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Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice.

The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.

Animals↗

Nonconscious associative learning: Pavlovian conditioning of skin conductance responses to masked fear-relevant facial stimuli.

We examined the possibility of nonconscious associative learning in a context of skin conductance conditioning, using emotional facial expressions as stimuli. In the first experiment, subjects were conditioned to a backwardly masked angry face that was followed by electric shock, with a masked happy face as the nonreinforced stimulus. In spite of the effectively masked conditioned stimuli, differential conditioned skin conductance responses were observed in a subsequent nonmasked extinction phase. This effect could not be attributed to differential sensitization or pseudo-conditioning. In the second experiment, the differential responding during extinction was replicated with angry but not with happy faces as conditioned stimuli. It was concluded that with fear-relevant facial expressions as the conditioned stimulus, associative learning was possible even in conditions where the subjects remained unaware of the conditioned stimulus and its relationship to the unconditioned stimulus.

Adult↗

Coherence of gamma-band EEG activity as a basis for associative learning.

Different regions of the brain must communicate with each other to provide the basis for the integration of sensory information, sensory-motor coordination and many other functions that are critical for learning, memory, information processing, perception and the behaviour of organisms. Hebb suggested that this is accomplished by the formation of assemblies of cells whose synaptic linkages are strengthened whenever the cells are activated or 'ignited' synchronously. Hebb's seminal concept has intrigued investigators since its formulation, but the technology to demonstrate its existence had been lacking until the past decade. Previous studies have shown that very fast electroencephalographic activity in the gamma band (20-70 Hz) increases during, and may be involved in, the formation of percepts and memory, linguistic processing, and other behavioural and perceptual functions. We show here that increased gamma-band activity is also involved in associative learning. In addition, we find that another measure, gamma-band coherence, increases between regions of the brain that receive the two classes of stimuli involved in an associative-learning procedure in humans. An increase in coherence could fulfil the criteria required for the formation of hebbian cell assemblies, binding together parts of the brain that must communicate with one another in order for associative learning to take place. In this way, coherence may be a signature for this and other types of learning.

Adult↗

Retardation of associative learning in the rabbit by an adenosine analog as measured by classical conditioning of the nictitating membrane response.

A series of 5 experiments examined the effects of the adenosine agonist, N6-(L-phenylisopropyl) adenosine (L-PIA) and its isomer, D-PIA, on the acquisition of conditioned responses in the rabbit. Extension of the nictitating membrane was classically conditioned to a tone and light stimulus presented for 800 msec before delivery of a 100 msec shock--the unconditioned stimulus--to the skin over the paraorbital region of the head. L-PIA (5.0 mumol/kg) retarded the rate of acquisition of conditioned responses to both the tone- and light-conditioned stimuli, while D-PIA, at doses of 5.0 and 10.0 mumol/kg, had no significant effect. Control experiments employing the explicitly unpaired presentations of tone, light, and shock stimuli indicated that the retarded acquisition of conditioned responses produced by L-PIA was due to an action on associative learning. L-PIA had no effect on the threshold of the shock's eliciting of the unconditioned response nor on the amplitude of the elicited response, but produced a large and significant reduction in the ability of the tone-conditioned stimulus to evoke conditioned responses. It was concluded that L-PIA blocked the rate of associative learning by decreasing the excitatory properties of conditioned stimuli. These effects of L-PIA suggest that endogenous adenosine may act to modulate the rate of associative learning.

Adenosine↗

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory.

Learning depends on surprise and is not engendered by predictable occurrences. In this functional magnetic resonance imaging (fMRI) study of causal associative learning, we show that dorsolateral prefrontal cortex (DLPFC) is associated specifically with the adjustment of inferential learning on the basis of unpredictability. At the outset, when all associations were unpredictable, DLPFC activation was maximal. This response attenuated with learning but, subsequently, activation here was evoked by surprise violations of the learned association. Furthermore, the magnitude of DLPFC response to a surprise event was sensitive to the relationship that had been learned and was predictive of subsequent behavioral change. In short, the physiological response properties of right DLPFC satisfied specific predictions made by associative learning theory.

Adult↗

Non-associative learning and serotonin induce similar bi-directional changes in excitability of a neuron critical for learning in the medicinal leech.

In studies of the cellular basis of learning, much attention has focused on plasticity in synaptic transmission in terms of transmitter release and the number or responsiveness of neurotransmitter receptors. However, changes in postsynaptic excitability independent of receptors may also play an important role. Changes in excitability of a single interneuron in the leech, the S-cell, were measured during non-associative learning of the whole-body shortening reflex. This interneuron was chosen because it is known to be necessary for sensitization and full dishabituation of the shortening response. During sensitization, S-cell excitability increased, and this enhancement corresponded to facilitation of the shortening reflex and increased S-cell activity during the elicited response. During habituation training, there was a decrement in both the shortening reflex and the elicited S-cell activity, along with decreased S-cell excitability. Conversely, dishabituation facilitated both the shortening response and S-cell activity during shortening, with an accompanying increase in S-cell excitability. Bath application of 1-10 micrometer serotonin (5HT), a modulatory neurotransmitter that is critical for sensitization, for full dishabituation, and for associative learning, increased S-cell excitability. S-cell excitability also increased after stimulation of the serotonergic Retzius cells. However, focal application of serotonin onto the S-cell soma hyperpolarized the interneuron, and bath application of a lower dose of serotonin (0.1 micrometer) decreased excitability. The observed changes in postsynaptic excitability appear to contribute to non-associative learning, and modulatory neurotransmitters, such as serotonin, evidently help regulate excitability. Such changes in S-cell excitability may also be relevant for more complex, associative forms of learning.

Animals↗

Learning associated increase in heat shock cognate 70 mRNA and protein expression.

The Morris water maze is a task widely used to investigate cellular and molecular changes associated with spatial learning and memory. This task has both spatial and aversive (swimming related stress) components. It is possible that stress may influence cellular modifications observed after learning the Morris water maze spatial task. Heat shock proteins, also known as stress proteins, are up-regulated in response to thermal stress, trauma, or environmental insults. In the rat hippocampus, psychophysiological stress increases the levels of heat shock protein 70 (HSC70). In this study, we investigated whether the expression of the hsc70 gene is modulated in the hippocampus during learning of the Morris water maze task. Five groups of rats were trained in the Morris water maze task for varying amounts of time (either 1, 2, 3, 4, or 5 days). Training consisted of 10 trials/day in which the animals were given 60s to find a submerged platform. Rats were sacrificed 24h after their last training trial. Results showed a significant increase in hsc70 mRNA and protein levels in the hippocampal formation after two and three days of training, respectively. The increase in mRNA and protein was associated with learning but not stress because the increase was not observed in the yoked control animals. These findings suggest that cellular and molecular changes can occur independent of stress. Moreover, the results are the first to implicate hsc70 expression in spatial learning.

Animals↗

Orbitofrontal cortex neurons: role in olfactory and visual association learning.

1. The orbitofrontal cortex is implicated in the rapid learning of new associations between visual stimuli and primary reinforcers such as taste. It is also the site of convergence of information from olfactory, gustatory, and visual modalities. To investigate the neuronal mechanisms underlying the formation of odor-taste associations, we made recordings from olfactory neurons in the orbitofrontal cortex during the performance of an olfactory discrimination task and its reversal in macaques. 2. It was found that 68% of odor-responsive neurons modified their responses after the changes in the taste reward associations of the odorants. Full reversal of the neuronal responses was seen in 25% of these neurons. Extinction of the differential neuronal responses after task reversal was seen in 43% of these neurons. 3. For comparison, visually responsive orbitofrontal neurons were tested during reversal of a visual discrimination task. Seventy-one percent of these visual cells showed rapid full reversal of the visual stimulus to which they responded, when the association of the visual with taste was reversed in the reversal task. 4. These demonstrate that of many orbitofrontal cortex olfactory neurons on the taste with which the odor is associated. 5. This modification is likely to be important for setting the motivational value of olfactory for feeding and other rewarded behavior. However, it is less complete, and much slower, than the modifications found or orbit frontal visual during visual-taste reversal. This relative inflexibility of olfactory responses is consistent with the need for some stability is odor-taste associations to facilitate the formation and perception of flavors.

Acoustic Stimulation↗

ERP correlates of associative learning.

We examined changes of event-related potentials (ERPs) while participants learned stimulus-to-stimulus relations in an S1-S2 task. The design allowed for separating processes of associative learning from nonspecific effects. Participants had to respond to S2 by a left or right key-press dependent on S2 identity (letter W or M). Preparation for S2 could be improved by using the associative information given by S1. The S1 was an arrow pointing to the left or right. In combination with its color, arrow direction was informative about location and identity of S2, but participants were not informed about the relevance of color. Arrows in two of the colors were fully predictive for the S2 whereas the third color gave no valid information. This third stimulus controlled for habituation and procedural learning. Six blocks with 200 trials each and all three S1 colors in random order were presented. Behavioral and ERP differences in each block between "learning" and control trials were used to identify processes of associative learning. Several effects of associative learning were identified indicating the involvement of specific stages of information processing: a continuous increase of P3 amplitude evoked by S1 was accompanied by a decrease of P3 evoked by S2. These changes reflected the modifications of stimulus weights for response selection and the strengthened association between the two stimulus complexes in the time course of learning. The related motor preparation benefited from learning too, expressed in a decrease of CNV amplitude and an increase of LRP amplitude. Finally a decrease of N1 amplitude evoked by S2 indicated the reduced need to allocate spatial attention to the S2 location according to the learned meaning of S1.

Adult↗

Conditional-associative learning in eating disorders: a comparison with OCD.

The acquisition of conditional associations using neutral and individually threatening verbal stimuli was assessed in 16 females with anorexia nervosa (AN), obsessive-compulsive disorder (OCD), bulimia nervosa and normal controls, respectively. Groups did not differ in terms of age, sex, intelligence, depression, verbal memory and verbal fluency measures. Patients and controls were widely comparable on tests assessing neuropsychological functioning. In the conditional-associative learning (CAL)-task only anorectic and OCD-patients displayed an impaired performance with neutral material but not with individually threatening material. Such a deficit was not evident in bulimics or in normal controls. These findings support the assumptions from functional neuroimaging investigations in AN and OCD and provide evidence that obsessive and compulsive behavior could have its origin within common neurobiological dysfunctions. The CAL possibly serves as a functional correlate of a neurophysiological dysfunction in obsessive-compulsive spectrum disorders.

Adolescent↗

Genetic deletion of CB1 receptors improves non-associative learning.

Habituation (a form of non-associative learning) was measured by assessing locomotion in novel activity monitors in CB1 receptor knockout mice and juxtaposed to habituation measured in muscarinic M2, M4, and double M2/M4 receptor knockout mice. M2 and M2/M4, but not M4, receptor knockout mice appeared to have an impaired ability to habituate, whereas CB1 receptor knockout mice showed enhanced habituation compared to wild-type animals. We conclude that CB1 receptor gene invalidation improves habituation tentatively through an increase in cholinergic neurotransmission.

Analysis of Variance↗

Intermediate and long-term memories of associative learning are differentially affected by transcription versus translation blockers in Lymnaea.

Aerial respiratory behaviour in the pond snail, Lymnaea stagnalis, can be operantly conditioned. This associative learning then undergoes consolidation into a long-lasting memory which, depending on the training procedure used, causes intermediate-term memory (ITM; lasting 3 h) or long-term memory (LTM; lasting >6 h) to be formed. We determined the differential susceptibility of these two forms of memory to translation and transcription blockers. The injection of a translation blocker, Anisomycin, 2.5 h before training prevents the establishment of both ITM and LTM. On the other hand, injection of the transcription blocker Actinomycin D, 2.5 h before training, did not prevent the establishment of ITM, but did, however, prevent LTM formation. Thus in Lymnaea, following associative learning, both ITM and LTM are dependent on new protein synthesis. ITM appears to be dependent on protein synthesis from preexisting transcription factors, whilst LTM is dependent on protein synthesis from new transcription messages.

Animals↗

Motor deficits cannot explain impaired cognitive associative learning in cerebellar patients.

There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.

Adult↗

Effects of aging on conditional associative learning: process analyses and comparison with focal frontal lesions.

Conditional associative learning (CAL), a measure validated in studies of frontal lesions, was used to evaluate the hypothesis that age-related cognitive decline is related to frontal dysfunction. Older adults and focal frontal participants showed impaired CAL performance, but the deficit was greater in the latter group, where it was specific to participants with dorsolateral prefrontal cortical (DLPFC) lesions. The deficits were attributable to strategic rather than basic associative processes. Error scores described ways in which past information failed to guide behavior, and they were related to lesion location. Congruence between older adults and DLPFC participants on a measure of defective inhibition suggests that age-related decline in inhibitory processes is due to DLPFC dysfunction.

Adolescent↗

Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins.

Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated beta-amyloid, beta-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when beta-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated alpha 7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for beta-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of alpha 7 nicotinic receptors.

Age Factors↗

Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans.

Mutations in the insulin/IGF-1 neuroendocrine pathway extend lifespan and affect development, metabolism, and other biological processes in Caenorhabditis elegans and in other species. In addition, they may play a role in learning and memory. Investigation of the insulin/IGF-1 pathway may provide clues for the prevention of age-related declines in cognitive functions. Here, we examined the effects of the life-extending (Age) mutations, such as the age-1 (phosphatidylinositol 3-OH kinase) and daf-2 (insulin/IGF-1 receptor) mutations, on associative learning behavior called isothermal tracking. This thermotaxis learning behavior associates paired stimuli, temperature, and food. The age-1 mutation delayed the age-related decline of isothermal tracking, resulting in a 210% extension of the period that ensures it. The effect is dramatic compared with the extension of other physiological health spans. In addition, young adults of various Age mutants (age-1, daf-2, clk-1, and eat-2) showed increased consistency of temperature-food association, which may be caused by a common feature of the mutants, such as the secondary effects of life extension (i.e., enhanced maintenance of neural mechanisms). The age-1 and daf-2 mutants but not the other Age mutants showed an increase in temperature-starvation association through a different mechanism. Increased temperature-food association of the daf-2 mutant was dependent on neuronal Ca2+-sensor ncs-1, which modulates isothermal tracking in the AIY interneuron. Interestingly, mutations in the daf-7 TGFbeta gene, which functions in parallel to the insulin/IGF-1 pathway, caused deficits in acquisition of temperature-food and temperature-starvation association. This study highlights roles of the Age mutations in modulation of certain behavioral plasticity.

Aging↗

Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala.

Neuronal activities were recorded from the amygdala and amygdalostriatal transition area of behaving rats during discrimination of conditioned auditory, visual, olfactory, and somatosensory stimuli associated with positive and/or negative reinforcements. Neurons were also tested with taste solution and various sensory stimuli that were not associated with reinforcement. Of the 1195 neurons tested, 475 responded to one or more sensory stimuli. Of these, 256 neurons responded exclusively to a unimodal sensory stimulus, 128 to multimodal sensory stimuli, and the remaining 91 could not be classified. Distribution of unimodal neurons was correlated with anatomical projections to the amygdala from sensory thalamus or sensory cortices. Multimodal neurons were located mainly in the basolateral and central nuclei of the amgydala. Response latencies of neurons in the basolateral nucleus were longer than those in other nuclei and neurons in the central nucleus had both short and long latencies. Neurons responsive to a given stimulus were more frequently encountered in the amygdalas of the trained rats than in those of the rats not trained to associate that stimulus with a reinforcement. Multimodal neurons that responded to conditioned and/or unconditioned stimuli used in the associative learned tasks were concentrated in the basolateral and central nuclei. The results indicate that some amygdalar neurons receive exclusive single sensory information, and the others receive information from two or more sensory inputs. Considering the long latencies and multimodal responsiveness, the basolateral and central nuclei of the amygdala might be foci where various kinds of sensory information converge. It is also suggested that the basolateral and central nuclei of the amygdala have critical roles in associative learning to relate sensory information to reinforcement or affective significance.

Acoustic Stimulation↗

Associative learning in hierarchical self-organizing learning arrays.

In this paper, we introduce feedback-based associative learning in self-organized learning arrays (SOLAR). SOLAR structures are hierarchically organized networks of sparsely connected neurons that define their own functions and select their interconnections locally. This paper provides a description of neuron self-organization and signal processing. Feedforward processing is used to make necessary correlations and learn the input patterns. Discovered associations between neuron inputs are used to generate feedback signals. These feedback signals, when propagated to the primary inputs, can establish the expected input values. This can be used for heteroassociative (HA) and autoassociative (AA) learning and pattern recognition. Example applications in HA learning are given.

Algorithms↗