A circuit mechanism linking past and future learning through shifts in perception.

Long-term memory formation is energetically costly. Neural mechanisms that guide an animal to identify fruitful associations therefore have important survival benefits. Here, we elucidate a circuit mechanism in , which enables past memory to shape new memory formation through changes in perception.

The role of non-coding RNAs in the formation of long-term associative memory after single-trial learning in .

Investigations of the molecular mechanisms of long-term associative memory have revealed key roles for a number of highly evolutionarily conserved molecular pathways in a variety of different vertebrate and invertebrate model systems. One such system is the pond snail , in which, like in other systems, the transcription factors CREB1 and CREB2 and the enzyme NOS play essential roles in the consolidation of long-term associative memory. More recently, epigenetic control mechanisms, such as DNA methylation, histone modifications, and control of gene expression by non-coding RNAs also have been found to play important roles in all model systems.

A combined bioinformatics and LC-MS-based approach for the development and benchmarking of a comprehensive database of Lymnaea CNS proteins.

Applications of key technologies in biomedical research, such as qRT-PCR or LC-MS-based proteomics, are generating large biological (-omics) datasets which are useful for the identification and quantification of biomarkers in any research area of interest. Genome, transcriptome and proteome databases are already available for a number of model organisms including vertebrates and invertebrates. However, there is insufficient information available for protein sequences of certain invertebrates, such as the great pond snail Lymnaea stagnalis, a model organism that has been used highly successfully in elucidating evolutionarily conserved mechanisms of memory function and dysfunction.

Interneuronal mechanisms for learning-induced switch in a sensory response that anticipates changes in behavioral outcomes.

Sensory cues in the natural environment predict reward or punishment, important for survival. For example, the ability to detect attractive tastes indicating palatable food is essential for foraging while the recognition of inedible substrates prevents harm. While some of these sensory responses are innate, they can undergo fundamental changes due to prior experience associated with the stimulus.

The unlimited potential of the great pond snail, .

Only a limited number of animal species lend themselves to becoming model organisms in multiple biological disciplines: one of these is the great pond snail, . Extensively used since the 1970s to study fundamental mechanisms in neurobiology, the value of this freshwater snail has been also recognised in fields as diverse as host-parasite interactions, ecotoxicology, evolution, genome editing and 'omics', and human disease modelling. While there is knowledge about the natural history of this species, what is currently lacking is an integration of findings from the laboratory and the field.

Proactive and retroactive interference with associative memory consolidation in the snail is time and circuit dependent.

Interference-based forgetting occurs when new information acquired either before or after a learning event attenuates memory expression (proactive and retroactive interference, respectively). Multiple learning events often occur in rapid succession, leading to competition between consolidating memories. However, it is unknown what factors determine which memory is remembered or forgotten.

Interneuronal mechanism for Tinbergen's hierarchical model of behavioral choice.

Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks [1]. We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors.

Susceptibility of memory consolidation during lapses in recall.

Memories that can be recalled several hours after learning may paradoxically become inaccessible for brief periods after their formation. This raises major questions about the function of these early memory lapses in the structure of memory consolidation. These questions are difficult to investigate because of the lack of information on the precise timing of lapses.

Axonal trafficking of an antisense RNA transcribed from a pseudogene is regulated by classical conditioning.

Natural antisense transcripts (NATs) are endogenous RNA molecules that are complementary to known RNA transcripts. The functional significance of NATs is poorly understood, but their prevalence in the CNS suggests a role in brain function. Here we investigated a long NAT (antiNOS-2 RNA) associated with the regulation of nitric oxide (NO) production in the CNS of Lymnaea, an established model for molecular analysis of learning and memory.

Distributed network organization underlying feeding behavior in the mollusk Lymnaea.

The aim of the work reviewed here is to relate the properties of individual neurons to network organization and behavior using the feeding system of the gastropod mollusk, Lymnaea. Food ingestion in this animal involves sequences of rhythmic biting movements that are initiated by the application of a chemical food stimulus to the lips and esophagus. We investigated how individual neurons contribute to various network functions that are required for the generation of feeding behavior such as rhythm generation, initiation ('decision making'), modulation and hunger and satiety.

Different circuit and monoamine mechanisms consolidate long-term memory in aversive and reward classical conditioning.

There has been considerable recent interest in comparing the circuit and monoamine-based mechanisms of aversive and reward-associative conditioning in a number of vertebrate and invertebrate model systems. The mollusc Lymnaea stagnalis provides a unique opportunity to explore changes in the neural and chemical pathways underlying these two different types of conditioning as its feeding circuitry has been thoroughly characterised. Animals can learn after a single trial to associate the same CS (amyl acetate) either with a punishment (quinine) or reward (sucrose), showing either a reduced or an elevated feeding response, respectively, to the CS.

Role of tonic inhibition in associative reward conditioning in lymnaea.

Changes in the strength of excitatory synaptic connections are known to underlie associative memory formation in the molluscan nervous system but less is known about the role of synaptic inhibition. Tonic or maintained synaptic inhibition has an important function in controlling the Lymnaea feeding system and is known to suppress feeding in the absence of food or in satiated animals. Tonic inhibition to the feeding network is provided by the N3t interneuron that has inhibitory monosynaptic connection with the central pattern generator interneuron, the N1M.

What roles do tonic inhibition and disinhibition play in the control of motor programs?

Animals show periods of quiescence interspersed with periods of motor activity. In a number of invertebrate and vertebrate systems, quiescence is achieved by active suppression of motor behavior is due to tonic inhibition induced by sensory input or changes in internal state. Removal of this inhibition (disinhibition) has the converse effect tending to increase the level of motor activity.

Balanced plasticity and stability of the electrical properties of a molluscan modulatory interneuron after classical conditioning: a computational study.

The Cerebral Giant Cells (CGCs) are a pair of identified modulatory interneurons in the Central Nervous System of the pond snail Lymnaea stagnalis with an important role in the expression of both unconditioned and conditioned feeding behavior. Following single-trial food-reward classical conditioning, the membrane potential of the CGCs becomes persistently depolarized. This depolarization contributes to the conditioned response by facilitating sensory cell to command neuron synapses, which results in the activation of the feeding network by the conditioned stimulus.

Time-window for sensitivity to cooling distinguishes the effects of hypothermia and protein synthesis inhibition on the consolidation of long-term memory.

The effects of hypothermia on memory formation have been examined extensively, and while it is clear that post-training cooling interferes with the process of consolidation, the nature of the temperature sensitive processes disrupted in this way remain poorly defined. Post-training manipulations that disrupt consolidation tend to be effective during specific time-windows of sensitivity, the timing and duration of which are directly related to the mechanism through which the treatment induces amnesia. As such, different treatments that target the same basic processes should be associated with similar time-windows of sensitivity.

Characterization of NO-sensitive guanylyl cyclase: expression in an identified interneuron involved in NO-cGMP-dependent memory formation.

In a number of neuronal models of learning signalling by endogenous nitric oxide (NO), produced by the enzyme NO synthase (NOS), is essential for the formation of long-term memory (LTM). For example, in the molluscan model system Lymnaea, NO is required for LTM formation in the first few hours after one-trial reward conditioning. Furthermore, conditioning leads to transient up-regulation of the NOS gene in identified modulatory neurons, the cerebral giant cells (CGCs), which are known to be involved in LTM formation.

Persistent sodium current is a nonsynaptic substrate for long-term associative memory.

Although synaptic plasticity is widely regarded as the primary mechanism of memory [1], forms of nonsynaptic plasticity, such as increased somal or dendritic excitability or membrane potential depolarization, also have been implicated in learning in both vertebrate and invertebrate experimental systems [2-7]. Compared to synaptic plasticity, however, there is much less information available on the mechanisms of specific types of nonsynaptic plasticity involved in well-defined examples of behavioral memory. Recently, we have shown that learning-induced somal depolarization of an identified modulatory cell type (the cerebral giant cells, CGCs) of the snail Lymnaea stagnalis encodes information that enables the expression of long-term associative memory [8].

Non-synaptic neuronal mechanisms of learning and memory in gastropod molluscs.

Gastropod molluscs provide important model systems for investigating the behavioral and neural basis of associative and non-associative learning. Habituation, sensitization, classical and operant conditioning are studied in motor reflex and central pattern generator circuits. Although synaptic plasticity has long been recognized as playing a key role in molluscan learning circuits, non-synaptic changes resulting in alterations in the excitability of neurons are increasingly recognized as an essential component of the memory trace.

Dynamic control of a central pattern generator circuit: a computational model of the snail feeding network.

Central pattern generators (CPGs) are networks underlying rhythmic motor behaviours and they are dynamically regulated by neuronal elements that are extrinsic or intrinsic to the rhythmogenic circuit. In the feeding system of the pond snail, Lymnaea stagnalis, the extrinsic slow oscillator (SO) interneuron controls the frequency of the feeding rhythm and the N3t (tonic) has a dual role; it is an intrinsic CPG interneuron, but it also suppresses CPG activity in the absence of food, acting as a decision-making element in the feeding circuit. The firing patterns of the SO and N3t neurons and their synaptic connections with the rest of the CPG are known, but how these regulate network function is not well understood.

Modulation of serotonergic neurotransmission by nitric oxide.

Nitric oxide (NO) and serotonin (5-HT) are two neurotransmitters with important roles in neuromodulation and synaptic plasticity. There is substantial evidence for a morphological and functional overlap between these two neurotransmitter systems, in particular the modulation of 5-HT function by NO. Here we demonstrate for the first time the modulation of an identified serotonergic synapse by NO using the synapse between the cerebral giant cell (CGC) and the B4 neuron within the feeding network of the pond snail Lymnaea stagnalis as a model system.

Role of delayed nonsynaptic neuronal plasticity in long-term associative memory.

Background: It is now well established that persistent nonsynaptic neuronal plasticity occurs after learning and, like synaptic plasticity, it can be the substrate for long-term memory. What still remains unclear, though, is how nonsynaptic plasticity contributes to the altered neural network properties on which memory depends. Understanding how nonsynaptic plasticity is translated into modified network and behavioral output therefore represents an important objective of current learning and memory research.

Associative memory stored by functional novel pathway rather than modifications of preexisting neuronal pathways.

Associative conditioning involves changes in the processing pathways activated by sensory information to link the conditioned stimulus (CS) to the conditioned behavior. Thus, conditioning can recruit neuronal elements to form new pathways for the processing of the CS and/or can change the strength of existing pathways. Using a behavioral and systems level electrophysiological approach on a tractable invertebrate circuit generating feeding in the mollusk Lymnaea stagnalis, we identified three independent pathways for the processing of the CS amyl acetate used in appetitive conditioning.

Activation of MAPK is necessary for long-term memory consolidation following food-reward conditioning.

Although an important role for the mitogen-activated protein kinase (MAPK) has been established for memory consolidation in a variety of learning paradigms, it is not known if this pathway is also involved in appetitive classical conditioning. We address this question by using a single-trial food-reward conditioning paradigm in the freshwater snail Lymnaea stagnalis. This learning paradigm induces protein synthesis-dependent long-term memory formation.