Group leader: Sylvie Granon

Neurobiology of Decision Making

In brief

The execution of behaviors appropriate in time and space require the subject to produce successive planned actions for which he has to estimate costs and benefits. Beside the impact of motivations which guide its behavior, these actions integrate external stimuli, autobiographical parameters (through memory processes) and emotional features. In everyday life situations, making choices request to deal with concurrent motivations. Decision-making processes are efficient when the subject is able to integrate appropriately the value of reinforcements (benefits) which he anticipates.

Besides, its ability to disengage from routine behaviors (control of impulsive or compulsive behaviors) and its ability to alternate between different motivations in a balanced way are fundamental components of successful decision-making processes. Different components participate in the construction of appropriate decision-making during complex behaviors. In a context of uncertainty, decision-making processes allow flexible and adapted behaviors encompassing environmental, motivational or emotional changes. These highly adapted behaviors are impaired in all psychiatric disorders, even if they do not all depend on the same neurobiological, neurochemical or genetic systems. Indeed, the basic components of flexible behaviors may be affected independently in mental disorders, the final effect being non adapted behaviors.

In this context, the team aims at indentifying the neural bases of flexible behaviors in uncertain environments. We model these behaviors in mice. This animal model allows the control and modulation of environmental, emotional and motivational features of a situation. Furthermore, it allows fine-tune behavioral dissections as well as a molecular and genetic analysis, thanks to numerous mice model available. Our experimental results obtained in mice has shown a dissociation of the basic components of flexible behaviors, and thus allow now the study of the impact of the different modulators on such components. These dissociations suggest that an integrator, for which neural, neurochemical and genetic bases are yet to be undermined, which would contribute to temporally coordinate the basic components of flexible behaviors together. On a neurobiological point of view, it is acknowledged that the prefrontal cortex -PFC- plays a crucial role.

A large part of our work has been to set up original behavioral paradigms specific to mice in order to target these behaviors. These paradigms has allow the characterization of cognitive deficits of mutant mice deleted for the beta2-nicotinic neuronal receptor -b2KO mice.

Two paradigms have been successfully developed during the past six years

  • a social interaction task which put in competition several natural motivations: spatial novelty exploration, social contact and food motivation. This paradigm increase the frequency of decisions to be made because it increase the level of uncertainty to which the subject faces but also allow us to manipulate and modulate the value of each reinforcement.
  • an operant conditioning task which allows the measure of impulsivity in mice. This protocol , originally designed by Sandra Suarez and myself, has been developped by Pierre Serreau, during his Master degree and his PhD.
Peer reviewed publications for different topics

Decision-making and the prefrontal cortex

• Granon S. & Poucet B. (1995) “Medial prefrontal lesions in the rat and spatial navigation: Evidence for impaired planning”. Behavioral Neuroscience, 109, 474-484
• Granon, S. & Poucet, B. (2000) “Involvement of the rat prefrontal cortex in cognitive functions: a central role for the prelimbic area”. Psychobiology, 28, 229-237.
• Granon S., Passetti F., Thomas K. L., Everitt B. J. & Robbins T. W. (2000) “Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into the rat prefrontal cortex”. The Journal of Neuroscience, 20, 1208-1215
• Cazalis F., Valabrègue R., Pélégrini-Issac M., Asloun S., Robbins TW. & Granon S (2003) Individual differences in prefrontal cortical activation on the Tower of London planning task: implication for effortful processing. European Journal of Neuroscience, 17, 2219-2225.
• Granon S. & Changeux J.-P. (2011) Deciding between conflicting motivations: what mice make of their prefrontal cortex. Behav. Br. Res, 229(2):419-26
• Bourgeois JP., Meas-Yeadid V., Lesourd AM., Faure P., Pons S., Maskos U., Changeux JP., Olivo-Marin JC., Granon S. (2011) Modulation of the mouse prefrontal cortex activation by neuronal nicotinic receptors during novelty exploration but not by exploration of a familiar environment. Cerebral Cortex, 22(5):1007-15.
• Avale ME, Chabout J, Pons S, Serreau P, De Chaumont F, Olivo-Marin JC, Bourgeois JP, Maskos U, Changeux JP, Granon S. (2011) Prefrontal nicotinic receptors control novel social interaction between mice. FASEB J. 25(7):2145-55.
• Pittaras E., Cressant A., Serreau P., Bruijel J., Dellu-Hagedorn F., Callebert J., Rabat A. & Granon S. (2013) Mice gamble for food: Individual differences in risky choices and prefrontal cortex serotonin. Journal of Addiction Research & Therapy, Special Issue: Behavioral Pharmacology Vol2, S4: 011.
• Cambon K, Dos-Santos Coura R, Groc L, Carbon A, Weissmann D, Changeux J-P, Pujol J-F, Granon S (2010) Aggressive behaviour during social interaction in mice is controlled by the modulation of Tyrosine Hydroxylase expression in the prefrontal cortex. Neuroscience,171, 840-861.
• Coura R.S., Cressant A., Xia J., de Chaumont F., Olivo-Marin J.-C., Pelloux Y., Dalley J.W., Granon S. (2013) Non aggressive and adapted social cognition is controlled by the interplay between noradrenergic and nicotinic mechanisms in the prefrontal cortex. The FASEB Journal 27(11):4343-54.
• Pittaras E., Callebert J., Chennaoui M., Rabat A.*, Granon S.* (2016). Individual behavioral and neurochemical markers of unadapted decision-making processes in healthy inbred mice. Brain Structure & Function. 221(9):4615-4629. * last co-authors

Behavior

• Cressant A. & Granon S. (2003) Definition of a new maze paradigm for the study of spatial behavior in rats. Brain Research Protocols, 12, 116-124.
• de Chaumont F., Dos-Santos Coura R., Serreau P., Cressant A., Chabout J., Granon S.*, Olivo-Marin J.C.* (2012) Comprehensive repertoire and temporal evolution of mice social interactions through computerized video analysis. Nature Methods, 9(4):410-7. * last co-authors
• Chabout J., Serreau P., Ey E., Bellier L., Aubin T., Bourgeron T., & Granon S. (2012) Adult male mice emit context-specific ultrasonic vocalizations that are modulated by prior isolation or group rearing environment. PlosOne, 7(1):e29401. Epub 2012 Jan 6.
• Lefebvre E., Granon S., Chauveau F. (2019) Social context increases ultrasonic vocalizations during restraint in adult mice. Animal Cognition, in press
• Pittaras E., Rabat A., Granon S. (2020) The Mouse Gambling Task: Assessing Individual Decision-making Strategies in Mice. Bio-Protocol, in press.

Neuronal nicotinic receptors and their functions

• Granon, S., Faure, P. & Changeux, J.P. (2003) Executive and social behaviors under nicotinic receptor regulation. Proc Natl Acad Sci U S A, 100, 9596-9601.
• Maskos U., Molles B.E., Pons S., Besson M., Guiard B.P., Guilloux J.-P., Evrard A., Cazala P., Cormier A., Mameli-Engvall M., Dufour N., Cloëz-Tayarani I., Bemelmans A.-P., Mallet J., Gardier A.M., David V., Faure P., Granon S. & Changeux J.-P. (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature, 436, 103-107.
• Besson M*, Granon S*, Mameli-Engvall M, Cloëz-Tayarani I, Maubourguet N, Cormier A, Cazala P, David V, Changeux JP, Faure P. (2007) Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci U S A, 104, 8155-60. * first co-author
• Avale ME, Faure P, Pons S, Robledo P, Deltheil T, David D, Gardier A, Maldonado R, Granon S, Changeux JP, Maskos U. (2008) Interplay of beta2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion. Proc Natl Acad Sci U S A 105, 15991-15996.
• Suarez SV, Amadon A, Giacomini E, Wiklund A, Changeux J-P, Le Bihan D, Granon S (2009) Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study. Psychopharmacology, 202, 599-610.
• Dos Santos Coura R. & Granon S. (2012) Prefrontal neuromodulation by nicotinic receptors for cognitive processes. Psychopharmacology, 221(1):1-18

Animal models of brain pathologies

• Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D, Frahm J, Fischer J, Bourgeron T, Ehrenreich H, Brose N. (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci U S A, 105, 1710-5.
• Lykhmus O, Koval L, Skok M, Zouridakis M, Zisimopoulou P, Tzartos S, Tsetlin V, Granon S, Changeux JP, Komisarenko S, and Cloëz-Tayarani I. (2011) Potential Role of Nicotinic Acetylcholine Receptor-Specific Antibodies in Alzheimer Disease. I. Antibodies against Extracellular Domains of a4 and a7 Subunits Alter the Levels of Nicotinic Receptors in the Mouse Brain and Affect Memory. Journal of Alzheimer diesease. 24(4):693-704.
• van den Bos R., Davies W., Dellu-Hagedorn F., Goudrian A., Granon S., Homberg J., Rivalan M., Swendsen J., Adriani W. (2013) Cross-species approaches to pathological gambling: a review targeting sex differences, adolescence and ecological validity of research tools. Neurosci Biobehav Rev. 2013 Jul 15
• Nosjean A., Cressant A., de Chaumont F., Olivo-Marin J.-C., Chauveau F., Granon S. (2015). Acute stress at adulthood impoverishes social choices and triggers aggressiveness in preclinical models. Frontiers in Behavioral Neuroscience, 8:447.
• Ciapa B. and Granon S. (2018) Expression of cyclin-D1 in astrocytes varies during aging. Frontiers in Aging. 10, 104.
• Pittaras E.C., Callebert J., Dorey R., Chennaoui M., Granon S.*, Rabat A.* (2018) Differential effects of acute sleep debt on decision-making and associated neurochemical changes. Sleep 1;41(11). doi: 10.1093/sleep/zsy168. * last co-authors
• Nosjean A., de Chaumont F., Olivo-Marin J.C., Granon S. (2018) Double dissociation for stress-evoked brain activation in mice lacking nAChRs: modulation by novelty exploration and social interaction. Brain Structure & Function, 223(9):4259-4274. doi: 10.1007/s00429-018-1745-7
• Faure A., Nosjean A., Pittaras E., Duchêne A., Andrieux A., Charvériat M., Granon S. (2019) Dissociated features of social cognition altered in mouse schizophrenia models: focus on social dominance and acoustic communication. Neuropharmacology, 159, 107334 (https://doi.org/10.1016/j.neuropharm.2018.09.009)
• Simola N. and Granon S. (2019) Ultrasonic vocalizations as a tool in studying emotional states in rodent models of social behavior and brain disease. Neuropharmacology, 159:107420. doi: 10.1016/j.neuropharm.2018.11.008
• Martucci L.L., Amar M., Chaussenot R., Benet G., Bauer O., de Zélicourt de, Nosjean A., Launay J.M., Callebert J., Sébrié C., Galione A., Edeline J.M., de la Porte S., Fossier P., Granon S., Vaillend C. and Cancela J.M. (2019) A multi-scale analysis in CD38-/- mice unveils major prefrontal cortex dysfunctions. FASEB J. 33(5):5823-5835. doi: 10.1096/fj.201800489R
• Faure A, Zoratto F, Chirico D, Romano E, Mancinelli R, Saso L, Callebert J, Laviola G, Granon S, Adriani W. (2019) Reduced adolescent risk-assessment and lower nicotinic beta-2 expression in rats exposed to nicotine through lactation by forcedly drinking dams. Neuroscience; 413:64-76. doi: 10.1016/j.neuroscience.2019.06.014.

Patents

• Suarez S.V., Eynard B.J., Granon S. (2019) Procédé et système de test de la cognition par traitement de la réaction d’un sujet à des stimuli. IT Trust innovation, France.

Book chapters in English

1. Bourgeron, T., Jamain S. & Granon S. (2006) Animal models of autism: Focus on genetic models and behavioral test paradigms. In G.S. Fisch & J. Flint (Eds) “Transgenic and knockout models of neuropschiatric diseases” Contemporary clinic neuroscience, Humana Press Inc., pp 151-174.
2. Granon S. & Changeux J.P. (2006) Attention-deficit/hyperactivity disorder: a plausible mouse model? Acta Paediatrica, 95, 645-9.
3. Granon S & Floresco S (2009). Functional Neuroanatomy of Flexible Behaviors in Mice and Rats. In “Endophenotypes of psychiatric and neurodegenerative disorders in animal models” S. Granon (Ed), Transworld Research Network. pp. 83-103.
4. Granon S., Alexis Faure, Frederic Chauveau, Arnaud Cressant, Elodie Ey (2018). Why should my mouse call me? Acoustic communication in mouse models of social disorders: ultrasonic vocalizations as index of emotional and motivational states. In “Handbook of ultrasonic vocalizations. A window into brain mechanisms of emotion and motivation” S. M. Brudzynski (Ed) Handbook of Behavioral Neuroscience Series.

Book chapters in French

Cazalis F. & Granon S. (2017) Faire face aux nouveaux défis de l’environnement. Comment notre cerveau permet les changements de nos comportements. In “Le soucis de la nature” CNRS éditions, pp. 165-177.