Nonassociative learning in invertebrates - PubMed (original) (raw)
Review
Nonassociative learning in invertebrates
John H Byrne et al. Cold Spring Harb Perspect Biol. 2015.
Abstract
The simplicity and tractability of the neural circuits mediating behaviors in invertebrates have facilitated the cellular/molecular dissection of neural mechanisms underlying learning. The review has a particular focus on the general principles that have emerged from analyses of an example of nonassociative learning, sensitization in the marine mollusk Aplysia. Learning and memory rely on multiple mechanisms of plasticity at multiple sites of the neuronal circuits, with the relative contribution to memory of the different sites varying as a function of the extent of training and time after training. The same intracellular signaling cascades that induce short-term modifications in synaptic transmission can also be used to induce long-term changes. Although short-term memory relies on covalent modifications of preexisting proteins, long-term memory also requires regulated gene transcription and translation. Maintenance of long-term cellular memory involves both intracellular and extracellular feedback loops, which sustain the regulation of gene expression and the modification of targeted molecules.
Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
Figures
Figure 1.
Heterosynaptic facilitation of the sensorimotor connection contributes to sensitization in Aplysia. (A) Sensitizing stimuli activate facilitatory interneurons (IN) that release modulatory transmitters, one of which is 5-HT. The modulator leads to an alteration of the properties of the sensory neuron (SN) and motor neuron (MN). (B) The enhanced synaptic input to the MN during sensitization results from enhanced sensory input, partly caused by two mechanisms. First, the same peripheral stimulus can evoke a greater number of action potentials in the presynaptic SN (i.e., enhanced excitability). Second, each action potential fired by an SN produces a stronger synaptic response in the MN (i.e., synaptic facilitation). A component of sensitization is also caused by the effects of 5-HT on the MN. (Based on data from Byrne and Kandel 1996.)
Figure 2.
Cellular and molecular mechanisms of facilitation at sensory–motor neuron synapses that contribute to short- and intermediate-term learning in Aplysia. Dishabituation (DIS) involves presynaptic protein kinase C (PKC). Short-term (ST) sensitization involves presynaptic protein kinase A (PKA) and calmodulin-dependent protein kinase (CaMKII). Intermediate-term (IT) sensitization involves presynaptic PKA and CaMKII or PKC, protein synthesis (prot syn), and spontaneous transmitter release. In addition, it involves postsynaptic mGluRs, CaMKII or PKC, protein synthesis, and membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-like receptors, as well as recruitment of pre- and postsynaptic proteins to new synaptic sites. In contrast, long-term (LT) sensitization involves gene regulation and growth of new synapses. AC, Adenyl cyclase; cAMP, cyclic adenosine-3-monophosphate; DG, diacylglycerol; NMDA, _N_-methyl-
d
-aspartate; PKM, protein kinase M; PLC, phospholipase C; RNA syn, RNA synthesis. (Based on data in Hawkins et al. 2013.)
Figure 3.
Simplified scheme of the mechanisms that contribute to long-term sensitization in Aplysia. Sensitization training leads to cyclic adenosine 3-monophosphate (cAMP)-dependent regulation of cAMP-response element binding (CREB)1. Serotonin also leads to activation of extracellular signal-regulated kinase (ERK), which regulates CREB2. Although CREB1 acts as an initiator of gene transcription, CREB2 acts as a repressor of gene transcription. The combined effects of activation of CREB1 and suppression of CREB2 lead to regulation of the synthesis of at least 10 proteins, only some of which are shown. Aplysia tolloid/BMP-like protein (ApTBL) is believed to activate latent forms of transforming growth factor (TGF)-β, which can then bind to receptors on the sensory neuron (SN). TGF-β activates ERK, which may act by initiating a second round of gene regulation by affecting CREB2-dependent pathways. Serotonin can also increase the local synthesis of the Aplysia homolog of cytoplasmic polyadenylation element-binding protein (ApCPEB) and the peptide sensorin through phosphoinositide-3-kinase (PI3K). ApCPEB can exist in two conformations, one of which dominates and allows ApCPEB to self-perpetuate. Sensorin release is dependent on type II protein kinase A (PKA). Sensorin binds to autoreceptors leading to further activation of ERK. Because increased synthesis of sensorin requires elevation of postsynaptic calcium, a retrograde signal is also postulated. In addition to the retrograde signal, 5-HT-induced postsynaptic signaling also leads to an increased number of glutamate receptors. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ApCAM, Aplysia cell adhesion molecule; ApTrk, Aplysia tyrosine kinase autoreceptor; ApUch, Aplysia ubiquitin hydrolase; MEK, MAPK/ERK kinase; PKM, protein kinase M. (Based on data from Liu et al. 1997.)
Figure 4.
Cascade model of mechanisms contributing to the different stages of synaptic plasticity in Aplysia. In cascade models (Fusi et al. 2005), synapses have two levels of strength (weak and strong) and several increasingly long-lasting states. In Aplysia, relatively weak stimulation produces short-term facilitation (STF) that lasts minutes, stronger stimulation produces intermediate-term facilitation (ITF) that lasts minutes to hours, and even stronger stimulation produces long-term facilitation (LTF) that lasts days. The different stages of facilitation may involve a series or cascade of pre- and postsynaptic mechanisms that is initiated by spontaneous transmitter release during STF, progresses through two stages of ITF, and can culminate in synaptic growth during LTF. The mechanisms in this growth cascade are a subset of all mechanisms involved in facilitation, and some other mechanisms (not shown) may act in parallel and contribute only to specific stages. Thus, the idea of a cascade applies to the mechanisms and not the stages per se. In addition to this linear cascade, facilitation also involves feedforward and feedback loops. Dashed lines, transitions that are initiated by different durations or patterns of 5-HT; solid lines, spontaneous transitions; red, extracellular signaling molecules; blue, structural modifications. MN, motor neuron; SN, sensory neuron.
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