Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence a period when cannabis use in humans has been linked to the vulnerability of psychiatric disorders such as addiction and schizophrenia in early adulthood. Rodent models confirm the protracted behavioral associations but molecular insights are still lacking. Here, we investigated the effects of adolescent Δ9-tetrahydrocannabinol (THC) exposure on the arborization, spine density, and transcriptional profile of layer II/III pyramidal neurons using cell type- and lamina- specific high-resolution microscopy combined with laser capture microdissection and next generation RNA sequencing. The results confirmed known expansion in basal dendritic arborization and pruning of dendritic spines during the transition from late adolescence to early adulthood in control animals. This was accompanied by differential expression of gene networks associated with neurodevelopment. In contrast, THC exposure disrupted the normal developmental process inducing premature pruning of dendritic spines along with an allostatic atrophic dendritic arborization in early adulthood. Surprisingly, there was little overlap of the pyramidal transcriptome between adolescent THC-exposed and vehicle adult rats. THC-related gene networks related to cell morphogenesis, dendritic development and cytoskeleton organization. Profound gene network disturbances were also associated with chromatin modification indicative of epigenetic dysregulation. Overall, these findings demonstrate that adolescent THC exposure impacts the developmental trajectory of PFC pyramidal neurons to induce persistent perturbation of neuronal morphology accompanied with an aberrant transcriptional signature in early adulthood that could contribute to enhanced vulnerability to psychiatric disorders.
|Advisor:||Hurd, Yasmin L.|
|Commitee:||Lee, Francis, Morishita, Hirofumi, Russon, Scott S., Shapiro, Matthew L.|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 78/07(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Behavioral psychology|
|Keywords:||Cognition, Development, PFC, Pyramidal, Thc|
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