Role Of eCB Signaling Research Articles

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective.

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

Components of Endocannabinoid Signaling System Are Expressed in the Perinatal Mouse Cerebellum and Required for Its Normal Development.

Endocannabinoid (eCB) signaling system (ECS), encompassing cannabinoid receptors and enzymes involved in the synthesis and degradation of the endogenous cannabinoid signaling lipids, is highly expressed in the cerebellar cortex of adult humans and rodents. In addition to their well-established role in neuromodulation, eCBs have been shown to play key roles in aspects of neurodevelopment in the fore- and mid-brain, including neurogenesis, cell migration, and synapse specification. However, little is known about the role of ECS in cerebellar development. In this study, we conducted immunohistochemical characterization of ECS components through key stages of cerebellar development in mice using antibodies for 2-arachidonoylglycerol (2-AG) synthetizing and degrading enzymes and the major brain cannabinoid receptor, cannabinoid receptor 1 (CB1), in combination with cerebellar cell markers. Our results reveal a temporally, spatially, and cytologically dynamic pattern of expression. Production, receptor binding, and degradation of eCBs are tightly controlled, thus localization of eCB receptors and the complementary cannabinoid signaling machinery determines the direction, duration, and ultimately the outcome of eCB signaling. To gain insights into the role of eCB signaling in cerebellar development, we characterized gross anatomy of cerebellar midvermis in CB1 knock-out (CB1 KO) mice, as well as their performance in cerebellar-influenced motor tasks. Our results show persistent and selective anatomic and behavioral alterations in CB1 KOs. Consequently, the insights gained from this study lay down the foundation for investigating specific cellular and molecular mechanisms regulated by eCB signaling during cerebellar development.

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

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.

Endocannabinoid Signaling in the Stress Response of Male and Female Songbirds.

Endocannabinoid (eCB) signaling plays an important role in the stress response pathways of the mammalian brain, yet its role in the avian stress response has not been described. Understanding eCB signaling in avian species (such as the European starling, Sturnus vulgaris) allows a model system that exhibits natural attenuation of hypothalamic-pituitary-adrenal (HPA) responsiveness to stressors. Specifically, seasonally breeding birds exhibit the highest HPA activity during the breeding season and subsequently exhibit a robust HPA down-regulation during molt. Because eCB signaling in mammals has an overall inhibitory effect on HPA activity, we expected shifts in eCB signaling to regulate the seasonal HPA down-regulation during molt. However, our data did not support a role for eCB signaling in the molt-related suppression of HPA activity. For example, injection of the cannabinoid receptor (CB1) antagonist, AM251, did not potentiate molt-suppressed HPA activity. Instead, our data suggest eCB regulation of HPA plasticity as birds transition from breeding to molt. In support of this hypothesis, birds in the late breeding season demonstrated a more dynamic response at the level of avian amygdala eCB content in response to acute stress. The response and directionality of this effect match that seen in mammals. Overall, our data suggest that eCB signaling may allow for a dynamic range in HPA responsiveness (eg, breeding), but the signaling pathway's role may be limited when the HPA response is restrained (eg, molt). This first characterization of eCB signaling in the avian stress response also emphasizes that although the system functions similarly to other species, its exact role may be species specific.

Morphological and behavioral evidence for impaired prefrontal cortical function in female CB1 receptor deficient mice

The medial prefrontal cortex (mPFC) is known to regulate higher order processes like cognitive flexibility. Accumulating behavioral evidence suggests that endocannabinoid (eCB) signaling regulates neuronal architecture within the PFC, as well as certain forms of cognitive flexibility; however, all of these studies have been performed in male rodents and it is currently unknown whether the eCB system performs a similar role in females. To this extent, dendritic morphology of layer II/III neurons in the infra- and prelimbic regions of the mPFC was analyzed and cognitive ability and flexibility in a fixed-platform Morris water maze task was assessed in adult female CB1 receptor knockout (CB1KO) mice. Similar to data generated in male mice, female mice exhibited no difference in acquisition relative to wildtype (WT); however, during reversal learning, CB1KO females spent more time in the original training quadrant and took significantly longer to learn the location of the new platform relative to WT. Within the mPFC, female mice had reduced length and complexity of layer II/III neurons within the prelimbic, but not infralimbic region of the PFC. Taken together, these findings indicate that the role of eCB signaling in cognitive flexibility is independent of sex and disrupted CB1 receptor signaling results in compromised structure and function of the PFC, at least within the prelimbic division.