What Molecular Steps Determine the Time Course of the Memory for Short-term Sensitization in Aplysia?

188

Bilateral clusters of sensory neurons in the pleural ganglia of Aplysia contain cells involved in a defensive tail withdrawal reflex. These cells exhibit heterosynaptic facilitation in response to noxious skin stimulation that can be mimicked by the application of serotonin. Recently it has been shown that this facilitation can be selectively amplified by the application of a classical conditioning procedure to individual sensory neurons. We now report that an analog of this classical conditioning paradigm produces a selective amplification of the cAMP content of isolated sensory neuron clusters. The enhancement is achieved within a single trial and appears to be localized to the sensory neurons. These results indicate that a pairing-specific enhancement of cAMP levels may be a biochemical mechanism for associative neuronal modifications and perhaps learning.Associative modifications within individual neurons have recently been implicated as mechanisms for associative learning and memory (1-5). A recently developed preparation that offers particular promise for the analysis of biochemical and biophysical modifications underlying neural plasticity is the defensive tail withdrawal reflex in the marine mollusc Aplysia. An associative conditioning paradigm applied directly to individual sensory neurons can specifically modify monosynaptic connections between these cells and the motor neurons involved in tail withdrawal (3). This was shown with a differential conditioning procedure that utilized intracellular activation of individual tail sensory cells as the conditioned stimulus (CS) and shock to the skin as the unconditioned stimulus (US). Since the US was delivered outside the receptive fields of the sensory neurons examined, these neurons were not activated by the US. However, they were exposed to diffuse neuromodulatory effects of the US that produced heterosynaptic facilitation of all of the connections of the sensory neurons (3). Paired presentation of the CS and US resulted in a significant enhancement of the excitatory postsynaptic potential (EPSP) amplitude compared to the facilitation produced when the CS and US were separated by 2 min or when the US was presented alone (3). We termed this enhancement "activity-dependent neuromodulation" because the effects of a presumed neuromodulator released by the US are specifically enhanced by spike activity that immediately precedes the US. Although models formally similar to activity-dependent neuromodulation have been proposed previously as candidate mechanisms for associative memory (6-8), these and similar results obtained independently by Hawkins et al. (4) in Aplysia provided direct experimental evidence for such a phenomenon at the cellular level.The tail withdrawal is sensitized by the same weak electrical stimulation of the skin used as the US (above), and the sensitization is accompanied by heterosynaptic facilitation of the monosynaptic connections between the sensory and motor neurons (9). This heterosynaptic facilitation can be mimicked by subs...

Section: Discussionmentioning

confidence: 99%

Associative conditioning analog selectively increases cAMP levels of tail sensory neurons in Aplysia.

Ocorr¹,

Walters²,

Byrne³

1985

188

“…Basal activity was 2.9 pmol of cAMP/min. withdrawal reflex, short-term memory in the monosynaptic component of the reflex may reside in the activity of the adenylate cyclase complex (12). We have therefore investigated whether activation of Aplysia neuronal cyclase is autonomous and persists after removal of facilitatory transmitter.…”

Section: Methodsmentioning

confidence: 99%

“…Both in the marine mollusk Aplysia californica (5-7) and in Drosophila (7)(8)(9)(10)(11) adenylate cyclase has been implicated in elementary forms of learning and short-term memory. In such cases temporal properties of interactions of the cyclase complex with transmitters and ions may be important for the enzyme's function in neuronal plasticity (7,(12)(13)(14)(15).…”

mentioning

confidence: 99%

“…Both electrophysiological and biochemical evidence suggested that in the monosynaptic component of the reflex, the duration of short-term memory ofthe learned response is primarily due to sustained elevation of cAMP in the sensory neurons (12). Following facilitatory stimuli, the increase in the synaptic connection between sensory neurons and motoneurons and the prolongation of the presynaptic action potential (a presynaptic change that contributes to synaptic facilitation) were substantially reduced by either injection of the protein inhibitor of the cAMP-dependent kinase (18) or injection of guanosine-5'-O-(2-thiodiphosphate) (GDP[,BS]) (19), which inhibits adenylate cyclase activation (20,21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Biochemical correlates of short-term sensitization in Aplysia: temporal analysis of adenylate cyclase stimulation in a perfused-membrane preparation.

Yovell

Kandel

Dudai

et al. 1987

During short-term sensitization, a simple form of nonassociative learning in Aplysia, the presentation of a single brief noxious stimulus results in enhancement of the defensive withdrawal reflex lasting minutes to tens of minutes. This behavioral plasticity involves presynaptic facilitation of synaptic transmission from the mechanosensory neurons that mediate the reflex to their central target cells. This facilitation is due to cAMP-dependent protein phosphorylation. To determine whether the time course of presynaptic facilitation might be due to a persistent increase in activity of adenylate cyclase (EC 4.6.1.1) itself, persistence of the transmitter, or yet other processes, we developed a perfused-membrane method to analyze the time course of activation of adenylate cyclase by transient stimuli. After stimulation by a pulse of stimulatory transmitter, activation of adenylate cyclase decayed within 60 sec. This finding indicates that the enzyme does not remain persistently active in the absence of transmitter and suggests that short-term retention is likely to be due to other mechanisms. Possible additional mechanisms include continued activation of the cyclase by transmitter, cellular factors extrinsic to the cyclase that prolong the time course of its activation, and persistence of processes downstream from the cyclase.

“…In invertebrates, there is specific neurophysiological evidence that serotonin is involved in sensitization and classical conditioning of the siphon-withdrawal reflex in Aplysia (9)(10)(11). Serotonin, applied to the relevant synapses in the circuit, can mimic behavioral sensitization, producing facilitation of synaptic transmission in the reflex pathway.…”

mentioning

confidence: 99%

Mutations in the dopa decarboxylase gene affect learning in Drosophila.

Tempel

Livingstone

Quinn

1984

145

Fruit flies synthesize several monoamine neurotransmitters. Dopa decarboxylase (Ddc) mutations affect synthesis of two of these, dopamine and serotonin. Both transmitters are implicated in vertebrate and invertebrate learning. Therefore, we bred flies of various Ddc genotypes and tested their learning ability in positively and negatively reinforced learning tasks. Mutations in the Ddc gene diminished learning acquisition approximately in proportion to their effect on enzymatic activity. Courtship and mating sequences of the mutants appeared normal, except for one aspect of male courtship that had previously been shown to be experience dependent. In contrast, the effect on behavior patterns that do not involve learning-phototaxis, geotaxis, olfactory acuity, responsiveness to sucrose-was relatively slight under these conditions. Moderate Ddc mutations affected the acquisition of learned responses while leaving memory retention unaltered. This is in contrast to the mutations dunce, rutabaga, and amnesiac, which primarily affect short-term memory.Biogenic monoamines (principally dopamine, serotonin, epinephrine, and norepinephrine in vertebrates; dopamine, serotonin, and octopamine in invertebrates) are a group of neurotransmitters formed from aromatic amino acids that seem to be related in their physiological and behavioral functions. Monoamines are implicated in synaptic modulation in a variety of animals (1-4). Numerous pharmacological studies in vertebrates indirectly but consistently suggest a role for monoamines in attentiveness and behavioral plasticity (5), particularly a role for dopamine in positively reinforced learning (6). In line with this, some neurophysiological and behavioral experiments suggest an involvement of norepinephrine in experience-dependent changes during a critical period of visual cortical development (7, 8; B. Gordon, J. Moran, P. Trombley, and J. Soyke, personal communication).In invertebrates, there is specific neurophysiological evidence that serotonin is involved in sensitization and classical conditioning of the siphon-withdrawal reflex in Aplysia (9-11). Serotonin, applied to the relevant synapses in the circuit, can mimic behavioral sensitization, producing facilitation of synaptic transmission in the reflex pathway. The behavioral effect of sensitizing stimuli can be blocked by cinanserine, a moderately specific antagonist of serotonin (9).Recently, however, this story has been complicated by a failure to find serotonin-like immunoreactivity in identified facilitatory neurons [those of the L29 group (12)], although serotonergic terminals from other cells are found in the relevant synaptic sites (12).In both vertebrates and invertebrates, therefore, the evidence linking biogenic monoamines to learning is cumulatively suggestive, but it is in no case unassailable. We decided to investigate this relation further, using Drosophila mutants.Wright and his colleagues (13,14,15) MATERIALS AND METHODSCulture Conditions, Fly Stocks, and Crosses. All Drosophila stocks were bred ...