Search PubMed⌕ Search

Biomedical subjects

E R Kandel

Publications and source records attributed to E R Kandel.

At least 217 records · Page 12Linked to original sources
PubMed1984

Serotonin increases intracellular Ca2+ transients in voltage-clamped sensory neurons of Aplysia californica.

Noxious stimulation of the tail of Aplysia californica produces behavioral sensitization; it enhances several related defensive reflexes. This reflex enhancement involves heterosynaptic facilitation of transmitter release from sensory neurons of the reflex. The facilitation is stimulated by serotonin (5-HT) and involves suppression of a 5-HT-sensitive K+ current (the S current). Suppression of the S current broadens the action potential of the sensory neurons and is thought to enhance transmitter release by prolonging entry of Ca2+ in the presynaptic terminals. We now report a component of enhanced Ca2+ accumulation that is independent of changes in spike shape. We have measured intracellular free Ca2+ transients during long depolarizing steps in voltage-clamped sensory neuron cell bodies injected with the Ca2+-sensitive dye arsenazo III. The free Ca2+ transients elicited by a range of depolarizing voltage-clamp steps increase in amplitude by 75% following application of 5-HT. Since it is observed under voltage-clamp conditions, this increase in the free Ca2+ transients is not merely secondary to the changes in K+ current but must reflect an additional mechanism, an intrinsic change in the handling of Ca2+ by the cell. We have not yet determined whether this change in Ca2+ handling reflects an increase in Ca2+ influx, a reduction in intracellular Ca2+ uptake, or a release of Ca2+ from intracellular stores. Regardless of the underlying mechanism, however, it seems possible that the enhancement of Ca2+ accumulation and the reduction in K+ current act synergistically in producing short-term presynaptic facilitation. Alternatively, this additional modulation of Ca2+ by 5-HT might contribute to processes such as classical conditioning or long-term sensitization that may depend on Ca2+.

Animals↗
PubMed1984

Two endogenous neuropeptides modulate the gill and siphon withdrawal reflex in Aplysia by presynaptic facilitation involving cAMP-dependent closure of a serotonin-sensitive potassium channel.

We have found that two endogenous neuropeptides in Aplysia, the small cardioactive peptides SCPA and SCPB, facilitate synaptic transmission from siphon mechano-sensory neurons and enhance the defensive withdrawal reflex that these sensory neurons mediate. Single-channel recording revealed that these peptides close a specific K+ channel, the S channel, which is sensitive to cAMP. Moreover, the peptides increase cAMP levels in these sensory neurons. This reduction in K+ current slows the repolarization of the action potential in these cells, which increases transmitter release. In these actions, the SCPs resemble both noxious sensitizing stimuli, which enhance the reflex, and serotonin. Bioassay of HPLC fractions of abdominal ganglion extracts and immunocytochemistry indicate that both the SCPs and serotonin are present in the ganglion and are found in processes close to the siphon sensory neurons, suggesting that these transmitters may be involved in behavioral sensitization. Recent evidence suggests that one group of identified facilitatory interneurons, the L29 cells, does not appear to contain either the SCPs or serotonin but may use yet another facilitatory transmitter. Thus, it appears that several transmitters can converge to produce presynaptic facilitation in the sensory neurons of the defensive withdrawal reflex. All of the transmitters studied here, the SCPs and serotonin, act via an identical molecular cascade: cAMP-dependent closure of the S-K+ channel, broadening of the presynaptic action potential, and facilitation of transmitter release.

Action Potentials↗
PubMed1984

Branch-specific heterosynaptic facilitation in Aplysia siphon sensory cells.

Aplysia siphon sensory cells exhibit heterosynaptic facilitation of transmitter release during both sensitization and classical conditioning of the siphon withdrawal response. In the present study, we asked whether facilitation must invariably enhance transmission at all terminals of a neuron or whether facilitation can instead occur at one set of terminals without also occurring at other terminals of the same cell. To examine this question, we compared effects of local application of serotonin and of connective stimulation on transmission at central and peripheral branches of single sensory cells. We found that heterosynaptic facilitation can be branch-specific and can occur at either central or peripheral synapses independently. We also found that siphon sensory cells exhibit homosynaptic post-tetanic potentiation, allowing us to compare effects of hetero- and homosynaptic facilitation in the same cells. By contrast to heterosynaptic facilitation, homosynaptic facilitation occurs concomitantly at both central and peripheral synapses of siphon sensory cells. Thus, while both heterosynaptic and homosynaptic facilitation involve increases in transmitter release from sensory neuron terminals, heterosynaptic facilitation provides a greater specificity and flexibility in the modification of synaptic connections.

Journal Article↗
PubMed1984

A test of Hebb's postulate at identified synapses which mediate classical conditioning in Aplysia.

In 1949, D. O. Hebb proposed a novel mechanism for producing changes in the strength of synapses that could account for associative learning. According to Hebb , the strength of a synapse might increase when the use of that synapse contributes to the generation of action potentials in a postsynaptic neuron. Thus, an essential feature of this postulate is that action potentials must occur in both a postsynaptic cell and a presynaptic cell for associative synaptic changes to occur. We have directly tested Hebb 's postulate in Aplysia at identified synapses which are known to exhibit a temporally specific increase in efficacy during a cellular analogue of differential conditioning. We find that the mechanism postulated by Hebb is neither necessary nor sufficient to produce the associative change in synaptic strength that underlies conditioning in Aplysia. In contrast, impulse activity in the presynaptic cell must be paired with facilitatory input, supporting the hypothesis that the temporal specificity of classical conditioning in Aplysia can be accounted for by activity-dependent amplification of presynaptic facilitation.

Action Potentials↗
PubMed1983

In situ hybridization to study the origin and fate of identified neurons.

Egg-laying behavior in Aplysia is mediated by a set of peptides, including egg-laying hormone (ELH), which are released by a cluster of identified neurons, the bag cells. A family of neuropeptide genes which includes the gene encoding ELH along with two additional genes encoding the A and B peptides thought to initiate the egg-laying process has been isolated and their nucleotide sequence has been determined. In situ hybridization and immunofluorescence was used to explore the origin and distribution of the neurons that express this family of genes. The ELH genes are expressed, not only in the bag cells, but in an extensive system of neurons distributed in four of the five ganglia of the central nervous system. The genes for ELH are expressed in these cells early in the animal's life cycle. As a result, it was possible to use in situ hybridization to trace the cells expressing ELH to their site of origin. The cells originate outside the central nervous system in the ectoderm of the body wall and appear to migrate to their final locations within the central nervous system by crawling along strands of connective tissue.

Age Factors↗
PubMed1983

A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation.

A training procedure analogous to differential classical conditioning produces differential facilitation of excitatory postsynaptic potentials (EPSP's) in the neuronal circuit for the siphon withdrawal reflex in Aplysia. Thus, tail shock (the unconditioned stimulus) produces greater facilitation of the monosynaptic EPSP from a siphon sensory neuron to a siphon motor neuron if the shock is preceded by spike activity in the sensory neuron than if the shock and spike activity occur in a specifically unpaired pattern or if the shock occurs alone. Further experiments indicate that this activity-dependent amplification of facilitation is presynaptic in origin and involves a differential increase in spike duration and thus in Ca2+ influx in paired versus unpaired sensory neurons. The results of these cellular experiments are quantitatively similar to the results of behavioral experiments with the same protocol and parameters, suggesting that activity-dependent amplification of presynaptic facilitation may make a significant contribution to classical conditioning of the withdrawal reflex.

Action Potentials↗
PubMed1983

Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica.

The defensive siphon and gill withdrawal reflex of Aplysia is a simple reflex mediated by a well-defined neural circuit. This reflex exhibits classical conditioning when a weak tactile stimulus to the siphon is used as a conditioned stimulus and a strong shock to the tail is used as an unconditioned stimulus. The siphon withdrawal component of this reflex can be differentially conditioned when stimuli applied to two different sites on the mantle skin (the mantle shelf and the siphon) are used as discriminative stimuli. The differential conditioning can be acquired in a single trial, is retained for more than 24 hours, and increases in strength with increased trials. Differential conditioning can also be produced within the field of innervation of a single cluster of sensory neurons (the LE cluster) since two separate sites on the siphon skin can serve as discriminative stimuli. The finding that two independent afferent inputs that activate a common set of interneurons and motor neurons can be differentially conditioned restricts the possible cellular loci involved in the associative learning.

Afferent Pathways↗
PubMed1983

Mechanoafferent neurons innervating tail of Aplysia. I. Response properties and synaptic connections.

Mechanical, chemical, or electrical stimulation of the tail elicits a short-latency (less than 1 s) tail-withdrawal reflex that is graded with the intensity of the stimulus. The tail-withdrawal reflex is not elicited by stimulation of parts of the body outside of the tail region. Mechanoafferent neurons innervating the tail are located in a small subcluster within a large, homogeneous group of medium-size (40-80 micron) cells on the ventrocaudal (VC) surface of each pleural ganglion. The tail sensory neurons within this large VC cluster are activated by tactile pressure or by electrical stimulation of discrete regions of the tail. They adapt slowly to maintained stimulation and sometimes respond to stimulus offset as well. Both mechanical and electrical stimuli produce responses that are graded with the intensity of the stimulus. Cells in the VC cluster appear to be primary mechanoreceptors because they have axons in peripheral nerves (including nerves innervating the tail), they exhibit action potentials lacking prepotentials in response to tactile stimulation, and these action potentials are still produced by cutaneous stimulation when peripheral and central chemical synaptic transmission is blocked. Stimulation of fields all over the body surface evokes synaptically mediated hyperpolarizing responses in individual mechanoafferent neurons that may represent afferent inhibition. Hyperpolarizing responses lasting many seconds can be produced by brief cutaneous stimuli. The mechanoafferent neurons innervating the tail region make strong monosynaptic connections to tail motor neurons in the ipsilateral pedal ganglion, and through these connections this subpopulation of the VC neurons appears to make a substantial contribution to the short-latency tail-withdrawal reflex. In addition, the combined excitatory receptive fields of these mechanoafferents match the excitatory receptive field of the tail-withdrawal reflex. Mechanoafferent neurons in the VC cluster that have receptive fields on other parts of the body (outside the excitatory receptive field of the tail-withdrawal reflex) have not been observed to make monosynaptic connections to the tail motor neurons. The neurons innervating the tail are reliably found in a discrete region within the larger VC cluster. In addition to this gross somatotopic organization, there is evidence of a finer level of somatotopic organization between the position of the excitatory receptive field on the tail and the position of the cell soma in the tail subcluster.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Mechanoafferent neurons innervating tail of Aplysia. II. Modulation by sensitizing stimulation.

The tail-withdrawal reflex of Aplysia can be sensitized by weak stimulation of a site outside the site used to test the reflex or by repeatedly stimulating the test site itself. The sensitization of tail-withdrawal responses is associated with enhanced activation of the tail motor neurons and heterosynaptic facilitation of the monosynaptic connections between the tail sensory neurons and tail motor neurons. This synaptic facilitation can occur under conditions in which neither posttetanic potentiation nor generalized changes in postsynaptic input resistance contribute to the facilitation. In addition to producing monosynaptic excitatory postsynaptic potentials (EPSPs), action potentials in tail sensory neurons often recruit longer latency polysynaptic input to the tail motor neurons during sensitization. Strong, noxious tail shock similar in intensity to that used previously for sensitization and aversive classical conditioning of other responses in Aplysia produces more heterosynaptic facilitation than does weak sensitizing stimulation. Heterosynaptic facilitation builds up progressively with multiple trials and lasts for hours. Very strong shocks to the tail can change the response characteristics of tail sensory neurons so that a prolonged, regenerative burst of spikes is elicited by a brief intracellular depolarizing pulse. This bursting response produced by sensitizing stimulation has not been described previously in Aplysia sensory neurons and can greatly amplify the synaptic input to tail motor neurons from the sensory neurons. In addition, strong shocks to the tail increase the duration and magnitude of individual sensory neuron action potentials. Sensitizing tail stimulation usually produces long-lasting depolarization of the tail motor neurons and often long-lasting hyperpolarization of the tail sensory neurons. The tail motor and sensory neurons show both increases and decreases of input resistance following sensitizing stimulation. However, the small, occasional increases in input resistance of the motor neuron are insufficient to explain the heterosynaptic facilitation produced by sensitizing stimulation. Serotonin (5-HT) application can mimic many of the effects of sensitizing tail shock, including facilitation of both tail withdrawal and the monosynaptic connections between tail sensory and motor neurons, hyperpolarizing and depolarizing responses in the tail sensory neurons, and an increase in the duration and magnitude of the sensory neuron action potential. In the nearly isolated sensory neuron soma, 5-HT usually produces a slow, decreased conductance depolarizing response, suggesting that the 5-HT-induced hyperpolarizing response see

Animals↗
PubMed1983

From metapsychology to molecular biology: explorations into the nature of anxiety.

Through the use of animal models, specific forms of mentation can now be explored on the cellular and molecular levels. Chronic anxiety and anticipatory anxiety in humans are closely paralleled by two forms of learned fear in the sea snail Aplysia: sensitization and aversive classical conditioning. In Aplysia's simple nervous system it is possible to delineate how the two forms are acquired and maintained. Both rely on the mechanisms of presynaptic facilitation. An augmented form of presynaptic facilitation accounts for the associative component of conditioning. These findings suggest that a surprisingly simple set of cellular and molecular mechanisms in various combinations may underlie a wide range of both adaptive and maladaptive behavioral modifications.

Animals↗
PubMed1982

Molecular biology of learning: modulation of transmitter release.

Until recently, it has been impossible to approach learning with the techniques of cell biology. During the past several years, elementary forms of learning have been analyzed in higher invertebrates. Their nervous systems allow the experimental study of behavioral, neurophysiological, morphological, biochemical, and genetic components of the functional (plastic) changes underlying learning. In this review, we focus primarily on short-term sensitization of the gill and siphon reflex in the marine mollusk, Aplysia californica. Analyses of this form of learning provide direct evidence that protein phosphorylation dependent on cyclic adenosine monophosphate can modulate synaptic action. These studies also suggest how the molecular mechanisms for this short-term form of synaptic plasticity can be extended to explain both long-term memory and classical conditioning.

Animals↗
PubMed1982

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.

Animals↗
PubMed1982

A family of genes that codes for ELH, a neuropeptide eliciting a stereotyped pattern of behavior in Aplysia.

We describe a particularly advantageous experimental system for studying gene structure, expression and modulation in the nervous system. In the marine mollusc Aplysia, the bag cells, two discrete clusters of neurons, secrete a peptide of known behavioral function. This neuroactive peptide, egg-laying hormone (ELH), produces a characteristic and stereotypic behavioral repertoire, consisting first of a cessation of walking and inhibition of feeding, followed by head waving and egg laying. We have cloned the genes encoding ELH and characterized their organization and expression. At least five distinct genes for ELH exist within the chromosome. Sequence analysis of one recombinant clone unambiguously identifies a contiguous stretch of nucleotides that encodes the 36 amino acids of ELH. Transcription of this small multigene family results in the expression of at least five distinct RNA transcripts encoding ELH. The pattern of transcripts differs strikingly in different tissues: bag cells express three distinct mRNA species, whereas the atrial gland, a secretory reproductive gland, expresses two distinct mRNAs. Several other neuronal and nonneuronal tissues do not express ELH RNA. In vitro these mRNAs produce a series of long polypeptide precursors that must be processed to generate the active ELH peptide. This processing event is likely to generate several additional neuroactive peptides. Thus the same peptide, ELH, may be released in association with different combinations of other neuroactive peptides. The concept of combinatorial sets of neuropeptides, each bearing one overlapping peptide ELH, and each directing a differing pattern of behavior, greatly expands the information potential of a small set of genes.

Animals↗