Nur, A. | bioRxiv Science

bioRxiv2022

Reelin deficiency exacerbates cocaine-induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum.

The Reln gene encodes for the extracellular glycoprotein Reelin, which regulates several brain functions from development to adulthood, including neuronal migration, dendritic growth and branching, and synapse formation and plasticity. Human studies have implicated Reelin signaling in several neurodevelopmental and psychiatric disorders. Mouse studies using the heterozygous Reeler (HR) mice have shown that reduced levels of Reln expression are associated with deficits in learning and memory and increased disinhibition. Although these traits are relevant to substance use disorders, the role of Reelin in cellular and behavioral responses to addictive drugs remains largely unknown. Here, we compared HR mice to wild-type (WT) littermate controls to investigate the contribution of Reelin signaling to the hyper-locomotor and rewarding effects of cocaine. After a single cocaine injection, HR mice showed enhanced cocaine-induced locomotor activity compared to WT controls. After repeated injections of cocaine, Reelin deficiency also led to increased cocaine-induced locomotor sensitization, which persisted after withdrawal. In contrast, Reelin deficiency did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine-induced hyper-locomotion in HR mice resulted in increased Fos expression in the dorsal medial striatum (DMS) compared to WT. Lastly, we found that Reln was highly co-expressed with the Drd1 gene, which encodes for the dopamine receptor D1, in the DMS. These findings demonstrated that Reelin signaling contributes to the locomotory effects of cocaine and improved our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine.

neuroscience↗

bioRxiv2020

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Heavy and frequent use of cannabis during adolescence increases the risk of developing psychiatric disorders. However, the neurobiological mechanisms underlying this vulnerability remain largely unknown. Here, we explore whether adolescent vulnerability to long-term behavioral effects of cannabis is modulated by Reelin, a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically exposed during adolescence to high doses (10mg/kg) of {Delta}9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Mice were tested in early adulthood with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed impaired social behaviors, elevated disinhibitory phenotypes and increased responsiveness to aversive situations, in a sex-specific manner. Independent of THC exposure, HR mice also spent more time exploring unfamiliar objects, indicating that Reelin modulates novelty seeking behavior. To identify the neuronal ensemble underlying this elevated novelty seeking in HR mice, we mapped the regional brain expression of the immediate early gene, Fos, in mice exposed to novel objects. HR mice exhibited reduced neuronal activation in the lateral septum, a subcortical brain structure implicated in emotions, cognition and reward processes. Overall, these findings show that (1) Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence, and (2) that Reelin plays a role in the neurobiological mechanisms underlying disinhibitory behaviors, such as novelty seeking. Significant StatementThe link between cannabis abuse and the development psychiatric disorders, especially in adolescents, makes understanding the neurobiological mechanisms underlying cannabis effects on the brain a significant biomedical problem. Reelin is a key signaling molecule in the development of the adolescent brain and of psychiatric disorders, but its role in modulating the behavioral changes induced by cannabis remain unknown. Here, we report an interaction between Reelin deficiency and chronic adolescent exposure to THC, a major psychoactive component of cannabis. This interaction led to cognitive deficits, disinhibitory behaviors and altered emotional reactivity in mice, in a sex-specific manner. These experiments are the first to establish a link between Reelin signaling and the endocannabinoid system targeted by THC.

neuroscience↗