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A nicotinic agonist (GTS-21), eyeblink classical conditioning, and nicotinic receptor binding in rabbit brain.

The septo-hippocampal cholinergic system is of demonstrated involvement in eyeblink classical conditioning (EBCC). To determine if a nicotinic cholinergic agonist, GTS-21, would facilitate acquisition of EBCC in older rabbits, three doses (0.1, 0.5, 1.0 mg/kg) in sterile saline vehicle and vehicle alone were administered to older rabbits (n = 48; mean age = 29.8 months). A control group of vehicle-treated young rabbits (n = 12; mean age = 3.5 months) was included. Rabbits were conditioned for fifteen 90-trial sessions in the 750 ms delay paradigm with a tone conditioned stimulus and corneal airpuff unconditioned stimulus. Dependent measures of trials to learning criterion, percentage of conditioned responses (CRs) and CR amplitude consistently showed significant improvement in older rabbits treated with 0.5 and 1.0 mg/kg of GTS-21. Acquisition was similar in vehicle-treated young and GTS-treated older rabbits. Vehicle-treated older rabbits conditioned more poorly than vehicle-treated young rabbits. No non-associative learning effects were observed in GTS-21 treated animals. Nicotinic receptor binding was similar in all groups of older rabbits, indicating that GTS-21 administration over a 15-day period did not affect nicotinic receptors. Alzheimer's disease (AD) has been associated with significant loss of nicotinic cholinergic receptors, and patients diagnosed with probable AD are seriously impaired on EBCC. These results demonstrating that the nicotinic agonist, GTS-21, facilitated EBCC in older rabbits suggest that the compound should receive additional investigation for its potential to affect cognition in AD.

Aging↗

Effect of isolation on classical conditioned histamine release in guinea pigs.

To investigate the effect of abrupt or non-abrupt isolation stress on the classical conditioned histamine release, socially isolated or paired guinea pigs underwent conditioning procedures in which ovalbumin (OA) as an unconditioned stimulus (US) and dimethylsulfide (sulfur smelling) as a conditioned stimulus (CS) were simultaneously inhaled, and the plasma histamine levels after the exposure to the CS in a state of isolation or pairing were measured. The plasma histamine levels significantly increased from baseline in response to the CS (P < 0.05), except in the animals which were abruptly isolated during the exposure to the CS. The guinea pigs which were isolated during either the conditioning procedures or the exposure to the CS displayed significantly lower levels of plasma histamine than did the paired animals during both periods (P < 0.01, respectively). The plasma histamine levels in the guinea pigs which were isolated or paired during both periods were significantly higher than those of the control animals which had received the CS and the US separately (P < 0.05 and P < 0.01). A change of social relations, particularly isolation during the presentation of the CS, may have a suppressive effect on immediate asthmatic responses due to the conditioning mechanism.

Animals↗

Concurrent eyeblink classical conditioning and rotary pursuit performance: implications for independent nondeclarative memory systems.

The authors examined whether 2 nondeclarative tasks, simple eyeblink classical conditioning (EBCC) and rotary pursuit (RP), would interfere with each other when performed simultaneously. In Experiment 1,100 participants were assigned to 1 of 5 groups: paired EBCC/RP, unpaired EBCC/RP, paired EBCC as a single task, unpaired EBCC as a single task, and RP as a single task. Participants in the paired EBCC/RP group showed significantly greater acquisition of conditioned responses than did participants in the unpaired EBCC/RP group, and the unconditioned eyeblink response was similar in both groups. Comparisons of the paired EBCC/RP and paired EBCC-as-a-single-task groups indicated no differences in trials to criterion, but on some measures the single-task group conditioned better. Controls introduced in Experiment 2 did not change this pattern. Results provide some evidence for the lack of interference between EBCC and RP.

Adult↗

Dopamine efflux in nucleus accumbens shell and core in response to appetitive classical conditioning.

Dopamine transmission within the nucleus accumbens has been implicated in associative reinforcement learning. We investigated the effect of appetitive classical conditioning on dopamine efflux in the rat nucleus accumbens shell and core, as dopamine may be differentially activated by conditioned and unconditioned stimuli (CS, US) in these subregions. After implantation of microdialysis cannulae, rats were food restricted and trained for three consecutive days with three acquisition sessions per day. A 10-s noise (CS) was immediately followed by the delivery of two reward pellets (US) for the conditioned group (paired presentation), whereas conditioned stimuli and unconditioned stimuli were presented at random for the control group (unpaired presentation). On the fourth day, all rats were given a further CS + US session and two CS-alone sessions, and extracellular dopamine concentrations were measured (7.5 min/per sample). Behavioural measures (number of nose pokes, latency to nose poke after conditioned stimuli onset, locomotor activity) demonstrated that the paired groups showed a high level of conditioning. CS + US presentation increased dopamine equally in both shell and core of the paired and unpaired groups. CS alone presentation induced a conditioned dopamine release only in the paired groups. No significant difference was found between shell and core. Unlike previous conditioning paradigms involving either a more salient US (foot shock, addictive drug) or a more complex CS, the present paradigm, using normal reward pellets as US and a discrete auditory stimulus as CS, did not lead to differential responses in dopamine efflux in shell and core subregions of the nucleus accumbens.

Animals↗

A nicotinic cholinergic agonist (GTS-21) and eyeblink classical conditioning: acquisition, retention, and relearning in older rabbits.

Previously we demonstrated that GTS-21, a nicotinic cholinergic agonist, ameliorated eyeblink classical conditioning deficits in older rabbits. The present experiment was undertaken to replicate and extend these results by examining the effects of GTS-21 on retention and relearning. Retired breeder rabbits received 15 daily injections of 0.5 mg/kg GTS 21 (n = 8) or sterile saline vehicle (n = 8) during acquisition training, and no further injections occurred. Acquisition of conditioned responses (CRs) was significantly better in GTS-21-treated rabbits. During the first tone-alone retention session in week 6 of the experiment, rabbits initially treated with GTS-21 produced significantly more CRs than vehicle-treated rabbits. There were no group differences in retention at the 13-week retest. Differences in relearning were in the predicted direction but did not attain statistical significance. Results indicate that treatment with GTS-21 ameliorates learning beyond the period when the drug is actually administered.

Aging↗

Neural mechanisms of classical conditioning in mammals.

Evidence supports the view that 'memory traces' are formed in the hippocampus and in the cerebellum in classical conditioning of discrete behavioural responses. In the hippocampus learning results in long-lasting increases in excitability of pyramidal neurons that resemble the phenomenon of long-term potentiation. Although it plays a role in certain aspects of conditioning, the hippocampus is not necessary for learning and memory of the basic conditioned responses. The cerebellum and its associated brain-stem circuitry, on the other hand, does appear to be essential (necessary and sufficient) for learning and memory of the conditioned response. Evidence to date supports the view that mossy fibre convey conditioned stimulus information and that climbing fibres conveys the critical 'reinforcement' information to the cerebellum and that 'memory traces' appear to be formed in cerebellar cortex and interpositus nucleus.

Animals↗

[Hippocampal neuronal activity in the switching of heterogeneous classical conditioned reflexes].

The impulsive activity of hippocampal neurons during the elaboration and specialisation of switching of the alimentary and defensive classical conditioned reflexes has been studied. The associative changes of the phasic and tonic neurons activity have been shown to be the neurophysiological background of the tonic and phasic mechanisms ensuring the conditioned switching. The differences between the tonic activity and the neuron response to the conditioned stimulus during different conditioned activity have been established. The difference of the neuronal activity to the conditioned stimulus during the change of its signal meaning is due to a great extend of the tonic activity. Motivation is supposed to play a leading role in the changing of the neurons activity under the conditioned switching.

Animals↗

Classical conditioning mediated by the red nucleus in the cat.

We have attempted to develop a behavioral and neuronal model for classical conditioning in the corticorubrospinal system. A conditioned stimulus (CS) was applied to the cerebral peduncle (CP) in cats which had lesions that interrupted the corticofugal fibers caudal to the red nucleus. The unconditioned stimulus (US) was an electric shock to the skin of the forelimb that produced flexion of the limb. After pairing of the CS and US in close temporal association, an initially ineffective stimulus to the cerebral peduncle was found to give rise to the flexion of the elbow. Extinction of the conditioned response was achieved by applying the CS alone or by reversing the sequence of the stimuli (US-CS: backward pairing). Furthermore, the US alone did not produce an increase in the effectiveness of the CS stimulus. Finally, pairing the fixed CS stimuli with the US at random intervals did not produce any increase in performance in response to the CS. In these respects, the observed behavioral modification has the features of associative conditioning. Because the thresholds for and the strength of elbow flexion induced by stimulation of the nucleus interpositus of the cerebellum were identical in the experimental and control animals, the interpositorubrospinal system cannot be the site of the plastic change. Since the conditioned response is most probably mediated by the corticorubrospinal system, it is likely that a modification of the corticorubral synapses underlies this behavioral change.

Animals↗

Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice.

1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of < 10% after pairings suggested that H-7 partially blocked PSD and that, in turn, PSD involved protein kinases. 6. The means of induction and the specificity of those means suggest that the phenomenology of PSD is fundamentally different from that of long-term depression. PSD only occurs with pairings of trains of parallel fiber and climbing fiber stimulation; it occurs without the need for bicuculline; and it can overcome the blocking effects of aniracetam. 7. Nevertheless, the involvement of protein kinases and the potential role of calcium suggest that the mechanisms involved in the induction of PSD and long-term depression have a number of features in common. 8. Because of the pairing-specific nature of the long-term synaptic depression observed in these experiments, PSD provides a mechanism that may contribute to the role of the cerebellar cortex in classical conditioning.

Animals↗

Impaired delay eyeblink classical conditioning in individuals with anterograde amnesia resulting from anterior communicating artery aneurysm rupture.

Anterior communicating artery (ACoA) aneurysm rupture can lead to an anterograde amnesia syndrome similar to that observed after damage to the hippocampus and medial temporal lobes (MT). It is currently believed that ACoA amnesia results from basal forebrain damage that disrupts hippocampal processing without direct hippocampal damage. Converging evidence from animal studies and computational modeling suggests that qualitative differences may exist in the pattern of memory impairment after basal forebrain or MT damage. For example, animals with basal forebrain but not hippocampal damage are impaired at delay eyeblink classical conditioning (EBCC). In this study, individuals with ACoA amnesia were shown to be impaired at delay EBCC compared with matched controls; this contrasts with the spared delay EBCC previously observed in MT amnesia. This finding suggests the beginning of a possible dissociation between the memory impairments in MT versus ACoA amnesia.

Adult↗

Inactivation of brainstem motor nuclei blocks expression but not acquisition of the rabbit's classically conditioned eyeblink response.

Rabbits were eyeblink conditioned while their accessory abducens nucleus (ACC), facial nucleus (FN), and surrounding reticular formation (RF) were temporarily inactivated with microinjections of muscimol to determine whether these structures are critically involved in acquisition of the conditioned eyeblink response (CR). Rabbits performed no CRs or unconditioned responses (URs) during inactivation training. Training was continued without inactivation and rabbits performed the CR at asymptotic levels from the start of training without inactivation. They had fully learned the CR while their ACC, FN, and RF were inactivated, despite performing no CRs or URs at all during inactivation. These results rule out any critical role for neurons within the ACC, FN, or surrounding RF in acquisition of the classically conditioned eyeblink response.

Abducens Nerve↗

Nimodipine facilitates retention of the classically conditioned nictitating membrane response in aged rabbits over long retention intervals.

Aged rabbits initially underwent 18 days of acquisition of the classically conditioned nictitating membrane response (NMR) using a tone conditioned stimulus (CS) and an air puff unconditioned stimulus (UCS). They were then treated with a low or high dose of nimodipine or a vehicle for 90 days. During this time no further CS-UCS pairings were presented. They underwent testing for retention of the conditioned response (CR) at 30 and 90 days. Retention testing consisted of 20 presentations of the CS alone. Rabbits in the control condition retained 46.4% of their predrug levels of conditioned responding and rabbits receiving the low dose of nimodipine retained 37.3% of their predrug levels after 30 days. After 90 days, retention in these animals declined to 8.1% and 14.1%, respectively. In contrast, rabbits receiving the high dose of nimodipine retained 85% of their predrug learning at 30 days with little decline at 90 days (77.1%). Nonassociative factors such as sensitivity to the CS or UCS could not explain these effects.

Aging↗

Lesion of the cerebellar interpositus nucleus or the red nucleus affects classically conditioned neuronal activity in the hippocampus.

1. The cerebellum and the hippocampus have been known to be neural structures involved in classical conditioning of the nictitating membrane response in rabbits. The neuronal activities related to conditioning are observed in both structures. It is uncertain, however, whether these conditioning-related neuronal activities are established in parallel or hierarchically. 2. The present study was conducted to observe the effects of lesions of the cerebellar interpositus nucleus(INT) or the red nucleus(RN) on conditioned hippocampal neuronal activity. 3. Rabbits in the first experiment were trained by standard delay conditioning and then given INT lesion by injecting the kainic acid through a cannula previously implanted. Lesions of INT abolished conditioned neuronal responses in the hippocampal CA1 area, which had been established before lesioning, as well as behavioral conditioned responses(CRs). 4. The second experiment was to examine if conditioning-related activities in the hippocampus would develop after RN was lesioned with INT intact. Rabbits were first given unilateral electrolytic lesions of RN followed by conditioning sessions. Besides a few CRs, they failed to show an increase in hippocampal CA1 activity. When training was switched to the contralateral eye, animals showed robust CRs and hippocampal responses immediately. However, training reswitched to the original eye, behavioral and neuronal responses disappeared again. 5. These results suggest that conditioned neuronal activities in the hippocampus depends on the cerebellum and that conditioning-related inputs from INT via RN may be critical for these conditioned neuronal response in the hippocampus.

Animals↗

Classical conditioning of the Aplysia siphon-withdrawal reflex exhibits response specificity.

The gill- and siphon-withdrawal reflex of Aplysia undergoes classical conditioning of its amplitude and duration when siphon stimulation (the conditioned stimulus, CS) is paired with tail or mantle shock (the unconditioned stimulus, US). This conditioning of a preexisting response exhibits both temporal and stimulus specificities, which can be accounted for by activity-dependent enhancement of presynaptic facilitation of the siphon sensory neurons. To test whether conditioning of the reflex also exhibits response specificity (development of a new type of response to the CS that often resembles the response to the US), we measured the direction of siphon withdrawal in response to siphon stimulation (the CS) with tail or mantle shock as the US. The unlearned response to siphon stimulation is straight contraction, the response to tail shock is backward bending, and the response to mantle shock is forward bending. In the first experiment, we trained different animals with the tail or mantle US paired or unpaired with the CS; in a second experiment, we trained each animal with two CSs, one of which was paired with the US; in a third experiment, we varied US intensity; and in a fourth experiment, we trained each animal with two USs, one of which was paired with the CS. There was a significant, pairing-specific tendency for the direction of the response to the CS to resemble the response to the US after training in each experiment, demonstrating response specificity in conditioning of the withdrawal reflex. This feature of conditioning could in principle be accounted for by an elaboration of activity-dependent facilitation.

Animals↗

[Rearrangement of the activity of orbital cortex neurons during second-order classical conditioning].

In chronic experiments on 8 dogs, rearrangements of unit activity were studied in the orbital cortex in the course of classic conditioning of the I and the II order. Histograms of the interspike intervals distribution changes of the mean firing rate revealed that, in the course of conditioning, the neuronal responses to presentation of conditioned stimuli of the I and II order (for the II order reflexes) underwent dynamic changes. The unit activity pattern under the effect of a conditioned stimulus approximates the form of the pattern in reinforcement. The data are discussed in the light of E.A. Asratian's ideas of the mechanism for formation of complex forms of conditioned reflexes.

Action Potentials↗

A discrete approach for a model of temporal learning by the cerebellum: in silico classical conditioning of the eyeblink reflex.

Cerebellar cortex is known to be involved in acquisition and expression of eyeblink conditioned reflex. These phenomena imply temporal intervals of learning. Several cellular and network mechanisms have been proposed to produce the eyeblink. In this paper we briefly review the main theories concerning temporal coding, and we propose an alternative way of producing and storing delays and signal sequences after supervised learning. A network of Leaky Integrate-and-Fire (LIF) neurons is built, taking into account several cerebellar features. This network is then trained to produce simple or multiple eyeblink delays using (i) the classical conditioning paradigm and (ii) known data on cerebellar spike timing dependent plasticity (STDP). The resulting model behaves like an adaptive temporal filter. It improves cell subpopulations effects according to their mean firing rate. This rate based selection allows robust supervised learning of temporal events (i.e., delayed signals) and gives the network ability to react with anticipation on the arousal of a noxious event.

Action Potentials↗

Classical conditioning in children with attention deficit hyperactivity disorder (ADHD) and anxiety disorders: a test of Quay's model.

Quay (1988) put forward a model of childhood mental disorders based on Gray's (1982) theory that there exists within the brain a behavioral inhibition system (BIS), which processes signals related to aversive or punishing stimuli. According to this model, children with attention deficit hyperactivity disorder (ADHD) show lower than optimal levels of activity in this system, which leads to less responsiveness at a physiological level to signals related to punishment. Children with ADHD and controls were compared on a classical conditioning paradigm. Skin conductance and cardiac responses were measured in response to a conditioned stimulus that had been paired with an aversive unconditioned stimulus. There were no differences between the groups, suggesting that, in terms of classical conditioning, ADHD children are equally responsive to signals related to punishment as controls.

Anxiety Disorders↗

Learning processes in the human newborn. Sensitization, habituation, and classical conditioning.

Data have been presented to document that the human newborn is a conditionable organism. Babies in the first days of life possess sensitivity to stimulation in all sensory modalities, an unconditioned repertoire of responses to some of these sensory stimuli, and a capacity for associating simultaneously presented stimuli. Thus a perceived but previously neutral stimulus with respect to the elicitation of some particular behavior can itself become an effective stimulus through paired associations with an effective stimulus, and may now produce a response similar to the initially effective stimulus. For such a phenomenon to occur, the organism must be capable of remembering. The duration of memory is empirically demonstrable through probes or tests with the neutral stimulus, at various time intervals following the last experience of the pairing. Besides engaging in classical conditioning involving transfer of elicitability from an effective stimulus to a previously ineffective stimulus (or its converse, as in extinction), demonstrating that human newborns do learn, babies are also demonstrably capable habituators. They exhibit diminution of response intensity or frequency to repetitively presented, and particularly closely spaced and essentially innocuous, stimuli. Newborns also exhibit generalized sensitization to stimulation such that, when neonates are aroused, stimuli will nondiscriminatively elicit behaviors. It is thus important that appropriate controls for nonconditioning processes, which may also involve change in behavior through experience, be included in any demonstrations that purport to show the conditionability of the newborn.

Conditioning, Classical↗