Developmental regulation of fear learning and anxiety behavior by endocannabinoids

Abstract

The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid (eCB) system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic eCB signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that eCB signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic eCB signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the eCB system and discuss clinical and rodent models showing eCB regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the eCB system in the central nervous system, and models of pharmacological augmentation of eCB signaling during development in the context of fear learning and anxiety.

Keywords: 2-AG; CB1 receptor; FAAH; adolescence; anandamide; cannabinoid; development; early life; emotional behavior; juvenile; neonatal; stress.

Figure 1. Major pathways of anandamide and 2-arachidonoylglycerol (2-AG) synthesis and degradation

Figure 2. Human and rodent development timelines with commonly used terms for referring to those stages of development (adapted from Lee & Gorzalka, 2012)

Figure 3. Corticolimbic endocannabinoid signaling changes dynamically across rodent development

(A) Distinct endocannabinoid signaling profiles in early life, adolescence and adulthood. Components of the endocannabinoid system are represented schematically within a synapse (adapted from(Long et al., 2012). (B) Developmental trajectories of the components of the endocannabinoid system. CB₁ receptor (CB₁) expression peaks with the onset of adolescence. 2-arachidonoylglycerol (2-AG) is highest around birth and may fluctuate throughout adolescence. N-arachidonoylethanolamine (anandamide; AEA) gradually increases during early life and fluctuates during adolescence. Fatty acid amide hydrolase (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, Rodriguez de Fonseca et al., 1993, Rubino et al., 2015, Wenger et al., 2002).