Endocannabinoid LTD in accumbal D1 neurons mediates reward seeking behavior
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.
Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood
Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core
The Journal of Neuroscience 2019
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
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
Trends Neurosci. 2019
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
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.
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.
Current Fundings– NIH (co-P.I. O. MANZONI & K. MACKIE) – FRC (De CHEVIGNY, P. CHAVIS) – FRM (P.I. O. MANZONI)
- NIH (co-P.I. O. MANZONI & K. MACKIE)
- FRC (De CHEVIGNY, P. CHAVIS)
- FRM (P.I. O. MANZONI)