Catégorie d'événements: PhD defense

PhD defense in french

Zoom link : https://univ-tlse3-fr.zoom.us/j/99150206269

Team : REMEMBER

Supervisor : Lionel MOULEDOUS (CRCA-CBI)

Committee members :

• Dr. Lionel Moulédous – CRCA
• Pr. Bruno Guiard – CRCA
• Dr. Catherine Mollereau-Manaute – CRCA
• Dr. Domonique Massotte – Institut des neurosciences cellulaires et intégratives INCI – Université de Strasbourg
• Dr. Sophie Tronel – Bordeaux Neurocampus
• Dr. Jean-Phillipe Guilloux – Université Paris-Sud, Université Paris Saclay

Abstract :

The physiological response to stress allows organisms to adapt. Nevertheless, when stress is sustained in time, the response becomes maladaptive and causes memory deficits and structural impairments in the hippocampus, a key region for memory. However, the mechanisms underlying these deleterious effects are not fully understood. Stress induces the release of a neuropeptide named Nociceptin/OrphaninFQ which acts on its receptors called NOP and possesses amnesic properties. We thus hypothesized that it could be a mediator of these negative effects of chronic stress.

We demonstrated that NOP receptor blockade restores long-term memory performance in mice models of chronic stress. Furthermore, we revealed a protective effect of NOP blockade on the alterations of hippocampus structure due to chronic stress.

This work paves the way for the development of new strategies using the NOP receptor as a pharmacological target for the treatment of memory deficits in stress-related disorders.

PhD defense in english

Zoom link : https://univ-tlse3-fr.zoom.us/j/92029196377?pwd=aGY4aTRDV2lSYUw3MFp6cmM4amZWZz09

Team : REMEMBER

Supervisors : Lionel DAHAN (CRCA-CBI) / Luc VALTON (CerCo)

Committee members :

• Pr. Marc Dhenain, Rapporteur, Université Paris-Saclay, Fontenay-aux-Roses
• Dr. Pierre-Pascal Lenck-Santini, Rapporteur, Aix-Marseille Université, Marseille
• Dr. Laure Peter-Derex, Rapporteure, Université Claude Bernard Lyon 1, Lyon
• Pr. Marie Sarazin, Examinatrice, Sorbonne Université, Paris
• Pr. Maria-Eugénia Soto-Martin, Examinatrice, Université Paul Sabatier, Toulouse
• Pr. Agnès Trebuchon-Da Fonseca, Examinatrice, Aix-Marseille Université, Marseille
• Dr. Lionel Dahan, Supervisor, Université Paul Sabatier, CRCA-CBI, Team REMEMBER, Toulouse
• Dr. Luc Valton, Supervisor, CHU de Toulouse, Université Paul Sabatier, CerCo, Team DYNAMO, Toulouse

Abstract :

Previous research on murine models of Alzheimer’s disease (AD) highlighted the potential role of cerebral excitatory-inhibitory imbalance in the pathophysiology of AD. Clinical research has since reported that this imbalance may give rise to epileptic activities in as much as 50% of AD patients as well. However, these epileptic events may remain undetected due to their silent, mostly sleep-occurring nature. Using a translational approach, the aim of this thesis was to better understand the link between AD, epilepsy, sleep and memory.

First, in the framework of a preclinical study, I aimed at (I) characterizing epileptic activities over the sleep-wake cycle in the Tg2576 mouse model and (II) gaining better insight into the mechanistic underpinnings of these peculiar epileptic events. Epileptic activities were frequent, showed a predominance during REM sleep, and were locked to the phase of the theta cycle corresponding to the maximal firing probability of pyramidal cells. Furthermore, these events seemed to be counterbalanced by noradrenergic signalling via α1 adrenoreceptors during wakefulness and partially during SWS, but this effect would be lost during REM sleep when noradrenergic cells cease firing. Given the early degeneration of the locus coeruleus – the primary source of noradrenaline in the brain – in AD patients, this could have important clinical implications in the future.

In the second part of this thesis, the objective was to explore the prevalence and the distribution of epileptic activities during sleep in a cohort of 30 AD patients (selected as early AD, & without epilepsy) compared to a group of age-matched, healthy controls, and to understand the impact of these activities on cognitive decline and sleep-related memory consolidation. To this end, a full-night video-EEG combined with polysomnography was undertaken, together with a two-part neuropsychological test battery with pre-and post-sleep memory tests. These measures were combined with brain imaging (MRI), genetic analyses and the evaluation of lifestyle-related risk factors. The preliminary results with 25 participants per group that are presented hint at a risk ratio for EA occurrence five times higher in patients than controls. In contrast to the preclinical results, epileptic events are predominant during non-REM sleep. Importantly, other sleep-related deficits were also observed, including an increased percentages of superficial sleep in patients at the detriment of deeper ones and unexpectedly high prevalence of newly diagnosed Sleep Apnea Syndrome: 63% in AD patients and 50% in controls. While our sample size is currently insufficient to draw steady conclusions from our results, our preliminary models suggest a combined impact of sleep quantity, sleep apnoea, epileptic events and AD itself on memory consolidation, especially on episodic memory. We suggest that treating EAs, sleep apnoea and improving sleep quality could potentially slow down or lessen memory complaints in AD patients.

PhD defense in english

Zoom parameters :

• https://univ-tlse3-fr.zoom.us/j/94449432049?pwd=M28rNGMvRnRKR2k5dEk5ZkRLeWMzdz09
• Meeting ID: 944 4943 2049
• Passcode: 623964

Supervisor : Lionel DAHAN, REMEMBeR team

Comitee members :

• M. Lionel DAHAN, Directeur de thèse, Université Toulouse III – Paul Sabatier
• M. Antoine ADAMANTIDIS, Rapporteur, University of Bern
  
• Mme Stéphanie DAUMAS, Rapporteure, Sorbonne Université
• M. Vivien  CHEVALEYRE, Rapporteur, Institute Psychiatry And Neuroscience De Paris
  
• Mme Stéphanie TROUCHE, Examinatrice, University of Montpellier
• Mme Elisa BOUTET-ROBINET, Examinatrice, Université Toulouse III – Paul Sabatier

Abstract :

The hippocampus is the main brain structure involved in episodic memory formation. The role of the hippocampus in learning, memory and their underlying mechanisms has been studied extensively in rodents, in particular by using contextual learning.

Long-Term Potentiation (LTP) is an increase in synaptic transmission of glutamatergic afferents that lasts for hours, days or months and is thought to underlie hippocampal memory formation. It can be triggered in the hippocampus by an artificial High frequency Stimulation (HFS). This mechanism helped in deciphering memory mechanisms, showing that both memory and LTP rely firstly on phosphorylation and later on de novo protein synthesis. The link between memory and LTP was confirmed by showing that blocking LTP mechanisms hinders memory formation, and that contextual learning induces LTP in the CA1 of the hippocampus. Since LTP, just like memory, can be saturated, the nervous system cannot store every sensory input that the animal encounters. Moreover, HFS is not compatible with neuronal activity. Hence, there must be a teaching signal that would be the natural molecular trigger of LTP during learning, acting as a filter choosing the pertinent inputs to store. Dopamine is a neuromodulator that has historically been thought of as a value signal, for dopamine gets released during rewarding events. However, dopamine has later been shown to be released whenever a salient unrewarding, or even punishing, event occurs. Dopamine receptors can trigger both phosphorylation and de novo protein formation in most brain structures showing plasticity, and D1/5 Dopaminergic receptors are necessary for LTP maintenance and long-term memory. Moreover, dopaminergic stimulation in vitro can modulate synaptic transmission in CA1. Thus, we hypothesized that dopamine could act as a teaching signal.

In this work, we use behavior and electrophysiology coupled with optogenetic manipulations of midbrain dopamine afferents and pharmacology inhibition of D1/5 dopaminergic receptors in order to study the role of dopamine as a teaching signal triggering LTP so that pertinent sensory inputs get stored. Using electrophysiology, we show that coupling optogenetic stimulations of midbrain dopamine with glutamatergic inputs in CA1 induces a progressive LTP that reaches its plateau 90 minutes after the pairing. This LTP endures at least 5 hours, is dependent on D1/5 receptors and partially occludes HFS-triggered LTP. Then, using contextual fear conditioning coupled with auditory cue conditioning we show that intraperitoneal injection of D1/5 receptor inhibitor, SHC23390, hinders both contextual and cue fear memories. Alternatively, intra-hippocampal infusion of SCH23390 blocks contextual memory but preserves cue fear memory intact. These results allowed us to conclude that hippocampal D1/5 receptors are necessary for contextual fear memories and in another brain structure for associative fear memories. Finally, we use a variation of contextual fear conditioning called contextual pre-exposure facilitation effect, which separates contextual learning from fear conditioning since the animal in this task learns each of them on two consecutive days. This allows studying dopamine as a teaching signal without the interference of any value inputs. We show that mice require between 2-8 minutes to encode contextual information. Furthermore, we show that D1/5 receptors are necessary for contextual and fear learning. Finally, we show that optogenetic stimulation of dopaminergic axons in the hippocampus promotes contextual learning and, conversely, their inhibition hinders contextual learning.

This work allows us to conclude that the dopaminergic pathway from the midbrain to the hippocampus has all the characteristics of a teaching signal, namely, triggering LTP on co-activated sensory inputs promoting the storage of contextual information in the hippocampus without the need for any value information.

Defense in english

Zoom Link: https://univ-tlse3-fr.zoom.us/j/93805472327?pwd=ZXFwaFVISENObXRlV0JXMFlReXM3UT09

• ID : 938 0547 2327
• Code secret : 073857

Supervisors : Martin Giurfa and Aurore Avarguès-Weber

Committee members :

• Ludovic Dickel
• Elisa Frasnelli
• Stéphane Viollet
• Aurore Avarguès-Weber
• Martin Giurfa

Abstract :

Equipped with a brain smaller than one cubic millimeter and containing ~950,000 neurons, honeybees display a rich behavioral repertoire, among which appetitive learning and memory play a fundamental role in the context of foraging activities. Besides elemental forms of learning, where bees learn specific association between environmental features, bees also master different forms of non-elemental learning, both in the visual and in the olfactory domain, including categorization, contextual learning and rule abstraction. These characteristics make them an ideal model for the study of visual learning and to explore the neural mechanisms underlying their learning abilities. In order to access the working brain of a bee during a visual learning tasks the insect needs to be immobilized. Hence, virtual reality (VR) setups have been developed to allow bees to behave within a virtual world, while remaining stationary within the real world. During my phd, I developed a flexible and open source 3D VR software to study visual learning, and used it to improve existing conditioning protocols in a virtual environment and to investigate the neural mechanism of visual learning.

Investigating the influence of optic flow on associative color learning I found that increased motion cues from the background impaired the bees’ performance. Which lead me to identify issues that may affect decision-making in VR landscapes, which require specific control by experimenters.

By means of the VR setup, I induced visual learning in tethered bees and quantified immediate early gene (IEG) expression in specific areas of their brain to detect regions involved in visual learning. In particular, I focused on kakusei, Hr38 and Egr1, three IEGs that have been related to bee foraging and orientation and thus may also be relevant when making appetitive visual association. This analysis suggests that the mushroom bodies are involved in associative color learning.

Finally, I explored the possibility of using the VR on other insect models and performed differential conditioning on bumblebees. Interestingly, not only bumblebees are able to solve this cognitive task as well as the honeybees, but they also engage more with the virtual environment, leading to a lower ratio of discarded individuals. These results indicate that the VR protocols I have established through the course of this PhD may be applied to other insects, and that the bumblebee is a good candidate for the study of visual learning under VR conditions.

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.