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PubMed2006

Neonatal behavior and infant cognitive development in rhesus macaques produced by assisted reproductive technologies.

Assisted reproductive technologies (ART) used in fertility clinics include in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), followed by embryo transfer into the biological or a surrogate mother. Over 1,000,000 liveborn offspring--an estimated 1 in 150 United States newborns--have been produced worldwide by ART since 1978. IVF appears to produce healthy children in singleton pregnancies, though concerns remain regarding preterm deliveries, multiple pregnancies, as well as the longer-term consequences of all ART procedures. Clinical studies remain difficult to interpret and subject to confounding variables, as developmental problems may be due to a parent's reproductive conditions rather than, or in addition to, an ART procedure. Also, because of expense and time commitments, the United States ART clinical population is not fully representative of society diversities. This socio-economic skewing might compensate for negative effects, masking small, or modest developmental deficits. Embryo splitting (ES), an ART procedure used only with animals, can produce genetically identical offspring. ES involves dividing four- to eight-cell embryos into separate blastomeres and implanting them into empty zona pellucida, followed by embryo transfer. Although these ART techniques have produced nonhuman primate offspring, there has been no research on behavioral safety. Here, we report the first study of behavioral development by rhesus macaques infants produced through ES, ICSI, and IVF. We assessed neonatal reflexes, self-feeding ability, recognition memory, object concept attainment, simple discrimination learning and reversal, and learning set (LS) acquisition. Although the sample sizes are small, we found no overall ART group delayed development. Surprisingly, the ES and ICSI monkeys appeared to be accelerated in attaining age milestones involving sensory-motor behaviors and a difficult Well Hiding object concept task. We conclude that macaque monkeys may provide an excellent model for the study of early human development by offspring of parents with conditions requiring ART pregnancies, as well as a model for the behavioral study of genetic-environment interactions using identical twins produced by ES.

Analysis of Variance↗
PubMed2004

A molecular mechanism for stabilization of learning-induced synaptic modifications.

Olfaction is a principal sensory modality in rodents, and rats quickly learn to discriminate between odors and to associate odor with reward. Here we show that such olfactory discrimination (OD) learning consists of two phases with distinct cellular mechanisms: an initial NMDAR-sensitive phase in which the animals acquire a successful behavioral strategy (rule learning), followed by an NMDAR-insensitive phase in which the animals learn to distinguish between individual odors (pair learning). Rule learning regulates the composition of synaptic NMDARs in the piriform cortex, resulting in receptors with a higher complement of the NR2a subunit protein relative to NR2b. Rule learning also reduces long-term potentiation (LTP) induced by high-frequency stimulation of the intracortical axons in slices of piriform cortex. As NR2a-containing NMDARs mediate shorter excitatory postsynaptic currents than those containing NR2b, we suggest that learning-induced regulation of NMDAR composition constrains subsequent synaptic plasticity, thereby maintaining the memory encoded by experience.

Animals↗
PubMed2005

A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80.

delta-Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with mu-opioids e.g. morphine. In the present study, we evaluated the occurrence of antinociceptive and opioid-like side effects in rats (n=5-7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid-induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation-induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood-gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning). Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation-induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO(2) were observed with the higher doses of SNC80 (> or =40 mg/kg). In conclusion, the delta-opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of mu-opioids. However, the activity of SNC80 in the inflammatory model suggests delta-opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.

Animals↗
PubMed2003

An automated apparatus for presenting depth-rotated three-dimensional objects in human and animal object recognition research.

For practical reasons, research on the recognition of objects from different viewpoints has relied almost exclusively on the use of two-dimensional representations of three-dimensional objects. We describe an apparatus that enables the presentation of three-dimensional objects in a discrimination learning paradigm. Three chambers positioned on a movable table allow each of two objects to be presented on either the left or the right side; a viewing window exposes only two of the objects at a time. The objects can be arbitrarily designated as either an S+ or an S-. In addition, they can be placed precisely in any arbitrary start position and rotated in depth in 100 steps of 3.6 degrees each. We have successfully used this apparatus to investigate recognition of depth-rotated objects by both pigeons and humans. By varying the stimuli, number of stimulus chambers, and software programs, the apparatus can be used for other types of tasks and to investigate other types of processes.

Animals↗
PubMed1990

Teaching recognition skills to improve products.

All 86 first year dental students in a Conservative Restorations course completed five sets of instructional tasks. Tasks followed a discrimination learning paradigm, a sequence based on the principal that recognition skills are a prerequisite for production skills. Recognition skill measures and production quality measures were collected for pre- and post-test Class 1 amalgam preparations. Significant improvement was found in three of the five recognition skill measures and in quality of production. Stepwise multiple regression analysis showed that a measure of student agreement with faculty evaluations accounted for 46.3 percent of the variance in post-test production scores whereas traditional admissions measures accounted for less than 4 percent of the variance. Additionally, students who improved recognition skill showed a corresponding improvement in products. The paradigmatic teaching model appears to be valid for Class 1 cavity preparations.

Dental Amalgam↗
PubMed2002

The impact of reinforcement density on response differentiation in configural discrimination problems.

Two human Pavlovian conditioning experiments investigated the impact of reinforcement density (the number of reinforced trials divided by the total number of trials) on discrimination learning. Experiment 1 used a negative patterning problem (A+, B+, AB-) and Experiment 2 used a positive patterning problem (A-, B-, AB+). In both experiments, reinforcement density varied across four levels. Response differentiation between reinforced and non-reinforced stimuli was linearly related to the decrease in reinforcement density. Responses to nonreinforced stimuli did not differ between the four groups in either experiment. In contrast to this, responses to reinforced stimuli were considerably more pronounced in conditions with lower reinforcement density. For negative patterning, this replicates and extends similar observations from other species. For positive patterning, this is a finding that has not yet been reported in other experiments. The results are in agreement with the comparator hypothesis (Miller & Matzel, 1988) and with Wagner's (1981) "standard operating procedures" (SOP) model.

Adult↗
PubMed1999

Long-term effects of neonatal damage to the hippocampal formation and amygdaloid complex on object discrimination and object recognition in rhesus monkeys (Macaca mulatta).

Rhesus monkeys with neonatal aspiration lesions of the hippocampal formation or the amygdaloid complex were tested on concurrent discrimination learning (24-hr intertrial interval [ITI]) at 3 months, on object recognition memory (delayed nonmatching-to-sample [DNMS]) at 10 months, and retested on both tasks at 6-7 years of age. Neonatal amygdaloid damage mildly impaired acquisition at the 24-hr ITI and the performance test of DNMS at both ages. In contrast, early hippocampal lesions impaired performance only on the longest lists of 10 items in DNMS in adult monkeys. Thus, early amygdala lesions appeared to have resulted in a greater object memory loss than early hippocampal lesions. However, in light of recent findings from lesion studies in adult monkeys, the object memory impairment after early amygdaloid lesions is better accounted for by damage to the entorhinal and perirhinal cortex than by damage to the amygdaloid nuclei.

Amygdala↗
PubMed1996

Landmark stability: studies exploring whether the perceived stability of the environment influences spatial representation.

To investigate whether spatial learning complies with associative learning theories or with theories of cognitive mapping, rats were trained in three experiments exploring the effect of variations in spatial predictive relationships. In experiment 1, it was found that making one of two landmarks the sole spatial predictor of reward, by varying the spatial relationship between reward and other cues, reduced the control over search exerted by that landmark compared with that observed when the landmark and context cues were both reliable predictors of reward location. This requirement for landmark stability rather than predictive power appears to contradict results obtained in conventional conditioning paradigms. Discrimination learning was unaffected, suggesting a dissociation between discrimination and spatial learning with respect to the influence of geometric stability. Further experiments used arrays of both single and multiple landmarks. Experiment 2 revealed that the stability of a single landmark improved accuracy of search, but also showed that local stability between a pair of landmarks that moved around the arena together was sufficient to support spatial learning. Experiment 3 examined landmark stability using fixed directional cues in the absence of vestibular disorientation. This also revealed a relative advantage of stable landmarks, but animals presented with a landmark that moved from trial to trial did show some evidence of learning. Parametric manipulation of landmark stability offers an intriguing way of influencing the process of spatial representation and thus understanding better the processes through which egocentric representations of perceived space are transformed into allocentric representations of the real world.

Journal Article↗
PubMed1996

The development of children's strategies on an inductive reasoning task.

This paper reports an analysis of children's cognitive strategies on an inductive reasoning task, by means of a new methodological approach. A sample of 72 children aged 6, 8 and 10 were presented with three different versions of a multidimensional discrimination learning task, which was presented in such a way as to 'optimise' their performance. Their responses were analysed in terms of 10 Strategy Components, scores on which were analysed by means of cluster analysis. Overall, the children performed at more sophisticated levels than previously found. Five Strategy Clusters representing distinct patterns of strategic behaviour were revealed. A developmental sequence was established between these patterns of strategic behaviour and, significantly, two alternative developmental routes relating to strategic style. While the results support a complex model of strategy construction, as revealed by recent research, the distinct nature of the Strategy Clusters points to a discontinuous model of strategy development. This evidence of children's differing abilities to construct and select appropriate strategies in relation to a novel task strongly supports the educational imperative of encouraging children's early use and awareness of cognitive strategies.

Aptitude↗
PubMed1987

Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine.

Male Wistar rats were trained to discriminate the interoceptive effects of 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT; 1.25 mg/kg, IP) from saline in a two-lever operant chamber. Following discrimination learning, the following drugs (with ED50 dose in mg/kg IP) dose-dependently generalized: lysergic acid diethylamide (LSD, 0.04), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.11), 6-methoxy-4-(dipropyl-amino)-1,3,4,5-tetrahydrobenz(c,d)indole hydrochloride (BAY R 1531, 0.15), 5-OMe-DMT itself (0.63), ipsapirone (TVX Q 7821, 2.7), and buspirone (3.8). The potencies of these drugs in generalization tests were best correlated with their binding affinities for the 5-HT1A serotonin receptor subtype (as measured by displacement of 3H-ipsapirone in the hippocampus). Drugs not, or only partially generalizing included quipazine, bufotenin, m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole succinate (RU 24969), citalopram, clomipramine, 1,4-dihydro-2,6-dimethyl-3-nitro-4(2-trifluoromethylphenyl)-pyridine-5- carboxylate (BAY K 8644), the buspirone metabolite 1-pyrimidinyl-piperazine (1-PP), methysergide, metergoline, and metitepine. Of the last three compounds with antagonistic activity at 5-HT receptors, as well as ketanserin, pizotifen, and ritanserin, only metitepine and pindolol could fully block the 5-OMe-DMT stimulus. Pizotifen blocked the generalization of quipazine fully, that of 5-OMe-DMT only partially, and that of ipsapirone not at all. These data indicate that the 5-HT1A receptor subtype is strongly involved in the transduction of the interoceptive discriminative stimuli induced by 5-OMe-DMT, with 5-HT2 agonism also playing a possible role.

Animals↗
PubMed1989

Comparative effects of quisqualic and ibotenic acid-induced lesions of the substantia innominata and globus pallidus on the acquisition of a conditional visual discrimination: differential effects on cholinergic mechanisms.

Two experiments tested the hypothesis that the deficits in conditional discrimination learning produced by ibotenic acid-induced lesions of the ventral pallidum and substantia innominata are produced by loss of the magnocellular cholinergic cells in the nucleus basalis and adjacent regions. Experiment 1 replicated the previously reported deficit in conditional learning produced by ibotenate-induced lesions of the ventral pallidum/substantia innominata, but failed to demonstrate any restoration of learning by a subchronic regimen of the acetylcholinesterase inhibitor physostigmine sufficient to produce significant (30%), but equivalent, degrees of inhibition in the frontal cortex of ventral pallidum/substantia innominata-lesioned or sham-operated rats. Experiment 2 examined the effects of quisqualic acid-induced lesions of the ventral pallidum/substantia innominata. According to most of the measures of learning employed, the quisqualic acid-induced lesion of the ventral pallidum/substantia innominata failed to impair conditional learning, even though the quisqualate-induced lesion produced greater degrees of cholinergic neuron destruction than the ibotenate-induced lesion, as measured in terms of reductions in cortical choline acetyltransferase activity (44% vs 27%). Although consideration of individual data suggested that very high (60%) levels of choline acetyltransferase reduction in Experiment 2 might have detrimental effects of conditional learning, the overall failure of the quisqualate-induced lesions of the ventral pallidum/substantia innominata to impair learning is to be contrasted with the significant behavioural effects of ibotenate-induced lesions. Histological and immunocytochemical analysis showed that the quisqualate-induced lesion, unlike that produced by ibotenate, tended to produce less damage to the overlying dorsal globus pallidus and to parvocellular neurons of the ventral pallidum/substantia innominata, thus implicating these nonspecific effects of ibotenate-induced lesions in their behavioural effects. The present results question previous interpretations of the behavioural effects of ibotenate-induced lesions of the ventral pallidum/substantia innominata in terms of damage inflicted on the cortically-projecting cholinergic cells of the nucleus basalis, and suggest that quisqualic acid, although also nonspecific in its excitotoxic effects, is nevertheless more selective for producing damage to cholinergic neurons in the ventral pallidum/substantia innominata than ibotenic acid.

Animals↗
PubMed2003

Cognitive experience and its effect on age-dependent cognitive decline in beagle dogs.

Test-sophisticated beagle dogs show marked age sensitivity in a size discrimination learning task, with old and senior dogs performing significantly more poorly than young dogs. By contrast, age differences in learning were not seen in dogs naive with respect to neuropsychological test experience. These results indicate that old animals benefit less from prior cognitive experience than young animals, which is an example of an age-dependent loss in plasticity. This finding also suggests that behaviorally experienced animals are a more useful model of human cognitive aging than behaviorally naïve animals. We also looked at the effect of a program of behavioral enrichment in aged dogs. One year of enrichment did not lead to significant differences, but after 2 years the behaviorally enriched group performed significantly better than the control group. The effect after 2 years indicates that a prolonged program of cognitive enrichment can serve as an effective intervention in aged dogs. These findings demonstrate that cognitive abilities in aged animals can be modified by providing behavioral experience, indicating that cognitive abilities remain moderately plastic, even in very old animals.

Age Factors↗
PubMed1996

Auditory quality cues are more effective than auditory location cues in a R--no R (go--no go) differentiation: the extension of the rule to primitive mammals (American opossum, Didelphis virginiana).

Discrimination learning of instrumental responses to auditory compound stimuli was investigated in opossums using the R-no R (go-no go) differentiation. Each compound stimulus consisted of two factors: quality and location. Each correct response performed to the conditioned positive, or "safe" stimulus, was rewarded by food and never punished. Each incorrect response performed to the conditioned negative, or "warning" stimulus, was punished by an electric shock. In subsequent testing, each opossum proved to use only the quality cues to solve the task even though later testing showed them capable of using the location cues. Thus, the rule discovered in higher mammals, that the efficacy of auditory stimuli in differentiation depends on the perceptual ability of the animal as well as the type of the behavioral response with which the animal is confronted, may be extended to neurologically primitive mammals and also to a joint conditioned approach-avoidance method.

Acoustic Stimulation↗
PubMed1999

Specific cognitive deficits in mild frontal variant frontotemporal dementia.

Eight patients with relatively mild frontal variant frontotemporal dementia (fvFTD) were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, planning, visual discrimination learning/attentional set-shifting and decision-making were employed. Patients with fvFTD were found to have deficits in the visual discrimination learning paradigm specific to the reversal stages. Furthermore, in the decision-making paradigm, patients were found to show genuine risk-taking behaviour with increased deliberation times rather than merely impulsive behaviour. It was especially notable that these patients demonstrated virtually no deficits in other tests that have also been shown to be sensitive to frontal lobe dysfunction, such as the spatial working memory and planning tasks. These results are discussed in relation to the possible underlying neuropathology, the anatomical connectivity and the hypothesized heterogeneous functions of areas of the prefrontal cortex. In particular, given the nature of the cognitive deficits demonstrated by these patients, we postulate that, relatively early in the course of the disease, the ventromedial (or orbitofrontal) cortex is a major locus of dysfunction and that this may relate to the behavioural presentation of these patients clinically described in the individual case histories.

Adult↗
PubMed1979

The effects of introtacts on hypothesis testing in kindergarten and first-grade children.

Kindergarten and first-grade children were trained against their initial dimensional preference in a 2-dimensional simultaneous discrimination learning task. One third of the children received pretraining in using a sequential hypothesis-testing strategy, one third received pretraining in which they experienced solutions to tasks of the same type, and one third received no pretraining. Half of the children received introtact probes prior to each trial in the criterion task. Introtact probes had no effect on the performance of kindergarten children but facilitated the performance of first-grade children who received pretraining. Performance was generally better in the pretraining conditions than in the control condition and was generally better for first graders than for kindergarten children. Indices of the use of the sequential hypothesis-testing strategy were obtained from the responses to introtact probes. 75% of the first graders who received pretraining in hypothesis testing showed high proficiency in using the strategy, whereas only 38% of the kindergarten children did so. A strong tendency to become fixated on the irrelevant dimension was evident at both age levels.

Child↗
PubMed2003

Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling.

Vitamin A and its derivatives, the retinoids, have recently been reported to be implicated in the synaptic plasticity of the hippocampus and in cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. We recently showed that a moderate (about 30%) hypoexpression of brain (and hippocampal) retinoid signalling, like that naturally occurring in the aged brain of mice, might be related to a selective relational memory deficit. To further assess this hypothesis, the present study investigated the effects of Vitamin A deprivation of varying duration both on the brain expression of retinoid receptors (RARbeta and RXRbeta/gamma) and two associated target genes [tissue-type transglutaminase (tTG) and neurogranin, (RC3)], and on radial maze discrimination learning using young adult mice as subjects. We observed that irrespective of its duration (i.e. 31 or 39 weeks), Vitamin A deprivation resulted in a significant reduction (25-30%) in the expression of brain RARbeta, RXRbeta/gamma and tTG mRNAs. Conversely, only the 39-week condition was found to induce a significant decrease in brain RC3 mRNAs contents and a selective relational memory impairment. Finally, daily administration of retinoic acid (RA) failed to reverse the 39-week Vitamin A deficiency (VAD)-related cognitive deficit and to fully normalise the associated brain retinoid hyposignalling. In particular, there was no evidence for an up-regulating effect of RA on whole brain (and hippocampal) RC3 mRNAs of the 39-week-depleted mice. The results show that post-natal VAD may induce a selective memory impairment and give further support to the hypothesis that the fine regulation of retinoid-mediated gene expression is important for optimal brain functioning and higher cognition.

Animals↗
PubMed2003

Reduced attention in mice overproducing corticotropin-releasing hormone.

Data from several studies suggest that unrestrained secretion of corticotropin-releasing hormone in the CNS produces several signs and symptoms of depression. Recent evidence indicates that blockade of the CRH receptor 1 reduced depression scores in depressed patients. One of the symptoms that occur is depression is impairment in attentional processes. Whether these impairments are due to alterations in the CRH system are so far unknown. In order to investigate whether overproduction of CRH alters attentional process, transgenic mice overproducing CRH were tested on an operant five choice serial reaction time task, a task which taxes sustained and divided attention. Mutants showed impaired autoshaping. During initial discrimination learning, transgenics performed below wildtype level, but with extended training with long stimulus durations, transgenic animals reached similar accuracy levels as wildtype mice. When animals were tested at shortest stimulus duration (0.5s), a mild but significant impairment in accurate responding emerged in transgenics. This was accompanied by longer correct response latencies, while incorrect latencies did not differ between groups, suggesting attentional impairment in CRH transgenics. Because these animals have been reported to also show increased anxiety-related behaviour, animals were treated with the anxiolytic benzodiazepine diazepam. Diazepam failed to affect accuracy, but transgenic mice showed a stronger behavioural disinhibition. This suggests that the attentional impairment seen in CRH overexpressors is independent of alterations in anxiety-like behaviour. These findings may have implications for understanding the pathophysiology of psychiatric disorders such as depression, where it has been suggested that an overactivity of the CRH system accounts for a variety of symptoms, including hyper-arousal and attentional impairment.

Animals↗
PubMed2006

Consolidation of auditory cortex-dependent memory requires N-methyl-D-aspartate receptor activation.

The pharmacological basis of sensory cortex-dependent learning and associated cortical reorganizations is only partially understood. In the Mongolian gerbil, the auditory cortex is critical for discriminating the directions of modulation of linearly frequency-modulated tones (FMs). To examine the role of N-methyl-D-aspartate (NMDA)-type glutamate receptors in FM discrimination learning, selective antagonists were used. Compared to vehicle-treated controls, both systemic administration of MK-801 before but not after training, and infusion of D-AP-5 into the auditory cortex after training caused retention deficits detectable 24h later. The amnesic actions were reversible and in a close temporal relation to memory formation. Acquisition performance and performance of an established FM discrimination reaction were not affected. These findings suggest that NMDA receptor activation is required for long-term memory consolidation in auditory cortex-dependent learning.

2-Amino-5-phosphonovalerate↗