Serotonergic Modulation in Aplysia. II. Cellular and Behavioral Consequences of Increased Serotonergic Tone

Abstract

Marinesco, Stéphane, Nimalee Wickremasinghe, Kristine E. Kolkman, and Thomas J. Carew. Serotonergic modulation in Aplysia. II. Cellular and behavioral consequences of increased serotonergic tone. J Neurophysiol 92: 2487-2496, 2004. First published May 12, 2004 10.1152/jn.00210.2004. Serotonin (5-HT) plays an important role in sensitization of defensive reflexes in Aplysia and is also involved in several aspects of arousal, such as the control of locomotion and of cardiovascular tone. In the preceding paper, we showed that tail-nerve shock, a noxious stimulus that readily induces sensitization, increases the firing rate of a large number of serotonergic neurons throughout the CNS. However, the functional consequences of such an increase in serotonergic tone are still poorly understood. In this study, we examined this question by using the 5-HT precursor 5-hydroxytryptophan (5-HTP) to specifically increase 5-HT release in the CNS. Increased tonic 5-HT release after 5-HTP treatment was manifested by facilitation of sensorimotor (SN-MN) synapses, increased firing rate of serotonergic neurons in the pedal and abdominal ganglia, and enhanced 5-HT release evoked by tail-nerve shock. When 5-HTP was administered to freely moving animals, it produced a strong arousal response characterized by increased locomotion and heart rate, which was reminiscent of the defensive arousal reaction triggered by noxious stimulation such as tail-shock. In contrast, 5-HTP actually inhibited the tail-induced siphon-withdrawal reflex. It is possible that 5-HT-induced facilitation of SN-MN synapses was counteracted by inhibition of polysynaptic reflex pathways between SNs and MNs, resulting in transient behavioral inhibition of the reflex, which could favor escape locomotion and/or respiration shortly after an aversive stimulus. We conclude that a major function associated with the activation of the Aplysia serotonergic system evoked by noxious stimuli is the triggering of a defensive arousal response. It is known that tail-shock-induced serotonergic activation contributes to memory encoding at least in part by facilitating SN-MN synapses. However, this effect in isolation might not be sufficient for the behavioral expression of sensitization. I N T R O D U C T I O NSensitization of defensive reflexes by noxious stimuli in Aplysia relies at least in part on serotonin (5-HT) release in the CNS. For example, chemical lesioning of the Aplysia serotonergic system impairs the ability of tail-shock to enhance defensive reflexes (Glanzman et al. 1989), and 5-HT is released in the hemolymph and the CNS in response to sensitizing stimuli (Levenson et al. 1999;Marinesco and Carew 2002). Moreover, sensory neuron (SN) to motor neuron (MN) synapses are facilitated during sensitization and provide a cellular correlate for this form of memory (Castellucci and Kandel 1976). Exogenous 5-HT application in vitro is sufficient to produce SN-MN facilitation, and 5-HT receptor antagonists can block this effect (Brunelli et al. 1976;Mercer et al. 1991). Moreover,...

Transient Mitogen-Activated Protein Kinase Activation Is Confined to a Narrow Temporal Window Required for the Induction of Two-Trial Long-Term Memory inAplysia

“…The ability to enable the formation of LTM by coupling massed training with a single spaced TS suggests that the massed training may be encoded as a single training event. Consistent with this possibility are recent observations by Marinesco and colleagues (Marinesco and Carew, 2002;Marinesco et al, 2004b) who examined serotonin (5-HT), a critical neuromodulator in Aplysia. After a single sensitizing stimulus, serotonergic cells increase their firing rates and release 5-HT at tail SN cell bodies and synapses (Marinesco and Carew, 2002;Marinesco et al, 2004a).…”

Regulation of Behavioral and Synaptic Plasticity by Serotonin Release within Local Modulatory Fields in the CNS ofAplysia

“…For example, in the Aplysia and leech CNS, exogenous application of 5-HT is not always equivalent to stimulation of endogenous 5-HT release (Fox and Lloyd, 1998;Marinesco et al, 2004b;Calvino et al, 2005). These data supported the inference that exogenous 5-HT, even in physiological concentrations, can activate receptors that are not a natural target of 5-HT when it is endogenously released (for example, by nerve stimulation).…”

“…Effects of tail and head-nerve shocks on the firing rate of serotonergic neurons Serotonergic neurons have been implicated in both sensitization (Brunelli et al, 1976;Glanzman et al, 1989;Mackey et al, 1989;Marinesco and Carew, 2002a) and behavioral or synaptic inhibition (Fitzgerald and Carew, 1991;Bristol et al, 2001;Marinesco et al, 2004b). To understand the contribution of the serotonergic system to the modulation of the T-SW reflex by ipsilateral tail shock, contralateral tail shock, or head shock, we recorded the activity of these cells after they were prelabeled with 5,7-DHT.…”

“…Similarly, other nonserotonergic mechanisms probably contribute to sensitization in Aplysia (Abrams et al, 1984;Marinesco et al, 2004b). Therefore, our simplified model should not be viewed as an exhaustive description of the cellular events responsible for sensitization but rather as an illustration of the physiological role of local 5-HT modulatory fields during learning.…”

“…In addition, the serotonergic system of Aplysia presents many homologies with mammalian species. For example, serotonergic neurons in Aplysia are involved in arousal, feeding, and locomotion (Kupfermann and Weiss, 1982;Mackey and Carew, 1983;Lloyd et al, 1984;Rosen et al, 1989;McPherson and Blankenship, 1992;Marinesco et al, 2004b), like their counterparts in mammals (Veasey et al, 1995(Veasey et al, , 1997) ( for review, see Jacobs and Fornal, 1999;Meguid et al, 2000;Siegel, 2004). Moreover, as in the mammalian CNS, serotonergic neurons in Aplysia are tonically active at rest, fire at relatively low frequencies (usually Ͻ1 Hz) (Kupfermann and Weiss, 1982;Marinesco et al, 2004a), and can release 5-HT in a paracrine or volumic manner (Marinesco and Carew, 2002a;Zhang et al, 2003) (for review, see Bunin and Wightman, 1999).…”