• Fellowship 2017: 

Adolescence is a time of important neurobiological and behavioral changes, but is also the period in which several mental illnesses emerge, included psychosis, mood disorders, and substance abuse. Among all drugs, Cannabis is the most widely abused by teens and several clinical data suggest the presence of a relationship between adolescent Cannabis abuse and the risk for developing psychiatric diseases later in life. Consistently, we have demonstrated that adolescent female rats treated with the psychoactive compound of Cannabis delta-9-tetrahydrocannabinol (THC), develop a depressive/psychotic-like phenotype in adulthood. Interestingly, we observed that only adolescent, but not adult, THC exposure leads to this phenotype, suggesting that adolescence represents a vulnerable period for the psychiatric consequences of THC exposure. However, the molecular underpinnings of this vulnerability remain to be established. During adolescence, brain undergoes intensive processes of neuronal refinement, especially in cortical regions. Adolescent brain maturation involves a thinning of the gray matter (GM – it contains the cell bodies, dendrites and axon terminals of neurons) as result of synaptic pruning processes, through which “redundant” synapses overproduced in the early years of life are being eliminated; and an increase in white matter (WM – it is made of myelinated axons). Myelin improves neural transmission, contributing to the enhanced brain-regional connectivity and cognitive function that occur during adolescence. Thus, alterations in synaptic refinement as well as in myelination during this sensitive period could confer a vulnerability to psychiatric diseases. In the brain, the Endocannabinoid System (ECS) is an important neuromodulatory system involved in synaptic plasticity regulation. So far, many works have addressed adolescent brain maturation, but the involvement of the ECS in adolescent brain refinement remains to be elucidated. Recently, we have demonstrated that adolescent THC exposure deeply changes neuronal refinement, altering the expression of proteins involved in synaptic plasticity and brain functionality. Moreover, our preliminary data show that adolescent THC alters the expression of MOG and MBP, two important markers of myelination. Thus, it is alleged that Cannabis consumption during adolescent brain maturation may alter the EC tone, interfering with normal brain development, and eventually resulting in a major vulnerability to mental illnesses. On these bases, our proposal is to thoroughly investigate the role played by the EC signaling in processes occurring in the adolescent prefrontal cortex of female rats. To clearly depict each step of adolescent brain maturation, analyses will be performed every 5 day, from 28 to 75 PND focusing on the events of synaptic pruning and myelination. Next, through the administration of specific modulators of the ECS, we will study the impact of this modulation on markers of plasticity and myelination. Specifically, we will administer AM251, a selective antagonist of CB1 receptor, the major cannabinoid receptor in the CNS; URB597, an inhibitor of the enzyme fatty acid amide hydrolase (FAAH, the enzyme that catalyzes the intracellular hydrolysis of the endocannabinoid anandamide “AEA”), JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL, the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol “2-AG”) and THC. With this approach, we will be able to elucidate the role played by the specific components of the ECS (CB1R, AEA and 2-AG) during adolescent brain maturation. Moreover, we will also understand the impact of EC tone disruption in triggering brain vulnerability to psychiatric conditions.

• Fellowship 2018

The endocannabinoid system (ECS) is an important neuromodulatory system that plays a key role in perinatal brain development. However, the involvement of ECS in adolescent brain refinement remains to be elucidated. The ECS is the principal target of THC, the psychoactive compound of Cannabis, the most abused drug by teens. Evidence suggests the presence of a relationship between adolescent Cannabis abuse and the risk for developing mental illnesses. Interestingly, abused drugs, Cannabis included, impairs behavior in a sex-dependent manner: women develop depression/anxiety, whereas men suffer from attention-deficit hyperactivity and anti-social personality disorders. In line with this, we have demonstrated that adolescent THC exposure induces a depressive-psychotic-like phenotype in adult female rats, and a psychotic-like phenotype in males. Our hypothesis is that Cannabis consumption during adolescence may alter the EC tone, interfering with brain refinement and conferring a specific sex-vulnerability to mental illnesses. To understand the neurobiology of this sex-sensitivity, a thoroughly characterization of adolescent brain maturation is needed. Preliminary data obtained in our laboratory suggest an involvement of the ECS in adolescent brain maturation of female rats. However, we have no information regarding males. This year our proposal is to expand this investigation on the prefrontal cortex of male rats. To depict each step of adolescent brain maturation, analyses will be performed every 5 days (28-75 PND) exploring synaptic pruning and myelination. Through the administration of ECS modulators, we will study the impact of ECS modulation on plasticity and myelination. With this approach, we will elucidate the role played by specific components of the ECS during adolescent brain maturation in male rats. Moreover, this data will be compared to those obtained in female rats to understand whether a sex-dependent disruption of ECS tone may underlay the development of different phenotypes in male and female rats exposed to THC during adolescence