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PubMed2005

Silent synapses in a thalamo-cortical circuit necessary for song learning in zebra finches.

Developmental changes in synaptic properties may act to limit neural and behavioral plasticity associated with sensitive periods. This study characterized synaptic maturation in a glutamatergic thalamo-cortical pathway that is necessary for vocal learning in songbirds. Lesions of the projection from medial dorsolateral nucleus of the thalamus (DLM) to the cortical nucleus lateral magnocellular nucleus of the anterior nidopallium (LMAN) greatly disrupt song behavior in juvenile birds during early stages of vocal learning. However, such lesions lose the ability to disrupt vocal behavior in normal birds at 60-70 days of age, around the time that selective auditory tuning for each bird's own song (BOS) emerges in LMAN neurons. This pattern has suggested that LMAN is involved in processing song-related information and evaluating the degree to which vocal motor output matches the tutor song to be learned. Analysis of reversed excitatory postsynaptic currents at DLM-->LMAN synapses in in vitro slice preparations revealed a pronounced N-methyl-D-aspartate receptor (NMDAR)-mediated component in both juvenile and adult cells with no developmental decrease in the relative contribution of NMDARs to synaptic transmission. However, the synaptic failure rate at DLM-->LMAN synapses in juvenile males during the sensitive period for song learning was significantly lower at depolarized potentials than at hyperpolarized potentials. In contrast, the failure rate at DLM-->LMAN synapses did not differ at hyper- versus depolarized holding potentials in adult males that had completed the acquisition of a stereotyped song. This pattern indicates that juvenile cells have a higher incidence of silent (NMDAR-only) synapses, which are postsynaptically silent at hyperpolarized potentials due to the voltage-dependent gating of NMDARs. Thus the decreased involvement of the LMAN pathway in vocal behavior is mirrored by a decline in the incidence of silent synapses but not by changes in the relative number of NMDA and AMPA receptors at DLM-->LMAN synapses. These findings suggest that a developmental decrease in silent synapses within LMAN may represent a neural correlate of behavioral plasticity during song learning.

Age Factors↗
PubMed2006

Gene expression profiling in the hippocampus of rats subjected to focal cerebral ischemia and enriched environment housing.

PURPOSE: Enriched environment housing enhances brain plasticity and improves recovery of impaired sensorimotor and cognitive functions of rats subjected to transient middle cerebral artery occlusion (MCAO). The present study applied microarray technique to investigate the molecular basis through which enriched environment might improve spatial learning in MCAO rats. METHODS: MCAO rats were housed in enriched environment or in standard single cages, and sham-operated rats were housed in standard single cages. Spatial learning was assessed using the Morris water-maze on postoperative days 22 to 24. Total RNA from the ipsilateral hippocampus was extracted for microarray analysis after the follow-up period. RESULTS: Water-maze performance on postoperative days 22 to 24 showed that rats subjected to transient MCAO were impaired in the hippocampus-dependent Morris water-maze test. Enriched environment housing reversed the spatial learning impairment on postoperative day 23. Gene expression in the hippocampus was not affected by MCAO or following enriched environment housing. CONCLUSION: Spatial learning impairment following transient MCAO in rats and cognitive improvement following housing in enriched environment is not related to % related to extrahippocampal brain regions rather than altered hippocampal gene expression.

Animals↗
PubMed1998

Characteristics of a long-term procedural skill in the monkey.

The purpose of this study was to characterize the nature and structure of procedural memory. We have previously studied the process of learning sequential behavioral procedures using monkeys. The monkey's task was to press five consecutive pairs of buttons (indicated by illumination) in the correct order for every pair, which he had to find by trial-and-error in a block of trials. The whole sequence was called a "hyperset"; each pair was called a "set". We first examined whether monkeys learned to perform a hyperset as a single sequence or learned the order of button-presses individually for each set. To answer this question, we generated hypersets that were the same as the hypersets that had been extensively learned except that the order of the sets was reversed. The performance of these "reversed hypersets" was much worse than the performance of the original learned hypersets and was similar to the performance of new hypersets, as regards both the number of errors and the performance time. The result suggests that monkeys learned a hyperset as a sequence. To examine whether the learned performance was specific to the hand used for practice, we had monkeys use the same hand throughout the long-term practice of each hyperset, and then tested the opposite hand. The performance using the opposite hand was worse than the performance using the trained hand, but was better than the performance for new hypersets. This indicates that the memory for the sequential procedure is only partially accessible to the hand that was not used for the practice.

Animals↗
PubMed1997

Enhancement of contextual fear-conditioning by putative (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators and N-methyl-D-aspartate (NMDA) receptor antagonists in DBA/2J mice.

Previous studies demonstrated that DBA/2J (DBA) mice performed poorly while C57BL/6J (C57) mice performed normally on a number of complex learning and memory tasks. Chronic oxiracetam treatment dramatically improved the performance of DBA mice but not that of C57 mice on the Morris water task and in contextual fear conditioning. The present study demonstrates that acute treatment with nootropics, oxiracetam (10-1000 mg/kg) or aniracetam (10-100 mg/kg), and N-methyl-D-Aspartate (NMDA) antagonists, (+)-MK-801 (0.1-3 microg/kg), CPP (0.01-0.3 mg/kg), and (+)-HA-966 (0.1-3 mg/kg), administered prior to training and testing, reversed the contextual learning impairment in DBA mice in a dose-dependent manner without affecting auditory cue conditioning. These effects appeared to be independent of testing order (context vs. auditory cue tests) and were not due to state-dependent learning. The inactive stereoisomers, (-)-MK-801 and (-)-HA-966, were incapable of increasing contextual freezing in DBA mice. In DBA mice, the effects of 30 mg/kg oxiracetam and 100 mg/kg aniracetam were inhibited by the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonists, NBQX, and GYKI-52466. The combined administration of 30 mg/kg oxiracetam and 1 microg/kg (+)-MK-801 produced an additive response. None of the pharmacological treatments altered performance in C57 mice at doses that were effective in DBA mice. These results suggest that DBA mice may be learning impaired due to altered glutamatergic receptor function.

Acoustic Stimulation↗
PubMed1999

Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage.

Neuropsychological studies of patients with schizophrenia have consistently identified deficits on tests sensitive to frontal lobe function. One paradigm that has been widely used is that of attentional set-shifting using the Wisconsin Card Sorting Test (WCST). In the present study, patients with chronic schizophrenia and with frontal lobe lesions were assessed on a computerised set-shifting task that provides a componential analysis of the WCST by distinguishing between intra-dimensional and extra-dimensional set-shifting. Out of 51 patients with schizophrenia, those with high IQ (n =24) were compared with patients with lesions in prefrontal cortex (n = 22) and with normal control subjects (n= 18). These three groups were well matched for age, sex and National Adult Reading Test (NART) IQ. The schizophrenic group showed a significantly higher rate of attrition at the intra-dimensional shift stage of learning compared with the other two groups. At the extra-dimensional shift stage, both the schizophrenic and frontal lesioned groups showed greater attrition than controls. Further, patients with schizophrenia who were able to learn the intradimensional reversal stage required more trials and made significantly more errors at that stage than the other two groups. In comparison with high IQ patients with schizophrenia, those with low IQ performed at a lower level but showed a qualitatively similar pattern of performance, providing further evidence that the set-shifting deficits were not simply explained by any global intellectual decline. Patients with schizophrenia who dropped out at the extradimensional shift stage had higher negative symptom scores compared with patients dropping out at previous learning stages, while patients failing at the intra-dimensional shift stage had lower scores for bradyphrenia (slowness of thought). The results suggest that patients with chronic schizophrenia fail to 'learn set' and are impaired at both set-shifting and concept formation. The relevance of these findings to understanding the nature of prefrontal cortical deficits in chronic schizophrenia is discussed. The implication of these findings to the rehabilitation of these patients is considered.

Adult↗
PubMed1976

Effects of para-chlorophenylalanine and tryptophan on learning of a brightness discrimination in rats.

Both the learning of brightness discrimination, discrimination reversal and a simple oddity problem, and the pain-sensitivity to electric shock were studied in rats treated with 100 mg/kg of D, L-parachlorophenylalanine (PCPA), 100 mg/kg of D, L-tryptophan (TP) or 2.0 ml/kg of control solution (CS). At the end of the last behavioral session all animals were killed and the levels and rate of 5-hydroxytryptamine (5-HT) synthesis were measured. PCPA treatments produce rats which are more effective in coping with a problem; these animals were similar in that both the levels and turnover rate of brain 5-HT and the pain-sensitivity were lower. Results are tentatively explained suggesting that these differences in learning ability could be a result of the drug's action in pain-sensitivity. The possibility that 5-HT might be responsible for these differences is discussed.

Animals↗
PubMed1998

Effects of bilateral electrolytic lesions of the medial nucleus accumbens on exploration and spatial learning.

Rats with electrolytic lesions of the medial part of the nucleus accumbens, comprising the shell region, were compared to sham-operated rats in tests of exploration in a T-maze, in a hole-board, and in an elevated (+)-maze and in a test of water maze spatial learning. Rats with medial nucleus accumbens lesions had higher choice latencies than sham-operated controls during the beginning of the spontaneous alternation test. A higher number of hole pokes was found in the lesioned group, but only during the beginning of the second day of testing. In the elevated (+)-maze, lesioned rats had a higher number of closed and total arm entries and spent more time in the center region. The lesioned group did not differ from the control group for the number of alternations in the T-maze, for horizontal and vertical motor activity in the hole-board, and for acquisition or reversal of spatial learning in the Morris water maze. These results indicate that lesions of the medial nucleus accumbens slowed down decision time during spontaneous alternation testing and increased exploration in a time and test-specific manner without altering acquisition of a reference memory task.

Animals↗
PubMedDate not supplied

Practice-related changes in human brain functional anatomy during nonmotor learning.

Practice of a novel task leads to improved performance. The brain mechanisms associated with practice-induced improvement in performance are largely unknown. To address this question we have examined the functional anatomy of the human brain with positron emission tomography (PET) during the naive and practiced performance of a simple verbal response selection task (saying an appropriate verb for a visually presented noun). As a control state, subjects were asked to repeat the visually presented nouns. Areas of the brain most active during naive performance (anterior cingulate, left prefrontal and left posterior temporal cortices, and the right cerebellar hemisphere), compared to repeating the visually presented nouns, were all significantly less active during practiced performance. These changes were accompanied by changes in the opposite direction in sylvian-insular cortex bilaterally and left medial extrastriate cortex. In effect, brief practice made the cortical circuitry used for verbal response selection indistinguishable from simple word repetition. Introduction of a novel list of words reversed the learning-related effects. These results indicate that two distinct circuits can be used for verbal response selection and normal subjects can change the brain circuits used during task performance following less than 15 min of practice. One critical factor in determining the circuitry used appears to be the degree to which a task is learned or automatic.

Adult↗
PubMed1989

A comparison of the effects of fornix transection and sulcus principalis ablation upon spatial learning by monkeys.

In each of three experiments with Cynomolgus monkeys (Macaca fascicularis), there was a group of normal control animals, a group with bilateral cortical ablations in the principal sulcus, and a group with fornix transection. In Expt. 1, half of each group learned problems in which the position of a pair of visual stimuli, to the monkey's left or right, indicated which of the visual stimuli was the correct (rewarded) one. The other animals learned problems in which visual stimuli indicated, irrespective of their own spatial position, whether reward was to be found on the monkey's left or on the right. The animals with fornix transection were impaired in both tasks. The animals with sulcus principalis ablation were also impaired in both tasks. The impairment caused by fornix transection was more severe than that caused by sulcus principalis ablation. Within each of the two operated groups, the degree of impairment in the two tasks was equal, when assessed in proportion to the difficulty of each task for control animals. Expt. 2 showed that neither of the operated groups was impaired in visual discrimination learning with spatial position irrelevant. Expt. 3 tested spatial discrimination learning (acquisition and reversal of a left-right discrimination) with irrelevant visual cues. Here the fornix-transected group was impaired but the group with sulcus principalis ablations was normal. It is suggested, on the basis of these findings and previous results, that fornix transection produces a general deficit in remembering the spatial arrangement of whole scenes, while sulcus principalis ablation produces a deficit in high-order integration involving spatial information.

Animals↗
PubMed2005

Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain.

Intellectual function is impaired in patients with hyperammonemia and hepatic encephalopathy. Chronic hyperammonemia with or without liver failure impairs the glutamate-nitric oxide-cGMP pathway function in brain in vivo and reduces extracellular cGMP in brain as well as the ability of rats to learn a Y maze conditional discrimination task. We hypothesized that the decrease in extracellular cGMP may be responsible for the impairment in learning ability and intellectual function and that pharmacological modulation of the levels of cGMP may restore learning ability. The aim of this work was to try to reverse the impairment in learning ability of hyperammonemic rats by pharmacologically increasing extracellular cGMP in brain. We assessed whether learning ability may be restored by increasing extracellular cGMP in brain by continuous intracerebral administration of: (1) zaprinast, an inhibitor of the phosphodiesterase that degrades cGMP or (2) cGMP. We carried out tests of conditional discrimination learning in a Y maze with control and hyperammonemic rats treated or not with zaprinast or cGMP. Learning ability was reduced in hyperammonemic rats, which needed more trials than control rats to learn the task. Continuous intracerebral administration of zaprinast or cGMP restored the ability of hyperammonemic rats to learn this task. Pharmacological modulation of extracellular cGMP levels in brain may be a useful therapeutic approach to improve learning and memory performance in individuals in whom cognitive abilities are impaired by different reasons, for example in patients with liver disease who present hyperammonemia and decreased intellectual function.

Animals↗
PubMed1977

Classical conditioning with auditory discrimination of the eye blink in decerebrate cats.

Cats were subjected to complete lower brainstem transection, and were then tested for learning ability according to a classical conditioning paradigm. An auditory stimulus was systematically paired with a brief shock to the eyelid. Within a few weeks after the operation, the decerebrate cats could learn the conditioned response with a tone frequency discrimination and then a discrimination reversal. Our results support the notion that the brainstem reticular formation can support a conditioned response which isbehaviorally similar to that obtained in the intact animal.

Acoustic Stimulation↗
PubMed1986

Differential effect of posttraining naloxone, beta-endorphin, leu-enkephalin and electroconvulsive shock administration upon memory of an open-field habituation and of a water-finding task.

Rats were trained and tested in an open field for habituation of rearing responses, for a water-finding task, or for both tasks simultaneously. Training-test interval was 24 hr. The water-finding task consisted of locating a metal tube in one of the walls of the box, which was attached to a water bottle on the outside; animals were water deprived between training and testing. Retention was estimated by measuring the latency to lick from the tube on the test session. Rats learned this task either with or without water deprivation, also prior to training. Habituation learning (reduction of the number of rearings between the training and test session) occurred either simultaneously with the water-finding task or in animals trained without the water tube, so that they could not learn the water-finding task. As happens with many other tasks, training in the open field was followed by a large decrease of hypothalamic beta-endorphin immunoreactivity, attributable to a release of this substance. Posttraining IP naloxone (1.6 mg/kg) administration facilitated, and posttraining beta-endorphin (2.0 micrograms/kg), leu-enkephalin (5.0 micrograms/kg), or electroconvulsive shock (15 mA, 60 Hz, 2 sec) depressed the retention of habituation; this occurred regardless of whether the animals were trained and/or tested with or without water deprivation, and whether the task was acquired alone or simultaneously with the water-finding task. By contrast, none of these treatments had any effect on retention of the water finding task, acquired either with or without prior water deprivation. Thus, habituation was, and water-finding was not, sensitive to posttraining treatments known to affect endogenous opioids: the opioids themselves, their antagonist, naloxone, and electroconvulsive shock which releases brain opioids and causes naloxone-reversible retrograde amnesia. Learning of the water-finding task was merely incidental to exploration of the open field; it took place even when the animals were trained without the water tube. This suggests that the posttraining treatments that affect endogenous opioid function affect memory only of the task(s) that actually cause the release of brain beta-endorphin (in this case, probably habituation), and not of others that may occur simultaneously but are merely incidental (water-finding). A feature apparently common to the former is that they must directly involve either the recognition of novelty, or the initiation of an interaction with a new environment, or perhaps the habituation of such interaction.

Animals↗
PubMed1981

Comparison of biological and behavioral activities of alpha- and gamma-melanocyte stimulating hormones.

The biological and behavioral activities of gamma-MSH (gamma-MSH) and alpha-MSH (alpha-MSH) were compared using three different tests: darkening of the skin of Anolis, grooming behavior of rats, and performance of a visual discrimination task by rats. When incubated with the Anolis skin, both peptides cause skin darkening. However, alpha-MSH is much more potent than gamma-MSH. The alpha-MSH effect is not antagonized by coincubation with gamma-MSH. When given intraventricularly to rats, alpha-MSH induces a marked grooming behavior. This effect was not noted upon administration of gamma-MSH. Injection of gamma-MSH with the alpha-MSH did not produce a grooming response significantly different from alpha-MSH alone. In the visual discrimination task, the two peptides had opposite effects on the rate at which rats learned the initial discrimination and a subsequent reversal. The peptides were injected intraperitoneally prior to behavioral testing. Following alpha-MSH, rats learned the discrimination and subsequent reversal faster than the control rats. Following gamma-MSH, rats learned the initial discrimination at approximately the same rate as controls, and learned the reversal much slower. These results are discussed in terms of the similarity and differences in the mechanisms of action of alpha-MSH and gamma-MSH.

Animals↗
PubMed1998

Reversion of muscarinic autoreceptor agonist-induced acetylcholine decrease and learning impairment by dynorphin A (1-13), an endogenous kappa-opioid receptor agonist.

1. We investigated whether carbachol, a muscarinic receptor agonist, induces learning and memory impairment, and if so, dynorphin A (1-13), an endogenous kappa-opioid receptor agonist, ameliorates the impairment of learning and memory induced by carbachol, by use of a step-through type passive avoidance task. 2. Carbachol induced a dose-related dual response. Carbachol (1.66 pmol per rat) administered directly into the hippocampus significantly shortened the step-through latency, while lower (0.166 pmol per rat) and higher (16.6 pmol per rat) doses of carbachol did not induce learning or memory impairment. 3. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) administered 5 min after carbachol injection significantly reversed carbachol-induced impairment of learning and memory. 4. Perfusion with carbachol (3 x 10(-4) M) significantly decreased acetylcholine release in the hippocampus during perfusion as determined by in vivo brain microdialysis. This decrease in acetylcholine release was suppressed by co-perfusion with a low dose of atropine (10(-7) M). 5. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) immediately before carbachol perfusion completely blocked this decrease in extracellular acetylcholine concentration induced by carbachol. 6. These antagonistic effects of dynorphin A (1-13) were abolished by treatment with norbinaltorphimine (5.44 nmol per rat, i.c.v.), a selective kappa-opioid receptor antagonist, 5 min before dynorphin A (1-13) treatment. 7. These results suggest that the neuropeptide dynorphin A (1-13) ameliorates the carbachol-induced impairment of learning and memory, accompanied by attenuation of the reductions in acetylcholine release which may be associated with dysfunction of presynaptic cholinergic neurones via kappa-opioid receptors.

Acetylcholine↗