Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core

Deroche, Lassalle & Manzoni - bioRxiv doi: https://doi.org/10.1101/613497

The nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs and feedforward inhibition that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > BLA). Feedforward inhibition of MSN firing too, was input and cell-type specific: while minimal at vHipp-D1 and vHipp-D2 inputs; it inhibited with similar efficacy BLA-D1 or BLA-D2 inputs, was minimal at PFC-D1 but maximal at PFC-D2 inputs. We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway- and cell-specific plasticity. Thus, while CB1 receptors (CB1R) uniformly depress excitatory pathways irrespective of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity

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Sex differences in the behavioral and synaptic consequences of a single in-vivo exposure to the synthetic cannabimimetic WIN55,212-2 at puberty and adulthood

A. Scheyer. The Scientist, January 1, 2019

Prenatal Exposure to Cannabis Affects the Developing Brain

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Andrew F Scheyer, Jim Wager-Miller, Anne-Laure Pelissier-Alicot, Michelle N Murphy, Ken Mackie, Olivier JJ Manzoni

New Results: Maternal cannabinoid exposure during lactation alters the developmental trajectory of prefrontal cortex GABA-currents in offspring

Cannabis is the most widely used illicit drug in the world, and its usage is increasing with its widespread legalization. Use of the drug by mothers during lactation may transfer active cannabinoids to the developing offspring, altering postnatal neurodevelopment during this critical period. During early life, GABA undergoes a functional switch from an excitatory to an inhibitory neurotransmitter due to reciprocal changes in expression of the K+/Cl- co-transporters KCC2 and NKCC1. Here, we characterize the functional GABA switch in the prefrontal cortex of both male and female rats. We show that treating rat dams with Δ-THC or a synthetic cannabinoid during early lactation (PND01-10) retards KCC2 expression and delays the GABA switch in pups of both sexes via a CB1R-dependent mechanism. Our results indicate that the developmental trajectory of GABA in PFC neurons is significantly altered by perinatal exposure to cannabinoids through lactation during the early perinatal period.

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Join the Lab

If you are interested in being considered for a postdoctoral position, send an email to olivier.manzoni@inserm.fr / pascale.chavis@inserm.fr
Required qualifications for these positions are (1) at least one first-authored paper in areas related to systems, cellular, or computational neuroscience; (2) research experience in one of these fields: electrophysiology, imaging, MATLAB (or equivalent) programming or computational statistics. Preference will be given to applicants interested in research questions related to mental health.

A postdoctoral position is available in the CannaLab/Adolescence and developmental vulnerability to neuropsychiatric diseases team at INMED, Marseille.
The CannaLab associates our laboratory and the laboratory of Pr. Ken Mackie (Gill Center For Biomolecular Medicine, Indiana University, Bloomington USA). Our common project aims at shedding new light on the structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on behavior. The project will focus on the consequences of adolescent exposure to cannabis on mesocorticolimbic networks. The project will involve a multidisciplinary approach performed in animal models combining electrophysiological recordings and calcium imaging in vivo and in vitro.
This project is funded by the NIH-RO1 “Sex-specific critical periods of the effects of mesocorticolimbic system”. Marseille is France second largest city, a 3000-year-old port in the Mediterranean. Successful candidates will have a Ph.D. in Neuroscience and strong expertise in neuronal network, electrophysiology and imaging in rodent models of neuropsychiatric diseases. Salary will follow INSERM guidelines. Applicants should send their curriculum vitae, a list of publications, and a letter describing their interests and proposed research by email to Olivier Manzoni: olivier.manzoni@inserm.fr

Anissa Bara, Antonia Manduca, Axel Bernabeu, Milene Borsoi, Michela Servado, Olivier Lassalle, Michelle N Murphy, Jim Wager-Miller, Ken Mackie, Anne-Laure Pelissier-Alicot, Viviana Trezza, Olivier J Manzoni

New Publication: Sex specific endophenotypes of in-utero cannabinoid exposure

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

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Jillian Iafrati, Arnaud Malvache, Cecilia Gonzalez Campo, M. Juliana Orejarena, Olivier Lassalle, Lamine Bouamrane & Pascale Chavis

Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex

The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders.

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Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency

Molecular Psychiatry: Reelin a new mechanism for how eating high-fat foods in excess during adolescence alters executive functions

Chances are that children who eat excessive amounts of fatty foods will not only become obese, but will develop cognitive and psychiatric problems when they are older, a study in mice suggests. This is because, according to a recent study, diets rich in fat deplete the levels of a key protein known to help synapses in the brain to work properly. In turn, this leads to a dip in several forms of cognitive functions, such as behavioral flexibility and memory.

From ScienceDaily, Read the rest here.

And get the full paper here.

Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. M A Labouesse, O Lassalle, J Richetto, J Iafrati, U Weber-Stadlbauer, T Notter, T Gschwind, L Pujadas, E Soriano, A C Reichelt, C Labouesse, W Langhans, P Chavis# & U Meyer#; shared seniority ; Molecular Psychiatry volume 22, pages 961–971 (2017)

Research Project

Our general aim is to understand how meso-corticolimbic (MCL) microcircuits are shaped throughout early life critical periods especially adolescence, to give rise to harmonious emotional behaviors and cognitive functions in adulthood. Specifically, we want to understand how environmental and genetic insults modeling neuropsychiatric diseases transform the architecture and the functionality of synaptic networks and reduce the behavioral working range.

Our previous work fueled the concept that structural and functional damages during early life periods including adolescence are causal in disease-linked behavioral deficits. Our core hypothesis is that adolescence delineates a period of maximal vulnerability and consequently is a critical determinant of how environments and genes shape neuronal network functions into adulthood (Bara et al. 2018; Labouesse et. al. 2017; Manduca et al. 2017; Bouamrane et al. 2017; Iafrati et al. 2016; Iafrati et al. 2014).
Our research project will allow disambiguating complex phenotypes into new developmental endophenotypes and the design of innovative therapeutic strategies.

Our project is organized in three objectives:
First, we systematically audit structural and functional properties to determine how development shapes MCL microcircuits.
Second, we use a strategy that we recently conceived, based on multivariate analysis of bootstrapped datasets (Iafrati et al. 2016) to consider the multidimensional nature of the data and evaluate the interrelationship between structural, functional and behavioral parameters.
Third, we use optogenetic stimulation and pharmacological modulation of specific neuronal microcircuits to recreate/compensate/reactivate adapted behavioral in diseased rodents.

Our multidisciplinary approach combines, electrophysiology, ablation by toxin receptor cell targeting of selected neuronal population, in vitro and in vivo calcium imaging, quantitative tridimensional neuroanatomy, optogenetics and the analysis of naturalistic behaviors across the emotional and cognitive domains.

CannaLab: a new International Associated Laboratory

International Associated Laboratory INSERM - Indiana University

The International Associated Laboratory INSERM-Indiana University was created by INSERM. CannaLab associates our lab and the laboratory of Pr. Ken Mackie, Director of the Gill Center For Biomolecular Medicine (Indiana University, Bloomington USA). Our project aims at shedding new light on the structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on behavior.

Key words


Synapse; synaptic plasticity, Extracellular matrix; Accumbens, Prefrontal cortex; Reelin; Endocannabinoid, mGluR, NMDAR; Pharmacotherapy; Autism, Fragile X, Nutrition, Adolescence.


- Barbara Bardoni (Autism / CNRS UMR 7275, IPMC, Nice).
- Sophie Layé (Nutrition & Integrative Neurobiology / INRA UMR 1286, Bordeaux).


- Urs Meyer (University of Zürich, Switzerland)

- Ken Mackie (Indiana University, Bloomington USA).

-Rainer Spanagel (CB1R and mGluRs in the mesolimbic pathway / Mainz University, Germany)


Current Fundings





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