The Role of the Endocannabinoid System and Genetic Variation in Adolescent Brain Development

Abstract

During adolescence, both rodent and human studies have revealed dynamic changes in the developmental trajectories of corticolimbic structures, which are known to contribute to the regulation of fear and anxiety-related behaviors. The endocannabinoid (eCB) system critically regulates stress responsivity and anxiety throughout the life span. Emerging evidence suggests that during adolescence, changes in eCB signaling contribute to the maturation of local and corticolimbic circuit populations of neurons, such as mediating the balance between excitatory and inhibitory neurotransmission within the prefrontal cortex. This function of the eCB system facilitates efficient communication within and between brain regions and serves a central role in establishing complex and adaptive cognitive and behavioral processing. Although these peri-adolescent changes in eCB signaling promote brain development and plasticity, they also render this period a particularly sensitive one for environmental perturbations to these normative fluctuations in eCB signaling, such as stress, potentially leading to altered developmental trajectories of neural circuits governing emotional behaviors. In this review, we focus on the role of eCB signaling on the regulation of stress and anxiety-related behaviors both during and after adolescence. Moreover, we discuss the functional implications of human genetic variation in the eCB system for the risk for anxiety and consequences of stress across development and into adulthood.

Figure 1

Corticolimbic eCB signaling changes dynamically across rodent development. (a) Major pathways of endocannabinoid degradation. (b) Schematic of eCB signaling within a synapse. (c) Developmental trajectories of the components of the eCB system. CB1 receptor expression peaks with the onset of adolescence. 2-AG is highest around birth and may fluctuate throughout adolescence. AEA gradually increases during early life and fluctuates during adolescence. FAAH activity fluctuates in reciprocal fashion to AEA during adolescence (based on data from Berrendero et al, 1999; Ellgren et al, 2008; Fernandez-Ruiz et al, 2000; Heng et al, 2011; Lee et al, 2013; Rodríguez de Fonseca et al, 1993; Rubino et al, 2015; Wenger et al, 2002). Adapted from Lee et al (2016), Genes Brain and Behavior.

Figure 2

Functional and structural connectivity between ventromedial prefrontal cortex (vmPFC) and amygdala in adult humans and mice with FAAH C385A. (a) fMRI functional connectivity compared between subgenual vmPFC (x, y, z=0, 40, −3) and bilateral amygdala in A-allele carriers (n=17) relative to C homozygotes (n=18). (b) Anterograde tracer (AAV2-eGFP; eGFP), targeted to IL, labeled afferents in BLA in FAAHA/A mice (n=4) and controls (FAAHC/C; n=4). Drawing illustrates anatomical boundaries. (c) Retrograde tracer (fluorogold; FG), targeted to IL, labeled BLA cell bodies in FAAHA/A mice (n=4) and controls (FAAHC/C; n=4). (Scale bars, 100 μm.) Means±SEM. presented. *p<0.05, ***p<0.001. NS, not significant. Reprinted from Dincheva et al (2015), Nature Communications.

Figure 3

Phenotypic differences in frontolimbic circuitry resulting from FAAH polymorphism emerge during adolescence in human and mouse. (a, left) Post hoc analyses revealed a significant genotypic effect on uncinate fasciculus (UF) fractional anisotropy in participants 12 years of age and older (n=509; 249 females; F(1,491)=14.02; p=0.0002) but not in those under 12 years of age (n=541; 259 females; F(1,523)=0.513; p=0.474). (a, right) Mask in Montreal Neurological Institute standard space, where UF ascends from the temporal lobe used as the seed region for probabilistic tractography in humans (upper left); UF tract mask is derived from probabilistic tractography averaged across human participants (n=1050). (b, left) Consistent with the findings in humans, a significant genotype by age group interaction (F(2,36)=58.72; p<0.0001) in IL afferent fibers to BLA emerged, such that knock-in mice (AA: n=7 per age) had higher fiber density than WT mice (CC: n=7 per age) during adolescence at age P45 (p<0.0001) and adulthood at P75 (p<0.0001). (b, right) Drawing of anatomical boundaries and anterograde tracer targeted to IL and labeling afferents in BLA. CeA, central amygdala; MeA, medial amygdala; PL, prelimbic; *p<0.05. Reprinted from Gee et al (2016), Proc Natl Acad Sci USA.