Cellular mechanisms of environmental enrichment: Novel discovery-based strategies for target identification for neuropsychiatric disorders


Neuropsychiatric disorders such as anxiety, depression, and substance use disorders are highly prevalent disorders and immensely costly to society. Treatment options are limited, and cocaine use disorder in particular, has no FDA approved pharmacotherapeutic. These disorders are highly comorbid and are often more severe when they co-occur. Thus, it is critical to determine novel targets for substance use disorders with comorbid mood disorders. In order to identify novel targets, we examine an animal model of the resilience to depression and addiction, environmental enrichment. Environmental enrichment is a non-drug, non-surgical, non-genetic manipulation that produces protective depression and addiction phenotypes. Enriched rats are reared in a large cage with conspecifics and plastic toys that are changed and rearranged daily. Most individuals that use addictive substances do not become addicted. Environmental enrichment mimics these individual differences in susceptibility. Therefore, the overall goal of this study is to identify novel therapeutic targets for treating neuropsychiatric disorders using two discovery-based strategies. The first strategy to narrow the exciting leads is a convergent transcriptomic/proteomic analysis of mRNA and protein regulated by enrichment and cocaine. This strategy identifies AKT signaling as a promising pathway; therefore, we knocked down the downstream target of AKT, glycogen synthase kinase 3 (GSK3) beta, with a novel adeno-associated viral (AAV) vector in the nucleus accumbens shell (NAcSh) of rats and found increases in depression-like and cocaine taking behaviors. Additionally, GSK3 beta knockdown significantly reduced the activity of tonically active interneurons in the shell. The second discovery-based strategy is a convergent functional transcriptomics approach to examine the intersection of transcripts regulated by environmental enrichment, cocaine, and genes with enhanced expression in the NAcSh. NAcSh specific genes are identified through a topographic transcriptomic analysis with in situ hybridization from the Allen Mouse Brain Atlas. The second strategy identifies retinoic acid signaling as a potential underlying factor of enrichment and cocaine in the NAcSh. Therefore, we manipulated a gene with enhanced NAcSh expression in the retinoic acid signaling pathway, which was regulated by environmental enrichment, fatty acid binding protein 5 (FABP5), and found a decrease in cocaine taking behaviors. Thus, we identified novel targets through two discovery-based strategies investigating the underlying cellular mechanisms of environmental enrichment.



substance use disorder, anxiety, depression, preclinical rodent model, environmental enrichment, cocaine, drugs, psychiatric disorders