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Lymnaea stagnalis come modello per la ricerca traslazionale nell'ambito delle Neuroscienze: dallo stagno al bancone di laboratorio
No full textGli alti costi in termini di gestione, tempo e lavoro legati all'uso dei mammiferi nella ricerca biomedica hanno reso sempre più urgente la necessità di individuare modelli alternativi più economici e semplici ma altrettanto efficaci. Lo scopo della mia tesi è stata la caratterizzazione della chiocciola di stagno Lymnaea stagnalis come modello per le Neuroscienze Traslazionali. Gli studi bioinformatici, molecolari e comportamentali condotti hanno dimostrato la validità e la versatilità di questo modello e hanno permesso di esaminare fenomeni finora osservati solo nei mammiferi. In particolare, è emerso che:
(1) L. stagnalis consente di approfondire il dialogo tra il sistema nervoso e immunitario, inclusi gli effetti dell’infiammazione sulle funzioni cognitive. Il trattamento con uno stimolo infiammatorio (lipopolisaccaride - LPS) è stato in grado di modulare l’espressione degli enzimi della pathway delle chinurenine nel sistema nervoso centrale di L. stagnalis. Questa pathway è altamente conservata tra vertebrati e invertebrati e metabolizza il triptofano in diversi cataboliti neuroattivi, i quali possono essere sia neurotossici che neuroprotettivi. Lo stesso stimolo è stato in grado di alterare il comportamento e le performance cognitive delle chiocciole, come osservato in organismi più complessi, uomo incluso. Questi effetti possono essere eliminati trattando preventivamente gli animali con un composto antinfiammatorio come l’aspirina.
(2) L. stagnalis è in grado di formare il Garcia effect, una forma di apprendimento complesso che consiste in un’avversione condizionata a un sapore nuovo a seguito della sua associazione a uno stimolo avverso che induce un malessere viscerale, incontrato fino a 48h ore dopo. Come precedentemente dimostrato nel modello di roditore e nell’uomo, è stata sufficiente una singola presentazione dei due stimoli per generare una duratura e specifica avversione per questo sapore. L. stagnalis rappresenta quindi un modello semplificato per lo studio dei meccanismi alla base del Garcia effect negli organismi più complessi.
(3) L. stagnalis può essere utilizzata per studiare gli effetti del riscaldamento globale sulla resilienza, i comportamenti adattativi e le funzioni cognitive degli organismi. L'esposizione giornaliera a uno shock termico ha aumentato la sensibilità alle temperature delle chiocciole di laboratorio (mantenute a temperature costanti per generazioni), ma non è stato un fattore di stress per le chiocciole appena raccolte nei loro habitat naturali (dove sono state esposte a considerevoli escursioni termiche), né per la loro progenie nata e allevata in laboratorio. Questi risultati hanno suggerito un duplice ruolo della genetica e della plasticità fisiologica nella termo-tolleranza.
(4) L. stagnalis permette di studiare gli effetti di composti naturali bioattivi su apprendimento e memoria. L'esposizione acuta al flavonoide quercetina si è dimostrata in grado di migliorare la formazione della memoria a lungo termine, mentre a livello molecolare ha indotto un’up-regolazione della via serotoninergica e di CREB1 (cAMP response element-binding protein 1), i quali svolgono un ruolo chiave e altamente conservato nei processi di plasticità sinaptica.
Anche se i modelli animali non potranno mai riassumere l'intero fenotipo dei cervelli umani, i risultati presentati nella mia tesi hanno illustrato che, se spostata dallo stagno al banco di laboratorio, L. stagnalis rappresenta un modello valido per aprire nuove frontiere nelle Neuroscienze Traslazionali. L'obiettivo finale di questo progetto è quello di fornire un ulteriore strumento per promuovere lo spostamento della ricerca dal banco di laboratorio al letto dei pazienti, 'traducendo' i dati ottenuti nelle chiocciole ai mammiferi.The high costs in time and efforts associated with the use of mammals in biomedical research are creating a pressing demand for alternative models that are cheaper and simpler, but still effective. The aim of my thesis was the characterization of the pond snail Lymnaea stagnalis as a model for Translational Neuroscience. Different bioinformatics, molecular, and behavioural studies have been performed to show the validity and versatility of this model to study phenomena so far demonstrated only in mammals.
In particular, it has been shown that (1) L. stagnalis can be used to elucidate the conserved dialogue between the immune and nervous systems and to study the effects of inflammation on cognitive functions. An immune challenge (i.e., injection of lipopolysaccharide – LPS) affected the transcriptional levels of the enzymes of the kynurenine pathway in L. stagnalis’ central nervous ganglia. This conserved pathway in vertebrates and invertebrates catabolizes the aminoacid tryptophan into several neuroactive metabolites which can exert both neuroprotective and neurotoxic effects. The same immune challenge was able to alter snails’ adaptive behaviours and to obstruct their ability to form or show long-term memory (LTM), as observed for more complex organisms. These behavioural effects were prevented by exposing L. stagnalis to an anti-inflammatory compound, like aspirin, before the LPS injection, suggesting the involvement of immune-related molecules in mediating LPS-induced sequelae. The results of these studies gave important translational contributions for elucidating the effects of inflammation on the central nervous system.
(2) L. stagnalis is capable of the Garcia effect, a higher form of learning, consisting of a conditioned aversion to an appetitive food stimulus consumed hours before the exposure to an aversive, nausea-inducing stimulus. As previously demonstrated in rodents and humans, a single paired presentation of these stimuli was sufficient to create a long-lasting and taste-specific gustatory aversion. This study allowed to elucidate the causal underpinnings of the Garcia effect in higher animals.
(3) L. stagnalis can be used to predict the effects of the current global warming on animal resilience, adaptive behaviours, and cognitive functions. Daily exposure to a thermal shock increased the thermal sensitivity of laboratory-reared snails, which have been maintained under constant laboratory temperatures for generations. However, this ‘habitat-related challenge’ did not appear to be a stressor in freshly collected snails, that had experienced severe thermal fluctuations in their natural environment, nor in their progeny born and raised in lab conditions. These results allowed a better understanding of the role of genetic changes and physiological plasticity on thermotolerance.
(4) L. stagnalis is a versatile model to examine the effects of bioactive natural compounds on learning and memory. Exposure to the flavonoid quercetin upregulated the serotoninergic pathway and CREB1 (cAMP response element-binding protein 1), a key regulator of synaptic plasticity in several in vivo models, in L. stagnalis’ central ganglia. This molecular effect was accompanied by an enhancement of LTM acquisition, consolidation, recall, and reconsolidation.
Although animal models can never summarize the full phenotype of human brains, findings presented in my thesis illustrated that, when moved from pond to bench, L. stagnalis represents a valid model to open new frontiers in Translational Neuroscience. The ultimate goal of this project is to provide an additional tool to promote and sustain the rational and move research from bench to bedside, ‘translating’ data from snails to mammals, and maybe to humans
The temperature sensitivity of memory formation and persistence is altered by cold acclimation in a pond snail
No full textThere are reports on the inability of inbred, laboratory-reared Lymnaea stagnalis to perform feeding and aerial respiration in the cold. It has also been suggested that laboratory-bred snails have an inability to perform aerial respiration in winter months in the laboratory. Here, we used an inbred, laboratory-reared strain of Lymnaea (the S-strain) to demonstrate that the snails are capable of performing those behaviours in a cold (4 degrees C) environment after a 2 day acclimation period. In addition, the inbred snails were able to perform aerial respiration during winter months at room temperature (20 degrees C) in the laboratory. The persistence of long-term memory (LTM) was extended for at least 4 weeks by placing S-strain snails into a 4 degrees C environment following training. Typically, the cold block (CB) procedure (1 h at 4 degrees C) immediately after a training session blocks LTM formation in the S-strain but not in a freshly collected strain. Four weeks at 4 degrees C transformed the S-strain phenotype into one resisting the CB procedure. Thus, with a 4 week cold spell snails gain a resistance to the CB procedure, and that would explain why freshly collected snails are resistant to the procedure. However, we found that F1 progeny of a freshly collected strain reared in the laboratory were resistant to the CB procedure. This suggests that an unknown selection resulted in the Sstrain being susceptible to the CB procedure
Invertebrates as models of learning and memory: investigating neural and molecular mechanisms
No full text: In this Commentary, we shed light on the use of invertebrates as model organisms for understanding the causal and conserved mechanisms of learning and memory. We provide a condensed chronicle of the contribution offered by mollusks to the studies on how and where the nervous system encodes and stores memory and describe the rich cognitive capabilities of some insect species, including attention and concept learning. We also discuss the use of planarians for investigating the dynamics of memory during brain regeneration and highlight the role of stressful stimuli in forming memories. Furthermore, we focus on the increasing evidence that invertebrates display some forms of emotions, which provides new opportunities for unveiling the neural and molecular mechanisms underlying the complex interaction between stress, emotions and cognition. In doing so, we highlight experimental challenges and suggest future directions that we expect the field to take in the coming years, particularly regarding what we, as humans, need to know for preventing and/or delaying memory loss. This article has an associated ECR Spotlight interview with Veronica Rivi
A change in taste: the role of microRNAs in altering hedonic value
No full text: The mechanisms associated with neophobia and anhedonia remain largely unknown. Neuropsychological disorders such as depression and schizophrenia are associated with excessive fear and anhedonia, and have been linked to microRNA 137. We hypothesized that microRNAs (miRNAs) in the snail Lymnaea stagnalis are important for regulating feeding behaviour through either preventing neophobia or establishing hedonic value. To test these hypotheses, we used an injection of poly-l-lysine (PLL) to inhibit miRNA biogenesis and observed its effects on feeding behaviour. We repeated these experiments with pre-exposure to novel stimuli capable of eliciting neophobia to disentangle the processes predicted to regulate feeding behaviour. Next, we exposed snails to food stimuli of high hedonic value after PLL injection to reset their hedonic value for that food. Finally, we consolidated our results with previous research by examining the effect of PLL injection on a one-trial appetitive classical conditioning procedure (1TT) to induce long-term memory (LTM). We found that miRNAs are likely not required for preventing neophobia. Moreover, we discovered that snails experienced anhedonia in response to inhibition of miRNA biogenesis, resulting in diminished feeding behaviour for food stimuli with a previously high hedonic value. Snails showed diminished feeding behaviour for multiple food stimuli of high hedonic value post-1TT with PLL injection. This finding suggests that PLL causes anhedonia rather than an impairment of LTM formation following the 1TT procedure. This is the first evidence suggesting that inhibiting the biogenesis of miRNAs contributes to anhedonia in L. stagnalis
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Full text linkTo eat or not to eat: a Garcia effect in pond snails (Lymnaea stagnalis)
No full textTaste aversion learning is universal. In animals, a single presentation of a novel food substance followed hours later by visceral illness causes animals to avoid that taste. This is known as bait-shyness or the Garcia effect. Humans demonstrate this by avoiding a certain food following the development of nausea after ingesting that food ('Sauce Bearnaise effect'). Here, we show that the pond snail Lymnaea stagnalis is capable of the Garcia effect. A single 'pairing' of a novel taste, a carrot slurry followed hours later by a heat shock stressor (HS) is sufficient to suppress feeding response elicited by carrot for at least 24 h. Other food tastes are not suppressed. If snails had previously been exposed to carrot as their food source, the Garcia-like effect does not occur when carrot is 'paired' with the HS. The HS up-regulates two heat shock proteins (HSPs), HSP70 and HSP40. Blocking the up-regulation of the HSPs by a flavonoid, quercetin, before the heat shock, prevented the Garcia effect in the snails. Finally, we found that snails exhibit Garcia effect following a period of food deprivation but the long-term memory (LTM) phenotype can be observed only if the animals are tested in a food satiated state
Lymnaea stagnalis as model for translational neuroscience research: from pond to bench
Full text linkThe purpose of this review is to illustrate how a reductionistic, but sophisticated, approach based on the use of a simple model system such as the pond snail Lymnaea stagnalis (L. stagnalis), might be useful to address fundamental questions in learning and memory. L. stagnalis, as a model, provides an interesting platform to investigate the dialog between the synapse and the nucleus and vice versa during memory and learning. More importantly, the "molecular actors" of the memory dialogue are well-conserved both across phylogenetic groups and learning paradigms, involving single- or multi-trials, aversion or reward, operant or classical conditioning. At the same time, this model could help to study how, where and when the memory dialog is impaired in stressful conditions and during aging and neurodegeneration in humans and thus offers new insights and targets in order to develop innovative therapies and technology for the treatment of a range of neurological and neurodegenerative disorders
Long term memory of configural learning is enhanced via CREB upregulation by the flavonoid Quercetin in Lymnaea stagnalis
Full text linkA translational and multidisciplinary approach to studying the Garcia effect, a higher form of learning with deep evolutionary roots
No full text: Animals, including humans, learn and remember to avoid a novel food when its ingestion is followed, hours later, by sickness - a phenomenon initially identified during World War II as a potential means of pest control. In the 1960s, John Garcia (for whom the effect is now named) demonstrated that this form of conditioned taste aversion had broader implications, showing that it is a rapid but long-lasting taste-specific food aversion with a fundamental role in the evolution of behaviour. From the mid-1970s onward, the principles of the Garcia effect were translated to humans, showing its role in different clinical conditions (e.g. side-effects linked to chemotherapy). However, in the last two decades, the number of studies on the Garcia effect has undergone a considerable decline. Since its discovery in rodents, this form of learning was thought to be exclusive to mammals; however, we recently provided the first demonstration that a Garcia effect can be formed in an invertebrate model organism, the pond snail Lymnaea stagnalis. Thus, in this Commentary, after reviewing the experiments that led to the first characterization of the Garcia effect in rodents, we describe the recent evidence for the Garcia effect in L. stagnalis, which may pave the way for future studies in other invertebrates and mammals. This article aims to inspire future translational and ecological studies that characterize the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions
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