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Adolescence and developmental vulnerability to neuropsychiatric diseases

Our general aim is to understand how meso-corticolimbic 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). This research project will allow disambiguating complex phenotypes into new developmental endophenotypes and the design of innovative therapeutic strategies.

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Cannabis and the Developping Brain 1st Edition

Elsevier ISBN: 9780128234907

New book, now available

Book

Cannabis and the Developing Brain provides comprehensive research on the effects of cannabis during neurodevelopment stages (i.e., perinatal and adolescent ages). The book introduces readers to vivo neural circuits and molecular and cellular mechanisms affected by cannabis exposure during three different temporal windows of brain vulnerability. In addition, it offers unique insights on shared neurobiological features of cannabinoid exposure during different developmental periods. Lastly, the book determines the adverse impact of developmental cannabinoid exposure on specific cognition, emotion and behaviors. Marijuana is the most commonly used psychotropic drug in the United States after alcohol. According to a 2018 NIH report, more than 11.8 million young adults reported marijuana use. With the legalization and decriminalization of cannabis, momentum continues to build and be propelled by the reduction of stigma associated to its consumption, hence there is growing concern regarding long-term impacts on brain function and behavior.

Characterization of Nasco grape pomace-loaded nutriosomes and their neuroprotective effects in the MPTP mouse model of Parkinson’s disease

Frontiers in Pharmacology

Parekh, Serra, Allaw, Perra, Marongiu, Tolle, Pinna, Casu, Manconi, Caboni, Manzoni & Morelli

Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT- positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration

Cannabidiol and substance use disorder: Dream or reality

Neuropharmacology

Karimi-Haghighiab, Razavi, Iezzi, Scheyer, Manzoni, Haghparast

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Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD’s safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer’s disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed.

Sex-specific divergent maturational trajectories in the postnatal rat basolateral amygdala

iScience

Guily, Lassalle & Manzoni

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The basolateral amygdala (BLA), the part of the amygdala complex involved in the transduction of perceptual stimuli into emotion, undergoes profound reorganization at adolescence in rodents and humans. How cellular and synaptic plasticity evolve throughout postnatal development in both sexes is only partially understood. We used a cross-sectional approach to compare the morphology, neuronal, and synaptic properties of BLA neurons in rats of both sexes at adolescence and adulthood. While BLA pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases, and resting potentials during pubescence, differences in these parameters emerged between sexes at adulthood: BLA neurons were more excitable in males than females. During pubescence, BLA neuron excitability was highest in females and unchanged in males; male action potentials were smaller and shorter than females and fast afterhyperpolarizations were larger in males. During post-natal maturation, no difference in spine density was observed between groups or sexes but spine length increased and decreased in females and males, respectively. A reduction in spine head diameter and volume was observed exclusively in females. Basic synaptic properties also displayed sex-specific maturational differences. Stimulus-response relationships and maximal fEPSP amplitudes where higher in male adolescents compared with adults but were similar in females of both ages. Spontaneous excitatory postsynaptic currents mediated by AMPA receptors were smaller in BLA neurons from adolescent female compared with their adult counterparts but were unchanged in males. These differences did not directly convert into changes in overall synaptic strength estimated from the AMPA/NMDA ratio, which was smaller in adolescent females. Finally, the developmental courses of long-term potentiation and depression (LTP, LTD) were sexually dimorphic. LTP was similarly present during the adolescent period in males and females but was not apparent at adulthood in females. In contrast, LTD followed an opposite development: present in adolescent females and expressed in both sexes at adulthood. These data reveal divergent maturational trajectories in the BLA of male and female rats and suggest cellular substrates to the BLA linked sex-specific behaviors at adolescence and adulthood.

Sex-specific maturational trajectory of endocannabinoid plasticity in the rat prefrontal cortex

BioRxiv

Axel Bernabeu, Anissa Bara, Antonia Manduca, Milene Borsoi, Olivier Lassalle, Anne-Laure Pelissier-Alicot and OJJ Manzoni

Full paper here

The prefrontal cortex (PFC) develops until early adulthood in rodents and humans, but how synaptic plasticity evolves throughout postnatal development is not known. Here, we used a cross-sectional approach to establish the postnatal maturational trajectories of intrinsic properties and synaptic plasticity in the PFC of rats of both sexes. We found that while layer 5 PFC pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases and resting potentials across all age groups, excitability was lower in female adults compared to the other developmental stages. NMDAR-dependent long-term potentiation and mGluR2/3-mediated long-term depression (LTD) were equally expressed at the juvenile, pubescent and adult developmental stages in animals of both sexes. However, the developmental course of endocannabinoid (eCB)-mediated LTD was sexually dimorphic. First, eCB-LTD emerged during the juvenile period in females. However, although CB1Rs were functional in both sexes at all developmental stages, eCB-LTD’s first emerged during pubescence in male. Second, eCB-LTD engaged distinct receptors in males and females depending on their developmental stages. Female rats employ both CB1R and TRPV1R to produce eCB-LTD at the juvenile stage but solely CB1R at pubescence followed by only TRPV1R at adulthood. In contrast, in pubescent and adult males eCB-LTD always and exclusively depended on CB1R. Pharmacological blockade of 2AG’s principal degrading enzyme allowed incompetent male juvenile synapses to express eCB-LTD. The data reveal different maturational trajectories in the PFC of male and female rats and provide new cellular substrates to the sex-specific behavioral and synaptic abnormalities caused by adolescent exposure to cannabinoids.

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

Scheyer, Borsoi, Pellissier and Manzoni NeuroPsychoPharmacology (IF:7.2)

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

Full paper here

Cannabis is the world’s most widely abused illicit drug and consumption amongst women during and surrounding the period of pregnancy is increasing. Previously, we have shown that cannabinoid exposure via lactation during the early postnatal period disrupts early developmental trajectories of prefrontal cortex maturation and induces behavioral abnormalities during the first weeks of life in male and female rat progeny. Here, we investigated the lasting consequences of this postnatal cannabinoid exposure on synaptic and behavioral parameters in the adult offspring of ∆9-tetrahydrocannabinol (THC)-treated dams. At adulthood, these perinatally THC-exposed rats exhibits deficits in social discrimination accompanied by an overall augmentation of social exploratory behavior. These behavioral alterations were further correlated with multiple abnormalities in synaptic plasticity in the prefrontal cortex, including lost endocannabinoid-mediated long-term depression (LTD), lost long-term potentiation and augmented mGlu2/3-LTD. Finally, basic parameters of intrinsic excitability at prefrontal cortex pyramidal neurons were similarly altered by the perinatal THC exposure. Thus, perinatal THC exposure via lactation induces lasting deficits in behavior and synaptic function which persist into adulthood life in male and female progeny.

Endocannabinoid LTD in accumbal D1 neurons mediates reward seeking behavior

iScience https://doi.org/10.1016/j.isci.2020.100951

The nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptors medium spiny neurons (MSNs) of the NAc and the endogenous cannabinoid (eCB) system have been implicated in reward-seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSN neurons (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.

Full paper here

 

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

Deroche, Lassalle, Castell, Valjent & Manzoni

The Journal of Neuroscience 2019

Full paper here

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 male mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs 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). 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 that the interplay of TRPV1R/CB1R shapes plasticity at 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.

A new international EU-funded project for our team

BESTMEDGRAPE

New Business opportunities & Environmental suSTainability using MED GRAPE nanotechnological products

Grape as a traditional crop in the Mediterranean area has a strong innovation potential, which has not been effectively exploited yet. People working in the grape cultivation sector are generally focused on improving the quality of grape and wine, but usually don’t consider how to make the most out of grape waste. Based on the R&D experience of the partners in the fields of grape valorization, waste exploitation and development of nanotechnological antioxidant/anti-inflammatory/anti-neurodegenerative formulations, BESTMEDGRAPE aims at supporting the creation of new startups/SMEs by transferring scientific/technological knowledge on local grape cultivars and the exploitation of wine by-products as a source of bioactive compounds that can be transformed into innovative commercial health products. Hence, the project will not only valorise a Mediterranean product – grape – but also the expansion of the grape value chain through the development of nanotechnological products, thus boosting the local economy, reducing environmental pollution and increasing employment opportunities. http://www.enicbcmed.eu/fr/node/525

Consequences of Perinatal Cannabis Exposure

Scheyer AF, Melis M, Trezza V, Manzoni OJ

Trends Neurosci. 2019

Series: Early-Life Stress and the Brain Review Get this article here

Cannabis exposure during the perinatal period results in varied and significant consequences in affected offspring. The prevalence of detrimental outcomes of perinatal cannabis exposure is likely to increase in tandem with the broadening of legalization and acceptance of the drug. As such, it is crucial to highlight the immediate and protracted consequences of cannabis exposure on pre- and postnatal development. Here, we identify lasting changes in neurons’ learning flexibility (synaptic plasticity) and epigenetic misregulation in animal models of perinatal cannabinoid exposure (using synthetic cannabinoids or active components of the cannabis plant), in addition to significant alterations in social behavior and executive functions. These findings are supported by epidemiological data indicating similar behavioral outcomes throughout life in human offspring exposed to cannabis during pregnancy. Further, we indicate important lingering questions regarding accurate modeling of perinatal cannabis exposure as well as the need for sex- and age-dependent outcome measures in future studies.

Cannabinoid exposure via lactation in rats disrupts perinatal programming of the GABA trajectory and select early-life behaviors

Andrew F. Scheyer, Milene Borsoi, Jim Wager-Miller, Anne-Laure Pelissier-Alicot, Michelle N. Murphy, Ken Mackie, Olivier J.J. Manzoni

Biological Psychiatry
Cannabis usage is increasing with its widespread legalization. Cannabis use by mothers during lactation transfers active cannabinoids to the developing offspring during this critical period and alters postnatal neurodevelopment. A key neurodevelopmental landmark is the excitatory to inhibitory GABA switch caused by reciprocal changes in expression ratios of the K+/Cl- transporters KCC2 and NKCC1.

Treating rat dams with cannabinoids during early lactation retards transcriptional upregulation and expression of KCC2, thereby delaying the GABA switch in pups of both sexes. This perturbed trajectory was corrected by the NKCC1 antagonist bumetanide and accompanied by alterations in ultrasonic vocalization without changes in homing behavior. Neurobehavioral deficits were prevented by CB1R antagonism during maternal exposure, showing that CB1R underlie the cannabinoid-induced alterations.

These results reveal how perinatal cannabinoid exposure retards an early milestone of development, delaying the trajectory of GABA’s polarity transition and altering early-life communication.

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.

Key words

Current Fundings

– NIH (co-P.I. O. MANZONI & K. MACKIE) – FRC (De CHEVIGNY, P. CHAVIS) – FRM (P.I. O. MANZONI)

Fundings

Current Fundings

– NIH (co-P.I. O. MANZONI & K. MACKIE)

– FRC (De CHEVIGNY, P. CHAVIS)

– FRM (P.I. O. MANZONI)

 

Nos publications

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Alumni

  • Marion Deroche
  • Milene Borsoi
  • Antonia Manduca
  • Anissa Bara
  • Henry Martin
  • Daniela Neuhofer
  • Jilian Iaffrati
  • Aurore Thomazeau
  • Cecilia Gonzalez-Campo
  • Fernando Kasanetz
  • Mathieu Lafourcade
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