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SUMMARY:Thesis defense - Jasmine Butler
DESCRIPTION:Batiment BBS \nSoutenance en anglais \n\nThesis supervisor : Philippe De Deurwaerdère \nTitle\nAction of 5-HT2A receptors on neurotransmitter systems in the mouse brain: application to Psychedelics \n  \nAbstract\nThe serotonin 2A receptor subtype (5-HT2AR) has gained interest following a resurgence of clinical and pre-clinical research on serotonergic psychedelics\, compounds with converging agonist action on the 5-HT2AR. Psychedelics have antidepressant and anxiolytic properties\, particularly when paired with therapy. Antagonism at the 5-HT2AR\, as part of the pharmacological profile of atypical antipsychotics\, may have benefits for schizophrenia and bipolar disorder. Despite their clinical relevance\, the known impact of 5-HT2ARs on brain function\, particularly neurotransmission\, is limited. Functional brain networks have been conceptualised by correlating electrical or metabolic neuroimaging signals between brain regions using functional magnetic resonance imaging or encephalography. These studies have shown that psychedelic 5-HT2AR agonists alter the connectivity of these brain-wide networks. However\, neuroimaging is currently unable to assess the neurochemistry of neurotransmitter systems and their interplay. This thesis addresses the hypothesis that psychedelic 5-HT2AR agonists disrupt the functional organization of brain-wide neurotransmitter systems. Tissue content of both classical (glutamate and GABA) and monoaminergic (serotonin\, dopamine and noradrenaline) neurotransmitters and their metabolites were measured in 28 regions of the mouse brain following high-affinity 5-HT2AR agonist and antagonist\, TCB-2 and MDL100\,907 respectively. To promote a coherent organisation of neurotransmitter systems mice were placed in a forced exploration paradigm and their behaviour was filmed before post-mortem neurochemical quantification. A significant challenge of this thesis lies in manipulating such a large neurochemical dataset that\, beyond quantitative modulation\, allows for a correlative approach incorporating graph theory to build networks of neurochemical connectivity. This novel analysis prompted the development of code to accompany the launch of a neurochemical database\, including this dataset\, making analysis using this new approach accessible. \nThe obtained results demonstrate that a variety of compounds across the 28 brain regions form distinct neurobiological networks that can be monitored with high-pressure liquid chromatography coupled to electrochemical detection. A striking density of neurochemical correlations between brain regions in vehicle-treated animals was observed\, with a distinct regional organisation for dopamine and noradrenaline. The 5-HT2AR agonist TCB-2 (0.3\, 3\, and 10 mg/kg) as well as the 5-HT2AR antagonist MDL-100\,907 (0.2 mg/kg) reduced the number of correlations and disrupted the organisation of correlations for all neurotransmitters across the brain. Some effects of TCB-2\, notably on serotonergic parameters were independent of 5-HT2ARs in several brain regions. Other effects including behavioural parameters such as head twitches or components of the exploratory behaviour\, as well as the levels of serotonin\, dopamine\, and noradrenaline in the anterior cingulate cortex were reduced by MDL-100\,907 pretreatment. MDL-100\,907 alone had very few effects on the quantity of neurochemicals across brain regions. Overall\, this thesis highlights that 5-HT2ARs likely play an important role in organising the coherence of neurotransmitter systems in response to a forced exploratory behaviour whether or not it is associated with quantitative changes. The thesis offers a new paradigm to address the function of neurotransmitter systems. It enlarges the understanding of the mechanism of psychedelic action in the brain including vast brain territories (sensory\, motor\, cognitive) with some lateralized effects\, and altered connectivity of neurotransmission systems. \nKeywords: Neurochemistry\, neurotransmitters\, neurochemical networks\, behaviour\, pharmacology\, serotonin 2A receptor \n  \nPublications\nButler\, J. J. *\, Parrot\, S. *\, Aman\, C.\, & De Deurwaerdère\, P. (2024). Neurochemical Databases: Purpose and Expectations. ACS Chemical Neuroscience\, acschemneuro.4c00812. https://doi.org/10.1021/acschemneuro.4c00812 \nButler\, J. J.\, Ricci\, D.\, Aman\, C.\, Beyeler\, A.\, & De Deurwaerdère\, P. (2024). Classical psychedelics’ action on brain monoaminergic systems. The International Journal of Biochemistry & Cell Biology\, 176\, 106669. https://doi.org/10.1016/j.biocel.2024.106669 \nMarty\, V.*\, Butler\, J. J.*\, Coutens\, B.\, Chargui\, O.\, Chagraoui\, A.\, Guiard\, B. P.\, De Deurwaerdère\, P.\, & Cavaillé\, J. (2023). Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances. Human Molecular Genetics\, 32(2)\, 244–261. https://doi.org/10.1093/hmg/ddac139 \nMartin\, H.\, Bullich\, S.\, Martinat\, M.\, Chataigner\, M.\, Di Miceli\, M.\, Simon\, V.\, Clark\, S.\, Butler\, J.\, Schell\, M.\, Chopra\, S.\, Chaouloff\, F.\, Kleinridders\, A.\, Cota\, D.\, De Deurwaerdere\, P.\, Pénicaud\, L.\, Layé\, S.\, Guiard\, B. P.\, & Fioramonti\, X. (2022). Insulin modulates emotional behavior through a serotonin-dependent mechanism. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01812-3 \nMartin\, H.\, Coursan\, A.\, Lallement\, J.\, Di Miceli\, M.\, Kandiah\, J.\, Raho\, I.\, Buttler\, J.\, Guilloux\, J.\, De Deurwaerdere\, P.\, Layé\, S.\, Routh\, V. H.\, Guiard\, B. P.\, Magnan\, C.\, Cruciani‐Guglielmacci\, C.\, & Fioramonti\, X. (2023). Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia. Journal of Neuroendocrinology\, 35(12)\, e13344. https://doi.org/10.1111/jne.13344 \nSubmitted\nButler JJ\, Virgili M\, Di Giovanni G\, Chagraoui A\, Beyeler A\, De Deurwaerdère P. 5-HT2A Receptors Structure Monoaminergic Connectivity in the male Mouse Brain. Submitted December 7th to Progress in Neuropsychopharmacology and Biological Psychiatry. \nButler JJ*\,  Aman C*\, Rivalan M\, Parrot S\, Dellu-Hagedorn F\, De Deurwaerdère P. Neurochemical assessment of tissue levels of neurotransmitters: from quantification to correlative networks. Submitted January 24th to ACS Chemical Neuroscience. \nIn preparation\nButler JJ\, Virgili M\, Di Giovanni G\, Chagraoui A\, Beyeler A\, De Deurwaerdère P. 5-HT2A Receptor Activation and Blockade Disrupt Amino Acid Connectivity in the Male Mouse Brain: Possible Role of Monoaminergic Neurotransmitters. To be submitted Included in the thesis. \nButler JJ\, Aman C\, Bharatiya R\, Chagraoui A\, Cathala A\, De Deurwaerdère P. Neurochemistry and post-mortem neurotransmitters: toward the study of neurochemical connectivity. To be submitted Included in the thesis. \nJury\n\nMme DARNAUDERY Muriel Université de Bordeaux\, Pr Président du jury\nNAASSILA Mickael Université Jules Vernes\, Amiens\, Pr Rapporteur\nMme BECAMEL Carine Université de Montpellier\, MCU Rapporteur\n\n  \n
URL:https://www.bordeaux-neurocampus.fr/en/event/thesis-defense-jasmine-butler/
CATEGORIES:Thesis
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