual field bias for the field ipsilateral to the preferred approach side.

Animals↗

Different patterns of human discrimination learning for two interaural cues to sound-source location.

Two of the primary cues used to localize the sources of sounds are interaural level differences (ILDs) and interaural time differences (ITDs). We conducted two experiments to explore how practice affects the human discrimination of values of ILDs and ongoing ITDs presented over headphones. We measured discrimination thresholds of 13 to 32 naive listeners in a variety of conditions during a pretest and again, 2 weeks later, during a posttest. Between those two tests, we trained a subset of listeners 1 h per day for 9 days on a single ILD or ITD condition. Listeners improved on both ILD and ITD discrimination. Improvement was initially rapid for both cue types and appeared to generalize broadly across conditions, indicating conceptual or procedural learning. A subsequent slower-improvement stage, which occurred solely for the ILD cue, only affected conditions with the trained stimulus frequency, suggesting that stimulus processing had fundamentally changed. These different learning patterns indicate that practice affects the attention to, or low-level encoding of, ILDs and ITDs at sites at which the two cue types are processed separately. Thus, these data reveal differences in the effect of practice on ILD and ITD discrimination, and provide insight into the encoding of these two cues to sound-source location in humans.

Acoustic Stimulation↗

Lateral hyperstriatal lesions disrupt simultaneous but not successive conditional discrimination learning of pigeons (Columba livia).

In 2 experiments we explored the effects of lateral versus medial laminar lesions of the hyperstriatum in pigeons (Columba livia); medical lesions were largely confined to the hyperstriatum accessorium, and lateral lesions to the hyperstriatum dorsale and hyperstriatum ventrale. In Experiment 1, lateral, but not medial, lesions disrupted acquisition of a simultaneous conditional discrimination; both medial and lateral lesions disrupted reversal of the discrimination. The reversal deficits of the medial and lateral groups were quantitatively similar, and both groups showed exaggerated positional responding. In Experiment 2, neither medial nor lateral lesions disrupted acquisition of a successive conditional discrimination. We conclude that lateral hyperstriatal damage does not obtain a general disruption of conditional learning; we speculate that the lateral hyperstriatum may play a critical role in configural learning.

Animals↗

Speeding up visual discrimination learning in cats by differential exposure of positive and negative stimuli.

We have developed an adaptive training method which considerably reduces the total time required to train cats to threshold in an orientation discrimination task. During training, the animals are given greater exposure in time to the positive stimulus compared to the negative one. Therefore, this method has been coined the differential exposure method (DEM). The greater exposure to the positive stimulus reduces the number of errors an animal commits during training and thereby enhances speed of learning. Indeed, with the DEM, 34 daily sessions sufficed to train cats to threshold for 2 different reference orientations. Furthermore, the DEM was effective not only for simple stimuli such as real bars but also for complex stimuli such as illusory contours. Finally, the DEM was equally effective for training naive cats which had undergone large visual cortical lesions as it was for normal animals.

Animals↗

GABAergic mechanisms gate tactile discrimination learning.

In contrast to mechanisms mediating synaptic plasticity, the pharmacological basis of perceptual learning remains to be clarified. Here we report that a specific form of perceptual learning is influenced by GABAergic mechanisms. We induced perceptual learning by Hebbian co-activation of the skin of the tip of the right index fingers in human subjects. Under placebo conditions, tactile 2-point discrimination was improved on the co-activated, but not on the left, index finger. This augmentation was completely eliminated by lorazepam, a GABAA receptor agonist. No drug effects were found on the left index finger indicating that the drugs had no effect per se on performance. The results demonstrate that perceptual learning is subject to pharmacological gating by basic mechanisms known to mediate and modulate synaptic plasticity.

Adult↗

Spatial discrimination learning induces LTP-like changes in the lateral septum of mice.

The efficacy of synaptic transmission from the fimbria to the lateral septum (LS) of freely moving mice was monitored electrophysiologically over 9 days of training in a spatial discrimination task (radial maze). Electrical stimulation of the fimbria evoked two negative waves (N2 and N3) in the ipsilateral LS. Compared to a control group exposed to muscular effort (treadmill), trained animals displayed a significant and progressive increase in the amplitude of N3 with no changes in N2. Moreover, this increase was of greater magnitude in fast learners than in slow learners and persisted for at least 24 h following the last (9th) training session. These changes might play a role in spatial learning through the regulation of septohippocampal cholinergic activity.

Animals↗

Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory.

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.

Analysis of Variance↗

Transverse compounding in the discriminative learning of moderately and mildly mentally retarded adolescents.

For adolescents in the range of moderate to mild retardation, the salience of transverse compound stimuli (combinations of positive and negative cues) was found to be low in two-choice visual discriminations. In problems allowing optional use of transverse compounds, no use whatever was made of these stimuli. In problems requiring use of transverse compounds, only the more intelligent subjects were able to learn to attend to such compounds, but this learned salience faded in a new problem that allowed optional compound use. These results were interpreted as an instance of developmental changes in unlearned stimulus salience hierarchies. We speculated that the low saliency of transverse compounds may be related to reading difficulties.

Adolescent↗

Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats.

Prenatal alcohol exposure can disrupt brain development and lead to a myriad of behavioral alterations, including motor coordination deficits, hyperactivity, and learning deficits. There remains a need, however, to identify treatments and interventions for reducing the severity of alcohol-related neurodevelopmental disorders. Some of the alcohol-induced deficits in learning may be related to alterations in cholinergic functioning. Interestingly, there is a growing literature demonstrating that pre- and/or early postnatal choline supplementation can lead to long-term enhancement in learning and memory and cholinergic activity in rats. The present study examined whether such early choline supplementation might counter the effects of prenatal alcohol treatment on a visuospatial discrimination task. Pregnant Sprague-Dawley rats were randomly assigned to one of three prenatal treatment groups. One group received a liquid diet containing 35% ethanol-derived calories (EDC) from gestational day (GD) 6-20. A second group served as a pair-fed (PF) control group and the third group served as an ad lib lab chow (LC) control. On postnatal day (PD) 2, pups were assigned within-litter to one of three postnatal treatments: choline, saline vehicle, or no treatment. Choline and vehicle pups were intubated with a choline chloride solution or vehicle daily from PD 2 to 21, whereas the non-treated pups were handled daily but not intubated. On PD 45, subjects were tested on a visuospatial discrimination task. Ethanol-exposed subjects who were not treated neonatally with choline committed a significantly greater number of errors both during acquisition and during delayed discrimination training compared to both PF and LC controls. Neonatal choline treatment significantly improved performance on the discrimination task in all groups; however, the beneficial effects of choline were significantly larger in ethanol-exposed subjects. Indeed, the performance of ethanol-exposed pups treated with neonatal choline did not differ from any of the PF or LC groups on any measure. Thus, early postnatal choline supplementation significantly attenuated the effects of prenatal alcohol on this learning task. Importantly, these effects were not due to the acute effects of choline, but rather to long-term changes in brain and behavioral development. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.

Animals↗

Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs.

The present experiment was part of a 3-year longitudinal study examining the effects of age and antioxidant treatment on cognitive decline in beagles. Two size-concept tasks were administered following pretraining on a series of two-choice (six subtests) and three-choice size discrimination tasks. Thirty-nine young and aged dogs were matched for age and cognitive ability then divided into four treatment groups. A combined antioxidant-mitochondrial cofactor treatment led to significantly improved performance in aged dogs on the first subtest of the two-choice size discrimination series. Treated aged dogs did not significantly differ from the young. Aged dogs on the antioxidant diet continued to perform better than aged controls on the second and third subtests, but these effects did not achieve significance. Young dogs performed significantly better than the aged dogs on the second and third subtests. The remaining two-choice tasks of the discrimination series were comparatively easy, leading to a floor effect. The antioxidant animals performed better on the three-choice size discrimination, but not on the two size-concept tasks. Antioxidants improved the performance of aged dogs on the initial learning tests, suggesting a selective improvement of factors related to the aging process and specific cognitive processes rather than general cognitive enhancement.

Age Factors↗

Responses of cells in the tail of the caudate nucleus during visual discrimination learning.

1. The tail of the caudate nucleus and adjacent ventral putamen (ventrocaudal neostriatum) are major projection sites of the extrastriate visual cortex. Visual information is then relayed, directly or indirectly, to a variety of structures with motor functions. To test for a role of the ventrocaudal neostriatum in stimulus-response association learning, or habit formation, neuronal responses were recorded while monkeys performed a visual discrimination task. Additional data were collected from cells in cortical area TF, which serve as a comparison and control for the caudate data. 2. Two monkeys were trained to perform an asymmetrically reinforced go-no go visual discrimination. The stimuli were complex colored patterns, randomly assigned to be either positive or negative. The monkey was rewarded with juice for releasing a bar when a positive stimulus was presented, whereas a negative stimulus signaled that no reward was available and that the monkey should withhold its response. Neuronal responses were recorded both while the monkey performed the task with previously learned stimuli and while it learned the task with new stimuli. In some cases, responses were recorded during reversal learning. 3. There was no evidence that cells in the ventrocaudal neostriatum were influenced by the reward contingencies of the task. Cells did not fire preferentially to the onset of either positive or negative stimuli; neither did cells fire in response to the reward itself or in association with the motor response of the monkey. Only visual responses were apparent. 4. The visual properties of cells in these structures resembled those of cells in some of the cortical areas projecting to them. Most cells responded selectively to different visual stimuli. The degree of stimulus selectivity was assessed with discriminant analysis and was found to be quantitatively similar to that of inferior temporal cells tested with similar stimuli. Likewise, like inferior temporal cells, many cells in the ventrocaudal neostriatum had large, bilateral receptive fields. Some cells had "doughnut"-shaped receptive fields, with stronger responses in the periphery of both visual fields than at the fovea, similar to the fields of some cells in the superior temporal polysensory area. Although the absence of task-specific responses argues that ventrocaudal neostriatal cells are not themselves the mediators of visual learning in the task employed, their cortical-like visual properties suggest that they might relay visual information important for visuomotor plasticity in other structures. (ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin gene products.

Duchenne muscular dystrophy is frequently associated with a non-progressive cognitive deficit attributed to the absence of 427,000 mol. wt brain dystrophin, or to altered expression of other C-terminal products of this protein, Dp71 and/or Dp140. To further explore the role of these membrane cytoskeleton-associated proteins in brain function, we studied spatial learning and ex vivo synaptic plasticity in the mdx mouse, which lacks 427,000 mol. wt dystrophin, and in the mdx3cv mutant, which shows a dramatically reduced expression of all the dystrophin gene products known so far. We show that reference and working memories are largely unimpaired in the two mutant mice performing a spatial discrimination task in a radial maze. However, mdx3cv mice showed enhanced emotional reactivity and developed different strategies in learning the task, as compared to control mice. We also showed that both mutants display apparently normal levels of long-term potentiation and paired-pulse facilitation in the CA1 field of the hippocampus. On the other hand, an increased post-tetanic potentiation was shown by mdx, but not mdx3cv mice, which might be linked to calcium-regulatory defects. Otherwise, immunoblot analyses suggested an increased expression of a 400,000 mol. wt protein in brain extracts from both mdx and mdx3cv mice, but not in those from control mice. This protein might correspond to the dystrophin-homologue utrophin. The present results suggest that altered expression of dystrophin or C-terminal dystrophin proteins in brain did not markedly affect hippocampus-dependent spatial learning and CA1 hippocampal long-term potentiation in mdx and mdx3cv mice. The role of these membrane cytoskeleton-associated proteins in normal brain function and pathology remains to be elucidated. Furthermore, the possibility that redundant mechanisms could partially compensate for dystrophins' deficiency in the mdx and mdx3cv models should be further considered.

Animals↗

Medial versus lateral hyperstriatal lesions in pigeons: effects on autoshaping, non-matching-to-sample and spatial discrimination learning at short and long intertrial intervals.

Three experiments contrasted the effects of medial and lateral hyperstriatal lesions in pigeons. Expt. 1 found that both types of lesion obtained slower acquisition of autoshaping, compared to unoperated controls. No group differences in maintained rate of autoshaped responding were found. Expt. 2 found that lateral but not medial lesions disrupted choice performance in a non-matching-to-sample (NMTS) task, in which initial preference was for the correct stimulus; birds with lateral lesions responded more slowly to the sample stimulus than did birds with medial lesions. Expt. 3 found that medial but not lateral lesions disrupted both acquisition and reversal of a spatial discrimination at a long, but not at a short intertrial interval (ITI). Medial lesions damage primarily the hyperstriatum accessorium and lateral lesions, the hyperstriatum ventrale; but no significant correlations between the extent of damage to either of these structures and severity of behavioural disruption were obtained. Implications of these findings for theoretical accounts of hyperstriatal involvement in learning processes are discussed.

Animals↗

Monocular pattern discrimination learning after unilateral lesions of anteromedial cortex in rat.

Monocularly patched rats were trained on a series of visual tilt discriminations ordered from simple to difficult to measure the angular difference threshold of each eye. Preoperatively there was no difference between discrimination performance for either eye. Unilateral lesions of anteromedial cortex did not alter the monocular angular difference threshold. However, there was a reduction in discrimination performance for all angular difference comparisons. Animals showed a visual neglect for stimuli in the field contralateral to the lesion. The neglect was independent of the eye used for the discrimination.

Animals↗

Discrimination learning as a function of stimulus location along an auditory intensity continuum.

Eight groups of rats were trained on an auditory intensity discrimination in which the discriminative stimuli were separated by 10 decibels (db). Four pairs of stimuli were selected from different regions along a 60-100 db (SPL) intensity continuum. Counterpart groups were trained on each stimulus pair, with the relative intensity positions of the reinforced stimulus (S(D)) and the non-reinforced stimulus (S(Delta)) reversed for the two groups. Discrimination acquisition curves were compared to determine whether stimuli separated by equal logarithmic units were of comparable "difficulty", and to determine the relative effectiveness of an S(D) serving as the more versus less intense member of a stimulus pair. It was concluded that: (1) When S(D) is the more intense, auditory intensities of constant logarithmic separation are graded in "difficulty" along the intensity continuum; high intensity discriminative stimuli are most readily discriminated. When S(Delta) is the more intense, this graded effect is not evident. (2) For a given continuum location, discrimination is inferior when S(Delta) is the more intense. This effect is most pronounced at the high intensity end of the continuum and is chiefly attributable to differences in the rate of S(Delta) responding.

Journal Article↗

Factors affecting conditional discrimination learning by pigeons.

In Experiment 1 (within subjects) and Experiment 2 (between subjects) it was shown that the sequential training of pigeons on a color discrimination and then on its reversal, each in a different floor-tilt/texture context, failed to produce conditional control of discriminative performance by those contexts. Daily alternation between the two problems (with correlated contexts) was successful, however. In each of these experiments conditional control was better reflected in generalization test performance in extinction than during sessions of training with reinforcement.

Journal Article↗