Simple Form Of Learning Research Articles

The neuropharmacological restoration of cognitive functions of cats following a lesion to the basal nuclei of the forebrain (Meynert's nucleus).

The functions of generalization and abstraction in an experimental model of Alzheimer's disease (the lesion of Meynert's nuclei in cats) were studied against the background of stimulation and inhibition of the cholinergic, GABAergic, and dopaminergic systems of the brain. It was demonstrated that the cholinergic system is a key system for the formation of the function of generalization, the dopaminergic system improves simple forms of learning, while the GABAergic system is actively involved in the establishment of complex types of associations.

Selective activation of Ca(2+)-activated PKCs in Aplysia neurons by 5- HT

Ca(2+)-activated and Ca(2+)-independent protein kinase Cs (PKCs) are present in the nervous system of the marine mollusk Aplysia californica (Kruger et al., 1991). Sensitizing stimuli or application of the facilitatory transmitter 5-HT to intact isolated ganglia produces the presynaptic facilitation of sensory-to-motor neuron synapses that underlies behavioral sensitization, which is a simple form of learning. Activation of PKC can also produce this presynaptic facilitation (Braha et al., 1990). To determine which type of PKC is activated, we developed a sensitive and selective assay to measure both Ca(2+)-activated and Ca(2+)-independent PKC activities in crude supernatant and membrane fractions of nervous tissue. This assay is based on the specific binding of the Ca(2+)-activated PKCs to phosphatidylserine vesicles in the presence of Ca2+ and makes use of a novel synthetic peptide with sequences conforming to phylogenetically conserved pseudosubstrate regions of the Ca(2+)-independent kinases. We provide evidence that the presynaptic facilitation is produced by a Ca(2+)-activated isoform: application of 5-HT increases the amount of the Ca(2+)-activated PKC activity associated with the membrane. Under these conditions, no increase in Ca(2+)-independent kinase activity is seen.

Effect of BMY 21502 on Classical Conditioning of the Eyeblink Response in Young and Older Rabbits

BMY 21502, a substituted pyrrolidionone, has been found to enhance a simple form of learning in older rabbits. In humans, this simple type of learning, classical conditioning of the eyeblink response, declines in normal aging and is seriously impaired in Alzheimer's disease (AD). We have demonstrated that eyeblink classical conditioning reliably discriminates patients diagnosed with probable AD from non-demented, age-matched elderly subjects. Older organisms can be classically conditioned, but they condition at a much slower rate than younger organisms. Our preliminary analyses indicate age differences in distribution of protein kinase C in the hippocampus. Here we also report that older rabbits that are administered two different doses of BMY 21502 classically condition at a rate approximating that of young rabbits.

Second messengers involved in the two processes of presynaptic facilitation that contribute to sensitization and dishabituation in Aplysia sensory neurons.

Presynaptic facilitation of transmitter release contributes to behavioral sensitization and dishabituation, two simple forms of learning in Aplysia. This enhancement of transmitter release can be simulated by the facilitatory transmitter serotonin and has been shown to result from two types of mechanisms. The first facilitating process involves broadening of the presynaptic action potential in the sensory neurons of the reflex and is maximally effective when the synapse has not been depressed by repeated stimulation, as during sensitization. The second process is independent of changes in spike duration and can enhance release even when the synapse is quite depressed, as during dishabituation. Earlier work suggests that the first process is mediated by an increase in the intracellular level of cyclic AMP in the sensory neurons. We show here that release of free cyclic AMP from a photolyzable analogue introduced into sensory neurons can enhance release even at depressed synapses, indicating that cyclic AMP can activate the second as well as the first process. In addition, we find that phorbol esters, activators of protein kinase C, enhance release at depressed synapses. This is consistent with the report in the accompanying paper [Sacktor, T. C. and Schwartz, J. H. (1990) Proc. Natl. Acad. Sci. USA 87, 2036-2039] that serotonin and sensitizing stimuli translocate protein kinase C from cytoplasm to membrane. Our findings suggest that the cyclic AMP-dependent phosphorylation system can mediate more than one facilitatory process and that both cyclic AMP-dependent kinase and protein kinase C may be involved in facilitation of depressed synapses.

Chronic neuroleptic effects on spatial reversal learning in monkeys

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.

Cognitive disturbances in schizophrenics: what are they, and what is their origin?

Cognitive disorders are neither a unique nor a constant phenomenon in schizophrenia. Among the dysfunctions that may be observed at times, primarily during acute phases and in patients with a non-paranoid symptomatology, certain disturbances in attention-focusing and information processing seem to be most conspicuous. Some of these cognitive dysfunctions may have been transmitted from parent(s) to the patient, either genetically or through simple forms of learning. the empirical evidence for this assumption is to be found in the fact that some of the same cognitive deficits as those found in schizophrenic patients also found in their first-degree relatives, although usually in a milder form. Other forms of cognitive dysfunction may have developed as complementary strategies in response to communication deviances and cognitive behavior found in their parents. A developmental model, in which genetic, physiological and environmental factors are included is described as a way of illustrating how predisposing factors, as well as intermediating and stress factors, contribute to the debut and maintenance of cognitive disorders in schizophrenics.

Neuronal Plasticity in the Mammalian Brain: Relevance to Behavioral Learning and Memory

Much recent activity in the neurosciences relates to the search for the brain mechanisms underlying learning and memory. In recent years a brain circuit in cerebellum and brainstem has been discovered that is responsible for the learning of a simple motor response (nictitating membrane movement). This has provided a model for neuroscientists to use in understanding the brain circuits involved in this simple form of learning and, by extension, to more complex forms ultimately, and a means of exploring the changes in neural function underlying the learning. An enduring change in neural function is represented by long-term potentiation (LTP), an alteration in synaptic efficacy seen in hippocampus and other areas. LTP can be induced experimentally and occurs as a concomitant of learning. We review data suggesting that different brain circuits may underlie different forms of learning and memory. Several current theories of learning and memory with respect to hippocampal and other brain circuit involvement are considered. We conclude with the behavioral and physiological effects of exposure to teratogens or toxins and the CNS alterations associated with dementia.

Distribution of cAMP and cAMP-dependent protein kinases in Aplysia sensory neurons

Sensitization of the gill- and siphon-withdrawal reflex in Aplysia is considered a simple form of learning. Previous work has provided physiological and pharmacological evidence that cAMP-dependent protein phosphorylation within identified sensory neurons of the abdominal ganglion underlies the short-term form of this behavioral modification. Our main goal in this paper is to determine the subcellular distribution of cAMP and to measure the amounts and properties of the 2 types of subunits (regulatory and catalytic) that constitute the cAMP-dependent protein kinase. Do these biochemical parameters differ in sensory cells from those in other parts of nervous tissue? We found that the increased cAMP synthesized under conditions of sensitization is distributed in 3 compartments in the neuron: most of it is free in the cytoplasm; the remainder is bound either to cytoplasmic or to particulate proteins, which are believed to be regulatory subunits of the cAMP-dependent protein kinase. Binding of cAMP within the neurons is a measure of activation of the kinase. At rest, 17% of the binding sites in sensory cells were occupied. After brief electrical stimulation of the connective, which released endogenous transmitter, occupancy increased to 34%. This treatment increased the amount of cAMP bound to the various binding proteins differentially. The biochemical characteristics of cAMP binding were found to be the same in sensory neurons as in the rest of the nervous system but different from those in muscle. Thus, memory and learning are likely to be mediated by enzymes that are shared by other nerve cells. We found that sensory neurons have greater cAMP-dependent protein kinase activity than other neurons, however, and as a result may be more sensitive to small increases of cAMP.

Can Learning and Memory Be Understood?

Progress in unraveling the mysteries of the mind has been slow, but recent work indicates that a complete mechanistic understanding of at least simple forms of learning will soon be in hand. For example, it is becoming evident that associative learning is due to changes in existing neural circuits and that the acquisition of a learned behavior is due to the activation of second messenger systems in nerve cells.

Synaptic plasticity in vitro: cell culture of identified Aplysia neurons mediating short-term habituation and sensitization

The gill withdrawal reflex of the marine mollusk, Aplysia californica, shows habituation and sensitization, two simple forms of learning. In order to extend the cellular studies on synaptic plasticity underlying the changes in the reflex behavior, and to explore further the development of synaptic plasticity during synapse formation, we have sought to establish the neural circuit of the gill withdrawal reflex in vitro. We report here the reconstruction of the elementary gill withdrawal circuit in cell culture and find that the cells show short-term homosynaptic depression and heterosynaptic facilitation, the cellular mechanisms of habituation and sensitization, respectively.

Differential emergence of cellular mechanisms mediating habituation and sensitization in the developing Aplysia nervous system

The development of the cellular substrates underlying habituation and sensitization, two simple forms of learning, was examined at a polysynaptic sensory-to-motor connection in the neural circuit mediating defensive mucus release in the marine mollusc, Aplysia californica. Animals were studied throughout juvenile life, stages 9 (40 days of development) to 12 (95 days), and into adulthood, stage 13 (120 days), starting just after metamorphosis when mucus release first becomes evident. Homosynaptic depression, which mediates habituation, was already present in its adult form in stage 9. Heterosynaptic facilitation, which mediates sensitization, appeared in stage 10 and reached maturity during stages 11 and 12. Thus, the development of synaptic plasticity in this circuit occurs in discrete phases in which the gradual emergence of heterosynaptic facilitation occurs only after homosynaptic depression is well established.

Is there a cell-biological alphabet for simple forms of learning?

Is there a cell-biological alphabet for simple forms of learning?

Behavioral changes in aging Aplysia: A model system for studying the cellular basis of age-impaired learning, memory, and arousal

The marine mollusc Aplysia californica was used to examine the effects of age on simple forms of learning, memory, and arousal. We have found that aging impairs the long-term retention of habituation and prevents the acquisition of sensitization in the siphon withdrawal reflex. In addition, aging reduces arousal as evident in the heart rate component of the response to food stimuli. Our results are similar to the age-dependent alterations in the capacity for behavioral plasticity that have been reported in a variety of vertebrates, including man. These similarities suggest that the mechanisms underlying the effects of age on behavior and its modification may share common features across phyla and therefore might be studied to advantage in Aplysia whose central nervous system is especially accessible to cell biological approaches.

Characterization and localization of adenosine 3':5'-monophosphate- binding proteins in the nervous system of Aplysia

Earlier work in Aplysia californica has indicated that sensitization of the gill reflex, a simple form of learning, is produced by cAMP-dependent protein phosphorylation which regulates the flux of ions in sensory neurons of the abdominal ganglion. These changes in ion flux result in the enhanced release of neurotransmitter from synapses of the sensory neurons which, in turn, mediate the behavior. Because it can be presumed that protein phosphorylation regulates the functioning of ion channel proteins, we have characterized cAMP-binding proteins photoaffinity labeled with 8-N3-cAMP and have found that, unlike other tissues, the nervous system contains a great variety of binding species. Also unlike other tissues, several of the binding proteins in neurons are associated with membrane, and these components are concentrated in fractions enriched in nerve endings. Selectivity of phosphorylation, not only between substrates in cytosol and membrane but also between different regions of the cell, is thus possible because of the variety of cAMP-binding proteins in neurons. We think that these membrane-associated binding proteins are the most likely candidates for the regulatory subunits of the cAMP-dependent kinases that control the functioning of ion channel proteins at the synapse.

Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones.

We have identified a serotonin-sensitive K+ channel with novel properties. The channel is active at the testing potential; its gating is moderately affected by membrane potential and is not dependent on the activity of intracellular calcium ions. Application of serotonin to the cell body or intracellular injection of cyclic AMP causes prolonged and complete closure of the channel, thereby reducing the effective number of active channels in the membrane. The closure of the channel can account for the increases in the duration of the action potential, Ca2+ influx, and transmitter release which underlie behavioural sensitization, a simple form of learning.

Intracellular injection of t he catalytic subunit of cyclic AMP-dependent protein kinase simulates facilitation of transmitter release underlying behavioral sensitization in Aplysia.

It has been difficult to establish whether cyclic AMP-mediated protein phosphorylation in nerve cells plays a specific role in synaptic transmission. This difficulty can be overcome in higher invertebrates because their large neurons allow the injection of protein molecules into the cell. We have used intracellular injection to study whether protein phosphorylation is involved in the mechanism of sensitization, a simple form of learning. Sensitization of the gill-withdrawal reflex in Aplysia involves enhancement of transmitter release by presynaptic facilitation at a particular set of synaptic connections between identified sensory neurons and their follower cells. We have found that injection of the catalytic subunit of cyclic AMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) purified from bovine heart mimics the action of the natural transmitter and of serotonin, the putative transmitter, by simulating the physiological changes that accompany presynaptic facilitation. Intracellular injection of the kinase into a sensory cell (i) broadens the action potential in the presence of tetraethylammonium, indicating an increase in Ca2+ current, (ii) decreases the input conductance of the cell, presumably as a result of a decrease in the K+ current, and (iii) increases the amount of transmitter released by terminals of the sensory cell onto follower neurons.

Habituation and dishabituation of the averaged auditory evoked response.

Two experiments investigated amplitude reduction in the averaged evoked response (AER) resulting from repeated auditory stimulation. The first experiment examined the effects of stimulus duration on the rate of AER habituation. Three groups of 10 normal-hearing young adults received 16 series of 1000-Hz tone bursts with durations of 50 msec, 500 msec, and 950 msec. A comparison of AER habituation rates revealed that longer stimulus durations resulted in faster rates of habituation. The second experiment was designed to determine if the AER demonstrated dishabituation (recovery of a habituated response when a parameter of the habituating stimulus is changed). Ten additional normal adults received series of 1000-Hz tone bursts. When the stimulus frequency was changed from 1000 Hz to 500 Hz, all subjects meeting the habituation criterion demonstrated recovery of the AER. The results of the two experiments are compatible with an interpretation of AER habituation as a simple form of learning.

RNA Changes during Protozoan Habituation

RNA changes accompanying learning have been found in rats, mice, goldfish and planaria1–8. We wanted to determine whether changes in the rate of RNA synthesis occurred during habituation in the protozoan Spirostomum ambiguum, for this would extend previous findings to a very simple form of learning in a single celled organism.

An isolated insect ganglion-nerve-muscle preparation.

ABSTRACT A preparation is described which consists of an isolated locust metathoracic ganglion, together with one motor nerve and the skeletal muscle which it supplies (the anterior coxal adductor) in a state suitable for tension recording. Mechanical responses were recorded from the whole muscle, or bundles of fibres and electrical responses of single fibres were recorded intracellularly. Some fibres were found in the muscle which have unusual properties. A single excitatory axon supplies the muscle. Preganglionic stimulation applied to cut nerve trunks may excite an inhibitory-conditioning axon supplying the same muscle. Direct stimulation of the motor nerve was combined with preganglionic stimulation in order to excite the two axons, and their interaction in relation to contraction of the muscle was studied. The preparation shows spontaneous activity in the single excitatory axon supplying the muscle. Various preganglionic stimulations were found to cause prolonged changes in the spontaneous motor output. By correlating the stimuli to the output in certain ways, long-lasting changes in mean output frequency were obtained. These may be regarded as a simple form of learning.

THE STATISTICAL ANALYSIS OF THE LEARNING PROCESS

The following paper deals with the application of factorial techniques to a special type of temporal variation, namely, that in which the successive measurements obtained show a progressive trend; and presents an elementary exposition, mainly from a factorial standpoint, of stochastic procedures as applied to learning and analogous processes. The formulas and methods deduced are illustrated by experiments on simple forms of learning (a) in animals and (b) in children.