The authors wish to thank the nursing and clinical staff of the Department of Gynecology & Obstetrics of the Manzoni Hospital of Lecco (Prof. Antonio Pellegrino and Dr. Roberta Tironi) and of the Hospital of Desio and Vimercate (branch of Carate Brianza; Prof. Anna Locatelli and Mrs. Rossella Fumagalli). Many thanks to Lara Lanzoni, Giulia Melesi, Chiara Miotti, Giulia Mornati and Vittoria Trezzi, for their help in data collection. Finally, special thanks go to all infants and their parents participating in this study and to two anonymous reviewers for their thoughtful suggestions. The research was supported by Grant RC2013 from the Italian Ministry of Health, by Fondazione della Provincia di Lecco Onlus/Rotary Club (Rotary Club Lecco, Rotary Club Le Grigne, Rotary Club Manzoni) and the l’Oreal-UNESCO Italy for Women in Science Fellowship (CC).
Adolescence has been characterized as a period of increased impulsivity and risky behavior that often leads to the initiation of health compromising behaviors such as substance use (Chambers et al., 2003). Indeed, national estimates indicate that rates of substance use during adolescence climb steadily from 20 to 70% between 12 and 17 years of age (Miech et al., 2015; Stagman et al., 2011). Of great concern is that substance use such as alcohol, cigarette, marijuana and other illicit drugs often increases the risk of dependency, unprotected intercourse, and interpersonal violence, leading to adverse health outcomes later in life (Verdejo-García et al., 2008). Developmental neuroscience research suggests that the increased risky behaviors including substance use in adolescence are due, in part, to imbalanced developmental trajectories of NU7441 manufacturer circuits between the subcortical limbic and prefrontal networks (Casey et al., 2008; see also Crone et al., 2016), and thus adolescents exhibit heightened emotional impulsivity and a lack of effective cognitive control (Hare et al., 2008), resulting in greater substance use behaviors (Casey and Jones, 2010). Therefore, investigating the neural underpinnings associated with substance use is critical to reduce risk of substance use and increase protective factors for adolescents.
A growing body of literature in developmental neuroscience provides considerable evidence that functional coupling between limbic and prefrontal systems plays an important role in emotion regulation and risk-taking behavior during adolescence, contributing to substance use (Cservenka et al., 2014; Fareri et al., 2015; Gabard-Durnam et al., 2014; Gee et al., 2013a,b, 2014; Hare et al., 2008; Porter et al., 2015; Qu et al., 2015; van Duijvenvoorde et al., 2016; Weissman et al., 2015). For example, functional MRI (fMRI) studies using task-based indexes of functional brain activation have demonstrated a developmental shift in functional connectivity between limbic and prefrontal circuitry, such that children show positive coupling, which switches to negative coupling by adulthood (Gee et al., 2013a,b, 2014; Hare et al., 2008). Thus, negative functional coupling between these circuitries is an index of maturation of neural networks of the brain, representing enhanced inhibitory projections from frontal to limbic regions. Consistently, a recent longitudinal fMRI study highlighted inverse connectivity between limbic and prefrontal systems by demonstrating that adolescents who show longitudinal declines in functional coupling between the ventral striatum (VS), a region in the limbic system, and medial prefrontal cortex (mPFC), a region in the prefrontal, executive system, exhibited greater decreases in risk-taking behavior over time (Qu et al., 2015). Tract-tracing studies in rodents further supports this view by showing that an inverse association between these two systems is derived from greater suppression of limbic activity via descending projections from the prefrontal region, which increasingly emerges over development (Bouwmeester et al., 2002a,b; Cressman et al., 2010; Cunningham et al., 2002). Resting-state fMRI (rs-fMRI) studies in humans have further demonstrated the importance of functional connectivity and links to adolescent behavior (Fareri et al., 2015; Gabard-Durnam et al., 2014; van Duijvenvoorde et al., 2016; Weissman et al., 2015). For example, higher positive functional connectivity between limbic and prefrontal circuits is associated with hyperresponsiveness and overvaluation of rewards (Fareri et al., 2015; van Duijvenvoorde et al., 2016), behaviors which contribute to higher frequency of substance-use behavior in adolescents (Casey and Jones, 2010). Indeed, a recent rs-fMRI study demonstrated that positive resting-state functional connectivity between the nucleus accumbens (NAcc) and prefrontal regions was related to earlier substance use (Weissman et al., 2015). Similarly, adolescents with a family history of alcoholism showed less negative connectivity between NAcc and other executive control regions including the inferior frontal gyrus and ventrolateral PFC (Cservenka et al., 2014). In sum, these findings suggest that inverse or segregated limbic-prefrontal connectivity is related to decreased risky-behaviors during adolescence