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Nimodipine facilitates associative learning in aging rabbits.

Nimodipine is one of several dihydropyridines that block calcium channels. Originally administered to improve cerebral blood flow in elderly patients with chronic cerebrovascular disorders, nimodipine was noted to facilitate learning. These observations led to the present investigation of the effects of nimodipine on associative learning in aging rabbits. Nimodipine accelerated acquisition of conditioned eye-blink in both young and aging rabbits without altering the amplitude of responses to the conditioned or unconditioned stimuli or causing nonspecific responding. Thus, nimodipine may be a candidate for an effective treatment for age-related learning deficits.

Aging↗

Effects of lesions to the hippocampus or the fornix on allocentric conditional associative learning in rats.

Rats with lesions of the fornix, the hippocampus, or normal control animals were trained on a visual-spatial conditional associative learning task in which they had to learn to go to a particular location based on the presence of a specific visual cue; the rats approached the cues from different directions. Animals with damage of the fornix were able to learn the task at a rate comparable to that of the control animals. The performance of the hippocampal rats was significantly impaired as compared with the control group. Both the fornix and the hippocampal animals were significantly impaired on a spatial working memory task, the eight-arm radial maze. These findings suggest that, under certain conditions, a functional dissociation exists between the effects of damage to the fornix or the hippocampus and that the fornix may be only selectively involved in spatial learning and memory.

Animals↗

Associative learning and short-term forgetting as a function of age, perceptual speed, and central executive functioning.

In a study of two components of associative learning, it was found that during acquisition older people were more likely to forget material on which they were previously correct, but only for associations which were not well learned. Older people also formed fewer correct associations in the course of the task. Differences in learners' perceptual speed were found to account for some of the age deficit in the number of learning attempts, but speed was less relevant in accounting for age differences in forgetting and in the ability to generate new responses. Measured central executive functioning was less important in accounting for age differences on all measures. It is argued that forgetting is less important as a source of learning performance than has been suggested elsewhere (e.g., Salthouse, 1994). Rather, it is the inability of older persons to form associations as rapidly as younger ones which accounts for most of the age effect.

Adult↗

The MAPK cascade is required for mammalian associative learning.

Mitogen-activated protein kinase (MAPK) is an integral component of cellular signaling during mitogenesis and differentiation of mitotic cells. Recently MAPK activation in post-mitotic cells has been implicated in hippocampal long-term potentiation (LTP), a potential cellular mechanism of learning and memory. Here we investigate the involvement of MAPK in learning and memory in behaving animals. MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning. Two other protein kinases known to be activated during hippocampal LTP, protein kinase C and alpha-calcium/calmodulin protein kinase II, also were activated in the hippocampus after learning. Inhibition of the specific upstream activator of MAPK, MAPK kinase (MEK), blocked fear conditioning. Thus, classical conditioning in mammals activates MAPK, which is necessary for consolidation of the resultant learning.

Animals↗

The role of level of representation in the use of paired associate learning for rehabilitation of alexia.

Patients with phonological alexia (difficulty reading pseudowords) frequently have concomitant difficulty reading functor words and verbs compared with concrete nouns. The current study compares two techniques for helping two patients with phonological alexia regain the ability to read functors and verbs. One technique follows the approach of reorganization of function, while the other relies on the stimulation approach. Study 1, employing a reorganization approach, resulted in both patients increasing their reading accuracy from approximately 10 to 90% or greater. Study 2, using a stimulation approach, resulted in significant improvement, however neither patient was able to achieve accuracy greater than 59%. Study 3 reverted back to the reorganization approach using the same words from Study 2. Both patients demonstrated significant success, achieving 90% or greater accuracy. Whereas the reorganization approach meets with far greater success than the stimulation approach, both approaches can be seen as instances of paired associate learning. An explanation of the advantage of the reorganization approach is developed which focuses on the nature of the pairings in the paired associate learning paradigm: it is proposed that pairings within the same level of representation are easier to learn than pairings that cut across levels of representation.

Aged↗

Dual antennular chemosensory pathways mediate odor-associative learning and odor discrimination in the Caribbean spiny lobster Panulirus argus.

Chemosensory neurons in the antennular flagella of lobsters mediate long-range responses to chemicals. These neurons are part of two parallel chemosensory pathways with different peripheral and central components. Aesthetasc sensilla on the lateral flagella are innervated by chemosensory neurons that project to the olfactory lobes. A diversity of other 'non-aesthetasc' sensilla on both lateral and medial flagella are innervated by mechano- and chemosensory neurons, and most of these non-aesthetasc neurons project to the lateral antennular neuropils. We investigated the roles of these two pathways in odor-associative learning and odor discrimination by selectively removing either aesthetasc or non-aesthetasc sensilla from the spiny lobster Panulirus argus. Lobsters lacking both aesthetasc and non-aesthetasc antennular sensilla show very reduced or no odor-mediated searching behavior. We associatively conditioned lobsters using two paradigms: aversive conditioning with generalization testing (which reveals the similarity in the lobsters' perception of odorants) and discrimination conditioning (which reveals the lobsters' ability to discriminate odorants). Sham-control intact lobsters performed these tasks well, as did lobsters lacking either aesthetascs or non-aesthetasc setae. There was a strong but statistically non-significant trend that lobsters lacking either aesthetascs or non-aesthetasc setae generalized more between complex odor mixtures than did intact lobsters. After aversive conditioning with generalization testing, aesthetasc-ablated lobsters had more difficulty discriminating among the most closely related complex mixtures than did intact or non-aesthetasc-ablated lobsters. However, after discrimination conditioning, aesthetasc-ablated lobsters were as proficient as intact animals in discriminating highly similar mixtures. These results indicate overlap and redundancy in the function of these two chemosensory pathways in odor-associative learning and odor discrimination, but these pathways also complement each other to enable better discrimination. This study presents the first evidence for a role of non-aesthetasc chemosensory neurons in complex odor-mediated behaviors such as learning and discrimination.

Animals↗

Effects of serotonin 5-HT(2A/2C) antagonists on associative learning in the rabbit.

The 5-HT(2A/2C) receptor antagonist, ritanserin, was reported to retard the acquisition of conditioned responses (CRs) during classical conditioning of the rabbit's nictitating membrane (NM) response. The present study compared the effects of ritanserin on acquisition of CRs to a tone conditioned stimulus (CS) with that of the 5-HT(2A/2C) receptor antagonist, LY-53,857 and the 5-HT2A selective antagonist, MDL-11,939. All three drugs were injected at equimolar doses of 0.067, 0.67 and 6.7 micromol/kg, SC, 1 h before behavioral testing. Ritanserin and MDL-11,939 retarded CR acquisition to a tone CS, while LY-53,857 had no effect. Control experiments demonstrated that ritanserin (1 micromol/kg), MDL-11,939 (1 micromol/kg) and LY-53,857 (2 micromol/kg) had no effect on baseline responding or non-associative responding to the CS. However, both ritanserin and MDL-11,939 impaired the performance of the unconditioned NM reflex, as measured by a decrease in UR amplitudes on US alone trials, while LY-53,857 had no effect. In previously trained animals, ritanserin robustly impaired the performance of CRs, as measured by a reduced ability of the CS to elicit CRs, while the effects of LY-53,857 and MDL-11,939 were marginal. The retardation of associative learning produced by ritanserin and MDL-11,939 may have been due, at least in part, to their impairment of the NM reflex arc. Since MDL-11,939 is a highly selective 5-HT2A antagonist, the retardation of learning and impairment of UR amplitudes produced by MDL-11,939 and ritanserin may have been due to blockade of the 5-HT2A receptor. The ability of ritanserin and MDL-11,939 to produce effects on learning and performance that were opposite to that of 5-HT(2A/2C) agonists suggests that they may be acting as inverse agonists at that receptor. These results stress the importance of the serotonergic system for optimal associative learning and motor function.

Animals↗

Metamorphosis of the mushroom bodies; large-scale rearrangements of the neural substrates for associative learning and memory in Drosophila.

Paired brain centers known as mushroom bodies are key features of the circuitry for insect associative learning, especially when evoked by olfactory cues. Mushroom bodies have an embryonic origin, and unlike most other brain structures they exhibit developmental continuity, being prominent components of both the larval and the adult CNS. Here, we use cell-type-specific markers, provided by the P[GAL4] enhancer trap system, to follow specific subsets of mushroom body intrinsic and extrinsic neurons from the larval to the adult stage. We find marked structural differences between the larval and adult mushroom bodies, arising as the consequence of large-scale reorganization during metamorphosis. Extensive, though incomplete, degradation of the larval structure is followed by establishment of adult specific alpha and beta lobes. Kenyon cells of embryonic origin, by contrast, were found to project selectively to the adult gamma lobe. We propose that the gamma lobe stores information of relevance to both developmental stages, whereas the alpha and beta lobes have uniquely adult roles.

Animals↗

Spatial association learning by rufous hummingbirds (Selasphorus rufus): effects of relative spacing among stimuli.

Gestalt theory predicts that when cues are spatially separated from response locations, associative learning is faster when distance between cue-response location pairs is increased. This prediction was tested with 20 rufous hummingbirds (Selasphorus rufus), which learned to select rewarding feeders signaled by a spatially separated light cue in 4 treatments in which distance between cues and feeders and between cue-feeder pairs was varied. As has been shown for other animals, the hummingbirds learned more slowly when the distance between cues and feeders was increased, and as predicted by Gestalt theory, they learned faster at a given distance when distance between cue-feeder pairs was increased. This result suggests that spatial association is influenced by the proximity of other stimuli in the visual field.

Animals↗

Ryanodine receptor modulation of in vitro associative learning in Hermissenda crassicornis.

Classical conditioning of the mollusc, Hermissenda crassicornis, is a model system used to study cellular correlates of associative learning. Paired presentation of light and turbulence, but not unpaired presentations, causes Hermissenda to contract its foot in response to light alone. Intracellular recordings from the type B photoreceptors of the Hermissenda eye reveal a learning specific increase of input resistance, and a reduction of voltage-dependent potassium currents, both of which depend on an elevation of intracellular calcium. Two previously demonstrated sources of calcium are influx through voltage-dependent channels, and release of calcium from intracellular stores through the IP3 receptor channel. Both modeling studies and identification of memory-related genes using RNA fingerprinting suggest that a third source of calcium, release from intracellular stores through the ryanodine receptor, may be involved in classical conditioning. We describe here an experiment suggesting that this third source of calcium is necessary for the cellular changes underlying associative memory storage. Paired presentations of a light stimulus with a turbulence stimulus resulted in a significant increase in input resistance. Unpaired presentations of light and turbulence did not produce a significant increase in input resistance. A third group of nervous systems first was incubated in dantrolene to block release of calcium through the ryanodine receptor, and then received paired training. There was no change in input resistance for this group. The effect of dantrolene on light adaptation of the photoreceptor was assessed by measuring the generator potential of a second light pulse presented some number of seconds after a first light pulse. The results show that at interpulse intervals of 5 s, 10 s and 20 s, the generator potential of the dantrolene group is significantly greater than that of the control group. These results suggest a role for the ryanodine receptor in both a cellular correlate of classical conditioning and light adaptation.

Action Potentials↗

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction.

Animals↗

Inhibition of nitric oxide synthase impairs early olfactory associative learning in newborn rats.

The present experiments examined the role of nitric oxide ( NO) in early associative olfactory learning in rats. A preference for peppermint odor was induced by pairing peppermint odor with tactile stimulation in Wistar rat pups, in either a repetitive training paradigm or in a one-trial olfactory learning paradigm. In a first experiment we studied the effect of nitric oxide synthase (NOs) inhibition on early olfactory learning in a repetitive paradigm, by systemic daily injections of NG-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg, i.p.). In order to exclude possible deleterous effects of repeated injections of l-NAME, we explored in a second experiment the effect of a single inhibitor injection in a one-trial olfactory learning paradigm. Inhibition of NOs was performed by either administration of l-NAME (50 mg/kg, i.p.), or 7-nitroindazole (7-NI, 30 mg/kg, i.p.), a more selective inhibitor of the neuronal NOs. We showed that both l-NAME and 7-NI impaired early olfactory associative learning when given before training but not before subsequent testing. Considering that NOs neurons are already widespread in the central nervous system (the olfactory bulb included) during the first postnatal week, the sites where NO inhibition may have acted to impair olfactory learning are discussed. The mechanisms of action of NO in relation with other neurotransmitters known to be necessary for olfactory conditioning in rat pups remain to be established. Impairment by NO synthesis inhibition of the acquisition during the first postnatal week of an olfactory conditioning, but not its recall, suggests a role for NO at synapses involved in that learning.

Animals↗

Crossed unilateral lesions of the medial forebrain bundle and either inferior temporal or frontal cortex impair object-reward association learning in Rhesus monkeys.

In an accompanying paper we showed that combined transection of the fornix, amygdala and temporal stem in monkeys produced dense amnesia, including an impairment in visual object-reward association learning. We proposed that this combined surgical section had its effect by isolating temporal cortex from the ascending projections of the basal forebrain and midbrain structures. To test this hypothesis, in the present experiment we disconnected the inferior temporal cortex from these basal forebrain and midbrain structures, while sparing cortical white matter, by crossed unilateral lesions of the medial forebrain bundle in one hemisphere and inferior temporal cortex in the opposite hemisphere. The aim of the medial forebrain bundle lesion was to section axons of cells, both those that project to the cortex via the medial forebrain bundle, and those which control the activity of these same structures. A single unilateral lesion alone had no effect on the ability to learn and remember visual object-reward associations, but the crossed unilateral lesions produced an impairment in this task which was equal in severity to the impairment seen earlier after bilateral section of the fornix, amygdala and temporal stem. The impairment was not an effect of interrupting fibres to the cortex from the ventromedial hypothalamus, or of unilateral sensory neglect. This supports the hypothesis that these midbrain and basal forebrain afferents to the inferior temporal cortex are important for new visual learning. Furthermore, an impairment of equal severity was demonstrated in a separate group of animals that received crossed unilateral lesions of the medial forebrain bundle in one hemisphere and of the frontal cortex in the opposite hemisphere. We propose that the frontal cortex acts to modulate basal forebrain activity which in turn reinforces object representations in the inferior temporal cortex during learning.

Animals↗

Selectively impaired associative learning in older people with cognitive decline.

Older people with declining cognitive function typically display deficits in declarative memory processes, often most evident on tests of associative learning (AL). The hippocampal formation (HF) is thought to be critically involved in the encoding and retrieval of such associations, consistent with neuroimaging findings that the HF is damaged in early stages of neurodegenerative disease and in older people with AL impairments. In the clinic, older people with cognitive decline commonly report difficulties associating names with faces. However, we have observed that such people are particularly impaired on tests requiring the association of novel stimuli. In Experiment 1, a series of AL tasks were administered to older people with cognitive decline to determine whether they were impaired at simply making associations, or at making associations between novel stimuli. In Experiment 2, we measured HF function in these subjects by administering an AL task designed to differentiate between HF-damaged and HF-intact individuals. Our experimental protocols were guided by a computational model of HF function in AL described by Gluck and Myers (1997). Older people with cognitive decline displayed impaired performance on tasks designed to be highly dependent upon intact HF function, including a task in which novel patterns and spatial locations were to be associated. These results suggest that the AL impairments observed in older people with cognitive decline may be due to HF dysfunction.

Aged↗

Motor activity, anticipated motor activity, and young children's associative learning.

The purpose of this study was to determine whether motor activity, previously assumed necessary to induce imagery in young children's associative learning, actually has to be executed. The results of our experiment with kindergartners clearly suggest not: In conditions where subjects simply planned to the potential motor activity (without executing it), learning was enhanced. Further, the temporal proximity of the planning to the potential motor activity did not prove to be important. These results, combined with those from 2 follow-up experiments, give rise to the speculation--among others--that young children can be "tricked" into imagery generation through appropriately worded instructions.

Association Learning↗

Associative learning modifies two behaviors in the leech, Hirudo medicinalis.

We report that 2 behaviors, stepping and shortening, are modified by associative learning in the leech, Hirudo medicinalis. Experiment 1 explored conditioning of the "stepping" response. Paired presentations of touch to the medial dorsal surface of the leech and shock to the tail of the leech resulted in the development of stepping to the touch. Leeches in control groups experiencing the CS alone, US alone, or explicitly unpaired presentations of the CS and US did not. In experiments 2-4, classical conditioning explored conditioning of the touch-elicited shortening reflex. We found that the reflex was enhanced following paired CS-US presentations but not following CS alone, US alone, or explicitly unpaired presentations of the stimuli. Moreover, the learning was extinguished following 15 unreinforced presentations of the CS but was retained for at least 24 hr without extinction training. Moreover, the associative effect was not evident when the CS and US were presented in a backward relationship. That is, no learning was observed when the US preceded the CS. Lastly, the hand-held stimuli were replaced with implanted electrodes. Using a 3 V pulse that mimicked the touch stimulus (CS), we found that paired CS-US presentations produced a significant enhancement in the shortening reflex. Again, no enhancement was observed following unpaired CS, US presentations.

Animals↗