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(A Study from Desmedt’s team in collaboration with PV Piazza & Lundbeck Lab.)
Comment

The paper shows (in collaboration with Lundbeck Laboratory) that acute administration of brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, (0.3 mg/kg) 7 days’ post-trauma persistently prevents the expression of PTSD-like memory in mice, while promoting normal fear memory. Specifically, It specifically blocks the emotional hypermnesia of PTSD while enhancing (with superior efficacy when compared to diazepam, prazosin and escitalopram) memory for the traumatic context, which is impaired in PTSD. Moreover, this treatment also normalizes most of the alterations in the hippocampal-amygdalar network activation associated with PTSD-like memory. These preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.
Reference

Ducourneau E.G., Guette C., Perrot D., Mondesir M., Mombereau C., Arnt J. Desmedt* A. and Piazza* P.V. Brexpiprazole blocks Posttraumatic stress disorder-like memory while promoting normal fear memory. Molecular Psychiatry. 2020 Aug 19.
*co-last authorship.

doi: 10.1038/s41380-020-0852-z
First author

Eva Ducourneau
Team Marighetto/Desmedt
(“Pathophysiology of declarative memory”)

Contact
Aline Desmedt
Team Marighetto/Desmedt
(“Pathophysiology of declarative memory”)






Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons
Maria‐Carmen Medrano, Imane Hurel, Emma Mesguich, Bastien Redon, Christopher Stevens, François Georges, Miriam Melis, Giovanni Marsicano, Francis Chaouloff
Addiction Biology. 2020-10-05; :


Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)-mediated EPSCs. As did acute cocaine, amphetamine, or Δ9 -tetrahydrocannabinol (THC) pretreatments, an acute 1-h wheel-running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel-running seeking and performance, mice went through an operant protocol wherein wheel-running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel-running increased the AMPAR/NMDAR ratio to a higher extent than free wheel-running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue-reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued-running motivated task, but it increased after a cue-induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue-induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.






PhD/HDR defense
02/10/2020 14h00
Anna BEYELER Habilitation à diriger des recherches (HDR)

Habilitation à diriger des recherches (HDR)
https://u-bordeaux-fr.zoom.us/j/91070959303?pwd=TnJwYVc3TE1zT3RreHZneTNXOHorUT09
Date de la soutenance: 02/10/2020 - 14h00
Lieu: Neurocentre Magendie Digital Meeting


Hottopic
30/09/2020 10h00
Marianne AINCY from Herry's lab will give a presentation entitled 'Long-range projecting prefrontal inhibitory neurons control fear expression'

Hottopic
30/09/2020 10h30
Céline NICOLAS from Beyeler's lab will give a presentation entitled "Role of insular cortex circuits in a model of alcohol use disorder"


Luigi Bellocchio (Marsicano team) and al. in eLife

Cannabis is the most common illicit drug of abuse in the US and globally. In addition, many states in the US, as well as several countries in the world, have legalized the medical and/or recreational use of cannabis. In this rapidly expanding landscape of cannabis use, huge efforts are made to find innovative interventions reducing potential cannabis-evoked harms. Here, we investigated the possible relation between cannabinoids and autophagy, the process of programmed cell “self-digestion”, and asked whether it could be related to the control of motor coordination behavior, one of the best established neurobiological processes impacted by cannabinoids.

We showed that Δ9-tetrahydrocannabinol, the major psychoactive ingredient of cannabis, impairs autophagy and accumulates P62 protein in neurons of the striatum, a brain area that plays a key role in the control of motor coordination. Second, we demonstrate that boosting autophagy, either by pharmacological manipulation (with the FDA-approved mammalian target of rapamycin inhibitor temsirolimus) or by dietary intervention (with the natural, non-toxic disaccharide trehalose), rescues the Δ9-tetrahydrocannabinol-induced impairment of striatal autophagy and motor coordination in mice. Furthermore, we provide evidence that cannabinoid CB1 receptors located on neurons of the striatal direct (stratonigral) pathway, by coupling to mammalian target of rapamycin activation and autophagy inhibition, are indispensable for the motor dyscoordinating activity of Δ9-tetrahydrocannabinol in mice.

Last but not least, using viral mediated genetic manipulation of striatonigral neurons we confirmed that disrupting mammalian target of rapamycin pathway, as well as boosting P62 accumulation in these cells, completely prevents Δ9-tetrahydrocannabinol-induced impairment of striatal autophagy and motor dyscoordination in mice.

Taken together, these findings identify impairment of autophagy as an unprecedented mechanistic link between cannabinoids and motor dyscoordination, and suggest that activators of autophagy might be considered as promising therapeutic tools to treat certain cannabinoid-evoked behavioral alterations.

Article

Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination. Cristina Blázquez, Andrea Ruiz-Calvo, Raquel Bajo-Grañeras, Jérôme M Baufreton, Eva Resel, Marjorie Varilh, Antonio C Pagano Zottola, Yamuna Mariani, Astrid Cannich, José A Rodríguez-Navarro, Giovanni Marsicano, Ismael Galve-Roperh, Luigi Bellocchio, Manuel Guzmán ; eLife 2020;9:e56811 doi: 10.7554/eLife.56811

https://elifesciences.org/articles/56811





Andreas Frick (Neurocentre Magendie) has received a Research Award from the Simons Foundation Autism Research Initiative (SFARI).

His project:
Atypical sensory experience is a core feature of Autism Spectrum Disorder (ASD) and may be strongly determinant of other core symptoms of the disorder. Atypical sensory information processing, and associated behavioral symptoms related to the perception of touch, are very common in ASD and exert a strong negative influence on day-to-day life. Nonetheless, there is a surprising paucity of neurobiological studies addressing this aspect of ASD pathology, or specifically attempting to target this symptom for therapeutic rescue. In collaboration with Prof. S. Heinemann (Friedrich-Schiller-University Jena), they are exploring a novel therapeutic strategy for treating sensory symptoms in ASD.