Intrinsic and extrinsic modulation of a single central pattern generating circuit.
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Intrinsic and extrinsic neuromodulation are both thought to be responsible for the flexibility of the neural circuits (central pattern generators) that control rhythmic behaviors. Because the two forms of modulation have been studied in different circuits, it has been difficult to compare them directly. We find that the central pattern generator for biting in Aplysia is modulated both extrinsically and intrinsically. Both forms of modulation increase the frequency of motor programs and shorten the duration of the protraction phase. Extrinsic modulation is mediated by the serotonergic metacerebral cell (MCC) neurons and is mimicked by application of serotonin. Intrinsic modulation is mediated by the cerebral peptide-2 (CP-2) containing CBI-2 interneurons and is mimicked by application of CP-2. Since the effects of CBI-2 and CP-2 occlude each other, the modulatory actions of CBI-2 may be mediated by CP-2 release. Although the effects of intrinsic and extrinsic modulation are similar, the neurons that mediate them are active predominantly at different times, suggesting a specialized role for each system. Metacerebral cell (MCC) activity predominates in the preparatory (appetitive) phase and thus precedes the activation of CBI-2 and biting motor programs. Once the CBI-2s are activated and the biting motor program is initiated, MCC activity declines precipitously. Hence extrinsic modulation prefacilitates biting, whereas intrinsic modulation occurs during biting. Since biting inhibits appetitive behavior, intrinsic modulation cannot be used to prefacilitate biting in the appetitive phase. Thus the sequential use of extrinsic and intrinsic modulation may provide a means for premodulation of biting without the concomitant disruption of appetitive behaviors. (+info)
Temporal pattern dependence of neuronal peptide transmitter release: models and experiments.
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In this paper we construct, on the basis of existing experimental data, a mathematical model of firing-elicited release of peptide transmitters from motor neuron B15 in the accessory radula closer neuromuscular system of Aplysia. The model consists of a slow "mobilizing" reaction and the fast release reaction itself. Experimentally, however, it was possible to measure only the mean, heavily averaged release, lacking fast kinetic information. Considered in the conventional way, the data were insufficient to completely specify the details of the model, in particular the relative properties of the slow and the unobservable fast reaction. We illustrate here, with our model and with additional experiments, how to approach such a problem by considering another dimension of release, namely its pattern dependence. The mean release is sensitive to the temporal pattern of firing, even to pattern on time scales much faster than the time scale on which the release is averaged. The mean release varies with the time scale and magnitude of the pattern, relative to the time scale and nonlinearity of the release reactions with which the pattern interacts. The type and magnitude of pattern dependence, especially when correlated systematically over a range of patterns, can therefore yield information about the properties of the release reactions. Thus, temporal pattern can be used as a probe of the release process, even of its fast, directly unobservable components. More generally, the analysis provides insights into the possible ways in which such pattern dependence, widespread especially in neuropeptide- and hormone-releasing systems, might arise from the properties of the underlying cellular reactions. (+info)
A novel function for serotonin-mediated short-term facilitation in aplysia: conversion of a transient, cell-wide homosynaptic hebbian plasticity into a persistent, protein synthesis-independent synapse-specific enhancement.
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Studies of sensitization and classical conditioning of the gill-withdrawal reflex in Aplysia have shown that the synaptic connections between identified glutamatergic sensory neurons and motor neurons can be enhanced in one of two ways: by a heterosynaptic (modulatory input-dependent) mechanism that gives rise with repetition to long-term facilitation and by a homosynaptic (activity-dependent) mechanism that gives rise with repetition to a facilitation that is partially blocked by 2-amino-5-phosphonovaleric acid and by injection of 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetate (BAPTA) into the postsynaptic cell and is similar to long-term potentiation in the hippocampus. We here have examined how these two forms of facilitation interact at the level of an individual synaptic connection by using a culture preparation consisting of a single bifurcated sensory neuron that forms independent synaptic contacts with each of two spatially separated motor neurons. We find that the homosynaptic facilitation produced by a train of action potentials is cell wide and is evident at all of the terminals of the sensory neuron. By contrast, the heterosynaptic facilitation mediated by the modulatory transmitter serotonin (5-HT) can operate at the level of a single synapse. Homosynaptic activation gives rise to only a transient facilitation lasting a few hours, even when repeated in a spaced manner. The heterosynaptic facilitation produced by a single pulse of 5-HT, applied to one terminal of the sensory neuron, also lasts only minutes. However, when one or more homosynaptic trains of spike activity are paired with even a single pulse of 5-HT applied to one of the two branches of the sensory neuron, the combined actions lead to a selective enhancement in synaptic strength only at the 5-HT-treated branch that now lasts more than a day, and thus amplifies, by more than 20-fold, the duration of the individually produced homo- and heterosynaptic facilitation. This form of synapse-specific facilitation has unusual long-term properties. It does not require protein synthesis, nor is it accompanied by synaptic growth. (+info)
Long-term regulation of neuronal high-affinity glutamate and glutamine uptake in Aplysia.
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An increase in transmitter release accompanying long-term sensitization and facilitation occurs at the glutamatergic sensorimotor synapse of Aplysia. We report that a long-term increase in neuronal Glu uptake also accompanies long-term sensitization. Synaptosomes from pleural-pedal ganglia exhibited sodium-dependent, high-affinity Glu transport. Different treatments that induce long-term enhancement of the siphon-withdrawal reflex, or long-term synaptic facilitation increased Glu uptake. Moreover, 5-hydroxytryptamine, a treatment that induces long-term facilitation, also produced a long-term increase in Glu uptake in cultures of sensory neurons. The mechanism for the increase in uptake is an increase in the V(max) of transport. The long-term increase in Glu uptake appeared to be dependent on mRNA and protein synthesis, and transport through the Golgi, because 5,6-dichlorobenzimidazole riboside, emetine, and brefeldin A inhibited the increase in Glu uptake. Also, injection of emetine and 5,6-dichlorobenzimidazole into Aplysia prevented long-term sensitization. Synthesis of Glu itself may be regulated during long-term sensitization because the same treatments that produced an increase in Glu uptake also produced a parallel increase in Gln uptake. These results suggest that coordinated regulation of a number of different processes may be required to establish or maintain long-term synaptic facilitation. (+info)
Distributed and partially separate pools of neurons are correlated with two different components of the gill-withdrawal reflex in Aplysia.
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We compared the spike activity of individual neurons in the Aplysia abdominal ganglion with the movement of the gill during the gill-withdrawal reflex. We discriminated four populations that collectively encompass approximately half of the active neurons in the ganglion: (1) second-order sensory neurons that respond to the onset and offset of stimulation of the gill and are active before the movement starts; (2) neurons whose activity is correlated with the position of the gill and typically have a tonic output during gill withdrawal; (3) neurons whose activity is correlated with the velocity of the movement and typically fire in a phasic manner; and (4) neurons whose activity is correlated with both position and velocity. A reliable prediction of the position of the gill is achieved only with the combined output of 15-20 neurons, whereas a reliable prediction of the velocity depends on the combined output of 40 or more cells. (+info)
Independence of and interactions between GABA-, glutamate-, and acetylcholine-activated Cl conductances in Aplysia neurons.
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In certain Aplysia neurons, glutamate, GABA, and acetylcholine (ACh) all elicit desensitizing Cl-dependent responses. This fact and the finding that the glutamate and GABA responses "cross-desensitize" led to the suggestion (Swann and Carpenter, 1975; King and Carpenter, 1987) that the responses to these transmitters were mediated by the same receptor-channel complex. This hypothesis is incompatible with the demonstration given here that the GABA- and glutamate-gated channels are clearly distinct; the GABA channel, but not the glutamate channel, shows outward rectification (Matsumoto, 1982; King and Carpenter, 1987, 1989) and is selectively blocked by intracellular sulfate. Exploiting these distinctive characteristics and the independent expression of the receptors in some cells, we have been able to reevaluate the so-called cross-desensitization by analyzing the ability of GABA, glutamate, and other agonists to interact with each of the receptor molecules. The cross-desensitization was found to be exclusively attributable to the ability of GABA to interact with the glutamate receptor (Oyama et al., 1990). The GABA receptor is unaffected by glutamate. Nevertheless, in cells expressing both receptors, glutamate can reduce the GABA response by auto-desensitizing the part of the response that is mediated by the glutamate receptor. No interactions were observed between ACh-induced responses and either of the responses elicited by the amino acids. The invertebrate glutamate-gated Cl channels that have been cloned resemble the vertebrate glycine receptor (Vassilatis et al., 1997). Our pharmacological evaluation of the molluscan glutamate receptor points in the same direction. (+info)
Enhancement of memory-related long-term facilitation by ApAF, a novel transcription factor that acts downstream from both CREB1 and CREB2.
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The memory for sensitization of the gill withdrawal reflex in Aplysia is reflected in facilitation of the monosynaptic connection between the sensory and motor neurons of the reflex. The switch from short- to long-term facilitation requires activation of CREB1, derepression of ApCREB2, and induction of ApC/EBP. In search for genes that act downstream from CREB1, we have identified a transcription activator, ApAF, which is stimulated by protein kinase A and can dimerize with both ApC/EBP and ApCREB2. ApAF is necessary for long-term facilitation induced by five pulses of serotonin, by activation of CREB1, or by derepression of ApCREB2. Overexpression of ApAF enhances the long-term facilitation further. Thus, ApAF is a candidate memory enhancer gene downstream from both CREB1 and ApCREB2. (+info)
Serotonergic and peptidergic modulation of the buccal mass protractor muscle (I2) in aplysia.
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Plasticity of Aplysia feeding has largely been measured by noting changes in radula protraction. On the basis of previous work, it has been suggested that peripheral modulation may contribute to behavioral plasticity. However, peripheral plasticity has not been demonstrated in the neuromuscular systems that participate in radula protraction. Therefore in this study we investigated whether contractions of a major radula protraction muscle (I2) are subject to modulation. We demonstrate, first, that an increase in the firing frequency of the cholinergic I2 motoneurons will increase the amplitude of the resulting muscle contraction but will not modulate its relaxation rate. We show, second, that neuronal processes on the I2 muscle are immunoreactive to myomodulin (MM), RFamide, and serotonin (5-HT), but not to small cardioactive peptide (SCP) or buccalin. The I2 motoneurons B31, B32, B61, and B62 are not immunoreactive to RFamide, 5-HT, SCP, or buccalin. However, all four cells are MM immunoreactive and are capable of synthesizing MMa. Third, we show that the bioactivity of the different modulators is somewhat different; while the MMs (i.e., MMa and MMb) and 5-HT increase I2 muscle relaxation rate, and potentiate muscle contraction amplitude, MMa, at high concentrations, depresses muscle contractions. Fourth, our data suggest that cAMP at least partially mediates effects of modulators on contraction amplitude and relaxation rate. (+info)