Lymnaea stagnalis as model of neuropsychiatric disorders

This paper describes the advantages of adopting a molluscan model for studying the biological basis of some central nervous system pathologies affecting humans. In particular, I will focus on the freshwater snail Lymnaea stagnalis, which is already the subject of electrophysiological studies related to learning and memory, as well as ecotoxicological studie

The many faces of mitochondrial dysfunction in depression: From pathology to treatment

Introduction The last years of neurobiological research have transformed the way we consider mental illnesses. We have gone from a deterministic genetic view to a broader vision that includes the involvement of non-cerebral systems. This is especially true for major depression (MD). Historically, MD has been perceived as a multifactorial disorder correlated to various neurobiological changes like neurotransmitter deficits, endocrine disturbances, impaired plasticity, and neural adaptation (Benatti et al., 2016). Indeed, the development and progression of depressive disorders has been conceived as the disruption of body allostasis, defined as the process of achieving stability of physiological and mental processes through dynamic change (Wang et al., 2019). The main player in the “allostatic game” is the brain, an organ designed to integrate signals from the periphery that anticipate fluctuations, changes, and needs and coordinates allostatic mediators in order to develop successful coping mechanisms that ultimately lead to an adaptative strategy and resilience (de Kloet et al., 2005). The establishment and maintenance of these mechanisms requires large amounts of energy from the organism. Without energy, or in a partial lack of energy, the biological mechanisms necessary to respond appropriately to stimuli may not occur or be established incorrectly or abnormally. Human and animal studies suggest an intriguing link between our body’s ability to produce energy and the brain’s ability to correctly perform the complex cellular and molecular processes involved in allostatic processes. In eukaryotic cells, mitochondria are the powerhouse that produces and distributes energy to all other components. Functional or quantitative alterations of the ability of mitochondria to adequately supply energy can have important repercussions primarily on cellular processes and cascades of serial events (Herst et al., 2017) as well as on the correct functioning of the organism including mechanisms of brain plasticity, mood, and behavior in general (Allen et al., 2018). In this framework, it is particularly intriguing to think of the mitochondria as an active regulator of many of the biological phenomena involved in depression and in the efficacy of or resistance to the most widely used pharmacological treatments. Once the energetic equilibrium is compromised, the body becomes more “vulnerable.” This is especially true for stress-related disorders, such as depression. In fact, depression is often associated with energetic imbalance leading to profound effects on the disease (Zuccoli et al., 2017). The driving questions then are as follows: What happens to the brain in the presence of an energetic imbalance? Does depression or depression-related symptoms impact mitochondrial energetic efficiency? Is antidepressant efficacy mediated by mitochondrial functionality

Lymnaea stagnalis as model for translational neuroscience research: from pond to bench

The 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

LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence

Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion—known as the Garcia effect—can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails’ central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect

The proinflammatory cytokine interleukin 18 regulates feeding by acting on the bed nucleus of the stria terminalis

The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra-/-), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons

Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats