Catégorie d'événements: PhD defense

PhD defense in french

Zoom link : https://us05web.zoom.us/j/88154670465?pwd=WGtGTTA5cWIwdkYxWUkvQkRaVG9YZz09

Supervisors : Bruno GUIARD / Claire RAMPON

Committee members :

• Mme Muriel KOEHL
• Mme Nathalie THIRIET
• M. Arnaud TANTI
• M. Jean-Marc DEVAUD
• Mme Claire RAMPON
• M. Bruno GUIARD

Abstract :

Major depressive disorders affect more than 300 million people worldwide. Although pharmacological compounds are available to treat depression, those marketed for this indication have some therapeutic limitations. In particular, all these compounds present a low response rate, a high relapse rate and/or a long onset of action. Indeed, most antidepressants require a long-term treatment before the first therapeutic outcomes, which is a major clinical drawback. Mechanistically, this can be explained by the fact that chronic administration of antidepressants results in brain changes requiring several weeks, or even months, to occur. In this context, it seems relevant to identify new therapies allowing a faster and long-lasting action on depressive symptoms.

To this end, there is growing interest in non-pharmacological strategies that target the causes of behavioral symptoms and thus appear to be alternatives to pharmacological treatments. Indeed, it is known that lifestyle is a triggering factor for major depression, and the protective effects of a healthy diet, rich social life, and physical exercise on mental health have been described.

This PhD work examined whether and how, these environmental elements contribute to treating depressive disorder when proposed alone or combined with a conventional antidepressant. Using a mouse model of depression, we showed that living in an enriched environment reduces the onset of action of venlafaxine. We then determined that the beneficial effect of this combination is associated with a rapid disruption of plasticity of GABAergic interneurons underpinned by the extracellular matrix surrounding these neurons and by regulatory effects on adult hippocampal neurogenesis. We observed in contrast, that the discontinuation of environmental stimuli aggravates the depressive-like phenotype of animals, whereas physical exercise in combination with an antidepressant treatment induces early, but partial, beneficial effects. Overall, our work shows a beneficial effect of non-pharmacological therapeutic strategies and identifies GABAergic parvalbumin interneurons as a relevant target to consider in order to reduce the delay of action of currently available antidepressants.

  Defense in english.

  Zoom link : https://us02web.zoom.us/j/81937076647?pwd=MEJkMzFsN1RNZDVGVDM4cmM2TGJldz09

Supervisors : Gabriela DE BRITO SANCHEZ and Martin GIURFA

Committee members : 

• • Prof. Ellouise Leadbeater (Royal Holloway, University of London) – Rapporteur
  • Prof. Frédéric Marion-Poll (Evolution Genome Comportement Ecologie, Gif-sur-Yvette) – Rapporteur
  • Dr. Axel Brockmann (National Centre for Biological Science, Tata Institute of Fundamental Research) – Rapporteur
  • Dr. Gabriela de Brito Sanchez (Centre de Recherche sur la Cognition Animale) – Co-directrice de thèse
  • Prof. Martin Giurfa (Centre de Recherche sur la Cognition Animale) – Directeur de thèse

Abstract :

Neuropeptide Y (NPY) signalling plays a crucial role for individual survival in vertebrates as it mediates both food- and stress-related behaviours. High NPY level correlates with increased hunger and leads to a larger food intake while it also reduces sensitivity to stressful stimuli. In invertebrates, two independent homologs of NPY have been identified: the neuropeptide F (NPF) and the short neuropeptide F (sNPF). In honey bees (Apis mellifera), both NPF and sNPF have been reported but only sNPF was found to have a dedicated receptor sNPFR, thus indicating that sNPF/sNPFR provides a functional signalling pathway in this insect. We thus studied the impact of sNPF on multiple behavioural components, including food-related behaviours such as ingestion of palatable and unpalatable food, appetitive and aversive responsiveness, and appetitive and aversive associative learning and memory retention.

Our results show that increasing artificially sNPF levels in honey bee foragers via topical expos ure, increases significantly their consumption of both palatable and unpalatable food. In addition, using various responsiveness tests, we showed that sNPF is a key player in the modulation of appetitive but not aversive responsiveness. Fed foragers treated with sNPF exhibited a significant increase in their responsiveness to sucrose solutions and to appetitive olfactory stimuli, matching the levels of starved bees. In agreement with this last finding, in vivo multiphoton recordings of neural activity in the antennal lobe, the primary olfactory centre of the bee brain, showed a decreased responsiveness to appetitive odours in fed bees, which was rescued by treatment with sNPF to the level exhibited by starved bees. Interestingly, the modulatory effect of sNPF was totally absent in responsiveness to aversive stimuli contrarily to what has been observed in vertebrates and flies, thus indicating that in bees, sNPF dos not increase tolerance to stressors.

Given the enhancing effect of sNPF on appetitive responsiveness, we next studied if this effect translates to different appetitive learning protocols in which bees are trained to discriminate a stimulus that is rewarded with a sucrose solution from another that is not. We studied the effect of sNPF on both appetitive visual and olfactory learning and memory retention. In the first case, free-flying bees were trained to discriminate two colors in a Y-maze following topical increase of sNPF. In the second case, harnessed bees were trained to discriminate two odorants following topical application of sNPF, using the conditioning of the proboscis extension reflex. In parallel, we studied the effect of sNPF for aversive gustatory learning in which harnessed bees learning the association of antennal taste with electric shock, following topical application of sNPF. Our results revealed a clear improvement of appetitive color learning and retention and a mitigated tendency in the same direction in the case of appetitive olfactory learning. On the contrary, no effect was observed in the case of the aversive gustatory learning and retention, consistently with the lack of effect of sNPF on aversive responsiveness.

To sum up, this work showed that sNPF affects multiple appetitive behavioural modules (ingestion, gustation, olfaction, vision, learning, memory) and central processing (antennal lobe activity) in the honey bee while being dispensable for aversive ones. It provides therefore a rich and multifaceted view of the effects of this neuropeptide on the behaviour of a social insect and opens new research perspective to study ingestion processes and appetitive behaviour in bees.

Defense in french

Zoom link coming soon

Supervisor : Bruno GUIARD

Committee members :

• Pr. Céline CRUCIANI-GUGLIELMACCI  – Reviewer – Université de Paris – CNRS UMR 8251Unité BFA – Equipe REGLYS “Régulation de la glycémie par le système nerveux central”
• Dr. Sebastian FERNANDEZ  – Reviewer – Université Côte D’Azur – Institut de Pharmacologie Moléculaire et Cellulaire – CNRS UMR7275
• Dr. Guillaume FERREIRA – Reviewer – Université de Bordeaux – Laboratoire Nutrition et de Neurobiologie intégrée
• Pr. Isabelle CASTAN-LAURELL, Examinator – Université de Toulouse III – UMR 1301 INSERM – 5070 CNRS – RESTORE/Metabolink
• Dr. Amandine GAUTIER-STEIN, Examinator – Université Lyon 1 – U1213 Nutrition
• Pr. Bruno GUIARD (**), Thesis Supervisor – Université Toulouse III – UMR5169 – Centre de Recherches sur la Cognition Animale

Abstract :

Epidemiological studies estimate a higher risk of developing major depression (MD) among diabetic patients compared to the general population. More specifically, human studies highlighted correlations between impairments of metabolic parameters and depressive symptoms. Peripheral insulin resistance could be determinant in this relationship since defect in insulin signaling positively correlates with the severity of MD. However, brain insulin resistance consequences on depressive disorders in humans and pre-clinical models are yet to be deeply investigated.  Because the brain is endowed with a high density of insulin receptor, it has been proposed that insulin could directly (or indirectly) modulates monoaminergic systems and more particularly serotonergic (5-HT) neuronal activity in the dorsal raphe nucleus (DRN). In agreement with the latter hypothesis, previous findings indicate that insulin influences the dopaminergic system and related feeding behaviors but only few studies have focused on the impact of this hormone on the 5-HT system yet indisputably involved in MD.

During this thesis, we were able to show that insulin receptor is expressed in DRN 5-HT neurons. Interestingly, although in-vitro patch-clamp experiments emphasize a direct excitatory effect of insulin on DRN 5-HT neuronal activity, in vivo electrophysiological and neurochemical data are consistent with a net inhibitory effect on this system leading to a decreased 5-HT tone in the hippocampus. These results led us to test whether insulin modulates neurobehaviors. Doing so, we demonstrated that acute intra-DRN or intra-nasal insulin injection produces anxiolytic-like effects in healthy mice. In a second part, we studied the activity of the 5-HT system and anxio-depressive-like behaviors in mouse models of type 1 or type 2 diabetes (T1D/T2D) thereby providing insight into the relationship between insulin signaling impairment and emotionality. In a context of insulinopenia (T1D) or insulin resistance (T2D), mice displayed apparent anxious behaviors accompanied by a significant reduction of 5-HT firing rate. Then, we tried to identify the implication of apelin, an adipokine known for its insulin-sensitizing properties, in T2D-induced behavioral anomalies. Our results showed that Apelin knock-out mice are more prone to develop insulin resistance in response to a diabetogenic diet but also marked behavioral disturbances reminiscent of anxiety. Interestingly, although chronic metformin treatment, an oral antidiabetic drug, did not improve peripheral metabolic parameters, it exerted anxiolytic-like effects in these mutant mice.

Thus far, this work highlights the existence of anatomic and functional interactions between insulinergic and serotonergic systems and their importance in anxiety, a psychiatric disorder often predictive of depressive episodes. Furthermore, we identified apelin as a potential actor implicated in the comorbidity between diabetes and depression anticipating putative pharmacological strategies targeting this adipokine. Indeed, this work strengthens the hypothesis in which insulin-sensitizers could alleviate anxio-depressive symptoms in patients displaying (or not) metabolic syndrome. It also paves the way for the development of potentiation strategies based on the use of insulin or antidiabetic treatments to reinforce antidepressant efficacy. However, the mechanisms underpinning such effects warrant further investigations for future studies.

Defense in english, entirely done via videoconference : https://us05web.zoom.us/j/84908965342?pwd=dUF1Mnh4ZUtWQkpLUnBsSFYybjZDZz09

Supervisor : Mathieu Lihoreau

Committee members :

• Dr. Mathieu Lihoreau, CRCA – Supervisor
• Prof. Andrew Barron, Macquarie University – Supervisor
• Prof. Ellouise Leadbeater, Royal Holloway, University of London – Reviewer
• Dr. Cedric Alaux, INRAE Avignon – Reviewer
• A/Prof. Natalie Hempel de Ibarra, University of Exeter – Examiner
• Prof. Raphael Jeanson, CRCA – Examiner

Abstract :

Effective foraging for food is such a necessity for most animals it is reasonable to expect natural selection to favour individuals that optimise their nutrient intake and minimise energy expenditure. One way to achieve these goals is through the use of specific behaviours, called “foraging strategies”. Pollinators such as bees present a very interesting case of foraging optimisation. Since the nectar offered by plants is a renewable resource bees have a strong incentive to learn and memorise the positions of the flowers they have discovered. Many studies have investigated the foraging behaviour of bees, leading to the identification of two foraging strategies: the use of stable, repeated routes between subsets of flowers (“traplines”) and the development of areas of exclusion of other bees in competitive situations (“resource partitioning”). The use of these two strategies by bees has been demonstrated multiple times in different situations, but we still know very little about how such strategies develop. These two strategies have mostly been described through cognitively complex mechanisms. However, while they have been observed and characterised in controlled environments, these strategies were seldom seen in more natural environments, suggesting our current explanations of these phenomena are incomplete. This gap in knowledge leads me to question what are the behavioural rules individual bees follow to establish these strategies? My thesis focused on attempting to gain some insight on how these foraging strategies form by complementing experiments with a modelling approach. I built an agent-based model of multiple bees foraging in a wide variety of environments. With it I tried to explain the establishment of these strategies through the use of simple positive and negative reinforcement rules as bees found flowers with or without rewards, respectively. Exploration of the model showed that both traplining and partitioning strategies could emerge in simple competitive situations with two bees foraging on 10 feeding sites. I then conducted three experiments to challenge the assumptions of the model. My results suggest that the foraging strategies of bees could emerge from simple foraging rules, but more importantly that their development in natural conditions could be mostly driven from the spatial and temporal constraints of the environment which are altering the availability in resources. Bees were able to improve their foraging efficiency in most experimental conditions, but how they did so was not limited to the establishment of traplines or resource partitioning. By explaining their formation mostly through these constraints, we are able to present these foraging strategies not as cognitively intensive processes, but rather paths of least resistance to environmental constraints.