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Thesis defense –Anna Petitbon

6 October 2023 / 14:00

Venue : Centre Broca

Thesis defense in french

Anna Petitbon
Team : Food Circus (NutriNeuro)
Thesis directed by : Pierre TRIFILIEFF


Implication of mesocorticolimbic dopamine transmission in behavioral flexibility: a role for dopamine and glutamate NMDA receptor heteromers


Throughout their life, nearly one in three people will be affected by a psychiatric disorder. However, conventional pharmacological treatments remain relatively ineffective, and are often accompanied by significant side effects due to their lack of selectivity. Therefore, a consensus is emerging on the need to identify mechanisms underlying symptomatic dimensions common to several psychiatric pathologies (transnosographic approach); in order to develop personalized medicine in psychiatry. In this context, executive function disorders – the cognitive processes that enable an individual to adapt to a constantly changing environment – are a common symptom of many psychiatric pathologies. Such symptoms are correlated with impaired dopaminergic transmission within the medial prefrontal cortex (mPFC) forming the mesocortical pathway, and subcortical areas such as the ventral striatum or nucleus accumbens (NAc) forming the mesolimbic pathway. However, the mechanisms by which this mesocorticolimbic dopaminergic transmission enables an individual to flexibly adapt his or her behavior remain unclear. Moreover, in both structures, the activity of dopaminoceptive neurons is strongly regulated by the convergence of glutamatergic and dopaminergic afferents. However, how neurons integrate these signals is still poorly characterized. My preclinical thesis project therefore aims at unraveling how of mesocorticolimbic dopaminergic projections modulates behavioral flexibility, and more specifically to establish the role of the physical interaction – or heteromerization – between D1 dopaminergic receptors (D1R) or D2 (D2R) and N-methyl-d-aspartate glutamatergic receptors (NMDA) within the mPFC and NAc. We show that this dopaminergic pathway is crucial for the animal’s ability to adapt to changes in the consequences of its actions. From a mechanistic point of view, we demonstrate that D1/NMDA and D2/NMDA receptor heteromers in the mPFC and NAc constitute a central mechanism for mediating the effects of dopamine on executive functions. Indeed, our results show that inhibiting mesocorticolimbic dopaminergic transmission through chemogenetic manipulation, or blocking the ability of dopaminergic and NMDA receptors to form heteromers in NAc or mPFC through the use of interfering peptides, specifically disrupts the ability of animals to update associations between lever pressing and reward, in tasks assessing behavioral flexibility. These results suggest that mesocorticolimbic dopaminergic transmission is selectively involved in updating associations between an action and its consequences, and that such effects are largely mediated by dopaminergic and NMDA receptor heteromers. Since these heteromers have distinct effects from their individual receptors, these data suggest that they could be prime targets for the development of more specific therapeutic treatments: their specific manipulation could allow avoiding the side effects associated with conventional pharmacological treatments that target the cognate receptors. Using a calcium sensor approach coupled with fiber photometry, we characterized i) the neural signature of mPFC dopaminoceptive neurons expressing D1R or D2R during Pavlovian and then operant conditioning, especially during the update of associations, and ii) the effect of heteromer blockade on these activities. We were able to demonstrate the presence of activity peaks at the time of reinforced lever pressing and of cues predicting the reward delivery, as well as a decrease in activity during reward consumption, and some of these signals are modulated by the D1/NMDA and D2/NMDA heteromers. This mechanism provides a better understanding of how behavioral adaptation processes are set in motion, and thus constitutes an innovative therapeutic target. It could lead to the development of personalized treatments targeting executive function disorders and, more specifically, alterations in behavioral flexibility.

Keywords: Behavioral flexibility – Dopamine – Glutamate – Receptor Heteromers – mPFC – NAc


Dr TRIFILIEFF Pierre, Research director, INRAE, Bordeaux Thesis Director

Dr FAURE Philippe, Research director, CNRS, Paris Reporter

Dr BURGUIERE Éric, Research fellow, CNRS, Paris Reporter

Dr PARKES Shauna, Research fellow, CNRS, Bordeaux Examinator

Dr FINO Élodie, Research fellow, CNRS, Marseille Examinator

Dr GROC Laurent, Research director, CNRS, Bordeaux Examinator

Dr VANHOUTTE Peter, Research director, CNRS, Paris Invited

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6 October 2023
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