Seminar – Julie Le Merrer

Venue: Centre Broca

Julie Le Merrer
DR CNRS
Université de Tours

Invited by Jean-Luc Morel (INCIA)

Title

Social behavior and striatum: reward matters

Abstract

Social interactions are experienced as pleasurable, which in turn fuels social motivation. Consistent with this, the so-called “social brain” widely overlaps with the brain reward circuit. Within this circuit, the nucleus accumbens (NAc) works as a hub structure and plays a unique role in reward processing and approach. Accumulating evidence suggest that the NAc is a key substrate for modulating social behavior. However, the respective contributions of the two main neuronal populations in the NAc, Striatal Projection Neurons (SPNs), bearing either D1 or D2 dopamine receptors, remains elusive. D1- and D2-SPNs play contrasted roles in modulating reward, with the former proposed to drive pro-reward/approach responses and the latter considered as inhibiting these responses. We previously evidenced that chronic facilitation of mGlu4 glutamate receptor activity, known to put a brake on D2-SPN activity, relieves social deficit in the Oprm1 null mouse model of autism. Here we tested the hypothesis that excessive D2-SPN activity may compromise social reward. We first explored the respective roles of D1- and D2-SPN of the NAc in driving social behavior by selectively ablating each of these neuronal populations using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy. We then used pharmacological tools to rescue behavior in ablated mice and transcriptome analysis to assess striatal physiology. Finally, we mimicked excessive NAc D2-SPN activation using optogenetics. This study allowed us to identify the respective roles of NAc D1- and D2-SPNs in driving social motivation, with exciting perspectives for the treatment of pathologies such as autism, schizophrenia or depression.

Key publications

1. Meng J, Xu C,Lafon P-A, Roux S, Mathieu M, Scholler P,  Blanc E, Becker JAJ, Le Merrer J, Gonzales-Maeso J, Chames P, Liu J, Pin J-P, Rondard P. Optical biosensors of native membrane protein complexes reveal a high proportion of mGlu heterodimers in the brain. Nature Chemical Biology, in press.
2. Derieux C, Léauté A, Brugoux A, Jaccaz D, Terrier C, Pin J-P, Kniazeff J, Becker JAJ*, Le Merrer J*. Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism. Neuropsychopharmacology, 47(9):1680-1692.
3. Bermudez-Martin P, Becker JAJ, Caramello N, Fernandez SP, Costa-Campos R, Canaguier J, Barbosa S, Martinez-Gili L, Myridakis A, Dumas ME, Bruneau A, Cherbuy C, Langella P, Callebert J, Launay JM, Chabry J, Barik J, Le Merrer J, Glaichenhaus N, Davidovic L (2021). The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota. Microbiome. 8;9(1):157.
4. Becker JAJ, Pellissier LP, Corde Y, Laboute T, Léauté A, Gandía J, Le Merrer J (2021). Facilitating mGlu4 activity reverses the deleterious long-term consequences of chronic morphine exposure in male mice. Neuropsychopharmacology. 46(7):1373-1385.
5. Laboute T, Gandía J, Pellissier LP, Corde Y, Rebeillard F, Gallo M, Gauthier C, Léauté A, Diaz J, Poupon A, Kieffer BL, Becker JA*, Le Merrer J* (2020). The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs. Elife, 31;9:e50519
6. Pujol CN, Pellissier LP, Clément C, Becker JAJ*, Le Merrer J* (2018). Back-translating behavioral intervention for autism spectrum disorders to mice with blunted reward restores social abilities. Translational Psychiatry, 8:197.
7. Pellissier LP, Gandia J, Laboute T, Becker JA, Le Merrer J (2017). Mu opioid receptor, social behaviour and autism spectrum disorder: reward matters. British Journal of Pharmacology, 175:2750-2769.
8. Becker JAJ, Clesse D, Spiegelhalter C, Schwab Y, Kieffer BL*, Le Merrer J* (2014). Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology, 39:2049-2060.
9. Le Merrer J, Rezaï X, Scherrer G, Becker JAJ, Kieffer BL (2013). Impaired hippocampus-dependent and facilitated striatum-dependent behaviors in mice lacking the delta opioid receptor. Neuropsychopharmacology, 38:1050-1059.
10. Le Merrer J, Becker JAJ, Befort K, Kieffer BL (2009). Reward processing by the opioid system in the brain. Physiological Reviews, 89:1379-1412.