ED Sciences de la Vie et de la Santé
Study of morpho-functional plasticity of RLN3/RFXP3 peptidergic system, in chronic pain condition
by Thibault DHELLEMMES (Institut des Maladies Neurodégénératives)
The defense will take place at 14h00 - Amphi Centre Broca 146 Rue Léo Saignat, Centre Broca Nouvelle-Aquitaine, 33000 Bordeaux
in front of the jury composed of
- Marc LANDRY - Professeur - Université de Bordeaux - Directeur de these
- Myriam ANTRI - Maîtresse de conférences - Université Clermont Auvergne, Laboratoire Neuro-Dol, INSERM (U1107) - Rapporteur
- Pierre VEINANTE - Professeur - Université de Strasbourg, INCI CNRS (UPR3212) - Rapporteur
- Cyril RIVAT - Maître de conférences - Université de Montpellier, INM INSERM (U1298) - Examinateur
- Matilde CORDERO-ERAUSQUIN - Directrice de recherche - INCI CNRS (UPR3212) - Examinateur
- Aude PANATIER - Directrice de recherche - Université de Bordeaux, Neurocentre Magendie (U1215) - Examinateur
At least 25% of the global population is currently affected by chronic pain, with 85% of these individuals presenting with psychiatric comorbidities. Despite this high prevalence, available treatments remain poorly adapted. Pain is a multidimensional process integrated across various regions of the pain matrix (somatosensory cortex, anterior cingulate cortex [ACC], amygdala). Under pathological pain conditions, these neural circuits undergo anatomical and functional rearrangements that are largely controlled by neuropeptides. Our hypothesis is that the relaxin-3 (RLN3)/RXFP3 peptidergic system plays a key role in pain neural networks and could represent an innovative target for the treatment of pathological pain. To test this hypothesis, we used models of persistent inflammatory pain (CFA model) and chronic neuropathic pain (Cuff model), induced in transgenic mice (RLN3-Cre, RLN3-Cre::SOM-Flp) as well as in wild-type mice. From an anatomical perspective, a tissue-clearing approach enabled visualization of all RLN3 projections originating from the nucleus incertus (NI). We developed an automated method for quantitative 3D analysis of fluorescence signals, which revealed, under CFA conditions, an increase in RXFP3 mRNA expression in somatostatin (SOM)-positive interneurons, and a decrease in interactions between RLN3 fibers in the ACC and SOM interneurons. This RLN3–SOM interaction, in proximity to PV (parvalbumin) neurons, was further confirmed using a correlative microscopy approach (CLEM). Functionally, we demonstrated an antinociceptive effect resulting from both acute and chronic activation of the RXFP3 receptor in the ACC and the amygdala, along with its impact on associated psychiatric comorbidities. We also confirmed this antinociceptive effect following optogenetic activation of the relaxin-3 system at the level of the NI or its projections in the ACC. The specificity of this effect was further confirmed by using a selective RXFP3 antagonist in the ACC. Patch-clamp experiments also showed a decrease in the activity of RLN3 neurons in the NI under CFA and Cuff conditions. These findings highlight RLN3 as a promising target for the development of effective therapeutic solutions addressing both the affective and sensory components of pain.
ED Sociétés, Politique, Santé Publique
Cognitive Remediation in Oncology: Application in Breast Cancer Survivors
by Pedro RODRIGUEZ (Laboratoire de Psychologie)
The defense will take place at 14h30 - Amphithéâtre E Université de Bordeaux, 3ter Pl. de la Victoire, 33000 Bordeaux
in front of the jury composed of
- Virginie POSTAL LE DORSE - Professeure - Université de Bordeaux - Directeur de these
- Florence COUSON-GELIE - Professeure - Université Montpellier 3 - Rapporteur
- David CLARYS - Professeur - Université de Poitiers - Rapporteur
- Élaine DE GUISE - Professeure - Université de Montréal - Examinateur
- Bruno QUINTARD - Professeur - Université de Bordeaux - Examinateur
Advances in cancer treatment have significantly increased patient survival (Torre et al., 2015), prompting growing interest in the long-term side effects of such treatments on quality of life (Rodríguez Martín et al., 2020). Among these effects, cognitive complaints reported by patients following chemotherapy have received increasing attention (Berglund et al., 1994). Neuropsychological assessments have confirmed these complaints, revealing impairments in executive functions, memory, and processing speed (Wefel et al., 2004; Fan et al., 2005). The term chemobrain has gradually been replaced by the more precise expression cancer treatment-related cognitive impairment (Hurria, Somlo, & Ahles, 2007). To address these difficulties, both pharmacological (Karschnia et al., 2019) and non-pharmacological interventions—such as meditation, physical activity, and cognitive training—have been proposed (Zeng et al., 2020). Cognitive remediation is a structured, non-pharmacological approach designed to improve cognitive functions (e.g., attention, memory, executive functions) and promote functional adaptation in daily life (Passerieux & Bazin, 2010; Wykes & Spaulding, 2011). This doctoral work examined the efficacy of cognitive remediation in women treated for breast cancer. A literature review was first conducted to characterize cognitive difficulties and remediation programs in this context. A meta-analysis then synthesized data from randomized trials and confirmed the efficacy of cognitive remediation, particularly for working memory, episodic memory, and perceived cognitive functioning. Finally, a randomized controlled trial involving 164 breast cancer survivors evaluated the Oncogite program, delivered over four months by neuropsychologists in post-treatment care. Standardized questionnaires and neuropsychological tasks were administered at baseline, post-intervention, and four months later to assess cognitive outcomes, psychological symptoms, and quality of life. A novel episodic memory task was also implemented to explore the contribution of updating processes to memory change. Results showed significant improvements in working memory, perceived cognitive functioning, anxiety, depression, physical well-being, and breast cancer-related concerns. No significant effects were observed for cognitive flexibility, inhibition, episodic memory, or emotional, functional, and social well-being. These findings support the relevance of cognitive remediation as an effective intervention for addressing cancer treatment-related cognitive impairments and enhancing the quality of life of breast cancer survivors.