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

Abstract

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 Δ9-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.

Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions

“…In line with previous reports in rodent models 28,44–50 , our behavioral analysis demonstrated that adolescent exposure to THC in mice led to long-term impairments in object recognition memory and social interaction, but not in anxiety-like behaviors. Our study also showed sex differences in the effects of THC on recognition memory, which was impaired more in females compared to male mice.…”

“…We measured several behaviors in adult mice of both sexes (n=12/group/sex) with or without chronic adolescent exposure to THC (Fig 1A). We used six different objects test (6-DOT) to assess the long-term effects of adolescent exposure to THC on object recognition memory 16,20 . THC exposure during adolescence significantly reduced the absolute (D1) and relative (D2) discrimination indexes by 36% and 30%, respectively, compared to vehicle control group (Fig 1B-C).…”

Thalamo-hippocampal pathway regulates incidental memory load in mice

“…Converging findings in rodents, primates and humans suggest that high memory load drives dHP recruitment in STM item tasks. We and others have previously reported that, in male mice, object STM capacity appears limited to about 6 elements 4–7 , which is very similar to that of humans (albeit measured in different tasks). These findings have been obtained by using the Different/Identical Object Task (DOT/IOT), a modified version of the spontaneous object recognition task, which stimulates incidental encoding based on the spontaneous interest of animals to explore novel objects.…”

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

“…Notably, the HR mice exhibit sex differences in the context of neurotransmitter signaling and receptor function 40,41 . Similarly, HR mice showed sex differences in behavioral disinhibition and stress reactivity following adolescent exposure to THC 22 . However, our study did not find specific sex-biased responses to cocaine in HR mice, demonstrating that sex does not play a role in the effects of enhanced locomotor activation after cocaine injection in HR mice.…”

“…The Heterozygous Reeler (HR) mice express reduced levels of Reelin and do not exhibit abnormal neuronal positioning during development 20 . In contrast, they show reduced dendritic spine density 21 and several behavioral abnormalities, including impaired learning and memory, decreased behavioral inhibition, and increased impulsivity 20,[22][23][24][25] . Therefore, HR mice have been proposed as a model for studying neurological disorders 20 .…”