New publication: Sex-dependent effects of in utero cannabinoid exposure on cortical function
Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of 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.
New Results: Sex differences in the behavioral and synaptic consequences of a single exposure to cannabinoid at puberty and adulthood
Heavy cannabis consumption among adolescents is associated with significant and lasting neurobiological, psychological and health consequences that depend on the age of first use. Chronic exposure to cannabinoid (CB) agonists during adolescence alters social behavior and prefrontal cortex (PFC) activity in adult rats. However, sex differences on social behavior as well as PFC synaptic plasticity after acute CB activation remain poorly explored. Here, we determined the consequences of a single CB activation differently affects PFC in males and females by assessing social behavior and PFC neuronal and synaptic functions in rats during pubertal or adulthood periods, 24h after a single in-vivo cannabinoid exposure (SCE). During puberty, SCE reduced play behavior in females but not males. In contrast, SCE impaired sociability in both sexes at adulthood. General exploration and memory recognition remained normal at both ages and both sexes. At the synaptic level, SCE ablated endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC of females of both ages and heightened excitability of PFC pyramidal neurons at adulthood, while males were spared. In contrast, SCE was associated to impaired long-term potentiation in adult males. Together, the data indicate behavioral and synaptic sex differences in response to a single in-vivo exposure to cannabinoid at puberty and adulthood.
Join the Lab
If you are interested in being considered for a postdoctoral position, send an email to firstname.lastname@example.org / email@example.com
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: firstname.lastname@example.org
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.
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.
Get the full preprint here
The Map and the Territory: Mapping the Territory Regulated by Serotonergic Signaling at Striatal Projection Neurons
Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice.
We investigated how metabotropic Acetylcholine receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed how M1 metabotropic Acetylcholine receptors trigger multiple and interacting forms of synaptic plasticity in the nucleus accumbens core of wild-type and fmr1y/- mice.
Preprint available for download here / Article published at ACS Chemical Neuroscience
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.
Paper submitted for publication.
Download full preprint here.
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.
Get the full paper here
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.
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)
Poor adolescent diet may influence brain and behavior in adulthood
Adolescent male mice fed a diet lacking omega-3 fatty acids show increased anxiety-like behavior and worse performance on a memory task in adulthood, according to our new research published in The Journal of Neuroscience. Our study suggests adequate nutrition in adolescence is important for the refinement of the adult brain and behavior. The structure and function of the brain continue to change throughout adolescence, at the same time that teenagers gain increasing independence and begin to make their own food choices. Since high-calorie, low-quality diets tend to be more affordable than healthy ones, teenagers may opt for foods that lack key nutrients important for brain health such as omega-3 polyunsaturated fatty acids (n-3 PUFAs), which cannot be produced by the human body and must be obtained from foods such as fish and vegetables. We fed mice a balanced diet until early adolescence, when some mice were switched to a diet lacking n-3 PUFAs. Mice fed the poor diet during adolescence had reduced levels of n-3 PUFA in the medial prefrontal cortex and the nucleus accumbens in adulthood compared to control mice. The low-quality diet impaired the brain’s ability to fine-tune connections between neurons in these regions.
Synaptic functions of endocannabinoid signaling in health and disease
Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized “on demand” following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB-mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling.
This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.
Cell Reports: Endocannabinoid plasticity is a synaptic marker of anxiety following social defeat.
Chronic social defeat stress (CSDS) is a clinically relevant model of mood disorders. The relationship between the CSDS model and a physiologically pertinent paradigm of synaptic plasticity is not known. Here, we found that cluster analysis of the emotional behavior states of mice exposed to CSDS allowed their segregation into anxious and non-anxious groups. Endocannabinoid-mediated spike-timing dependent plasticity (STDP) in the nucleus accumbens was attenuated in non-anxious mice and abolished in anxious mice. Anxiety-like behavior in stressed animals was specifically correlated with their ability to produce STDP. Pharmacological enhancement of 2-arachidonoyl glycerol (2-AG) signaling in the nucleus accumbens normalized the anxious phenotype and STDP in anxious mice. These data reveal that endocannabinoid modulation of synaptic efficacy in response to a naturalistic activity pattern is both a molecular correlate of behavioral adaptability and a crucial factor in the adaptive response to chronic stress.
Clementine Bosch-Bouju#, Thomas Larrieu#, Louisa Linders, Olivier J. Manzoni* and Sophie Laye*
Team FRM 2015-2018
Multi scale study of in utero cannabis exposure
Human studies converge to indicate psychiatric, cognitive, and behavioral effects of cannabis use/abuse in both adults and children and the progeny of women users as well as in animal models. Although cannabis (hashish, marijuana) is the most commonly consumed/abused illegal drug by pregnant women very little is known on the consequences of cannabinoid exposure during fetal neurodevelopment and its long term repercussions on neuronal processes. This project aims at understanding the cellular underpinnings of the pathological consequences of in utero cannabis exposure. We will decipher how exposure to cannabis during fetal life causes protracted changes in synaptic functions, brain circuits, in vivo neuronal ensembles activity and associated behaviors. We propose a multiple scale approach that combines well established methods of electrophysiology and imaging and cutting edge techniques (photometry of genetically encoded calcium indicators) in freely behaving rodents.
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)
- NIH (co-P.I. O. MANZONI & K. MACKIE)
- FRC (De CHEVIGNY, P. CHAVIS)
- FRM (P.I. O. MANZONI)
- Cannado / ANR Samenta (P.I. A.L. PELISSIER) -
- CYFIP-Aut / ANR Blanc (P.I. B. BARDONI)
Google Scholar P. Chavis