Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens

Abstract

Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA), both performed using protein quantitative data, demonstrate that cocaine increases vesicular transporters for dopamine and glutamate as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins implicated in a diverse number of neuronal functions (e.g., energy production, mRNA splicing, and ubiquitination), molecular cascades (e.g., protein kinases), psychiatric disorders (e.g., mood disorders), and neurodegenerative diseases (e.g., Huntington's and Alzheimer's diseases). Upregulation of energy metabolism components in EC rats was verified using RNA sequencing. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics. Proteomics data are available via ProteomeXchange with identifier PXD000990.

Inoculation stress hypothesis of environmental enrichment

“…Further, a recent proteomic study found that the microtubule-associated protein tau was upregulated in EC rats compared to IC rats (Fan et al, 2013a). That paper and two other proteomics papers also identified huntingtin, presenilin 1, tau and amyloid precursor protein as major upstream regulators for environmental enrichment (Fan et al, 2013b; Lichti et al, 2014). These results warrant further investigation of neurodegenerative disorders using the environmental enrichment paradigm.…”

Transcriptomics of Environmental Enrichment Reveals a Role for Retinoic Acid Signaling in Addiction

“…The right side was used for protein quantification (Lichti et al, 2014). The RNA was extracted and purified with the RNeasy mini kit (Qiagen, Valencia, CA, USA).…”

“…A secondary analysis of our previously published liquid chromatography tandem mass spectrometry (LC-MS/MS) protein data from these same rats (Lichti et al, 2014) was used to corroborate RNA results where appropriate.…”

Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k

“…Previous studies have demonstrated that genes related to memory formation, synaptic plasticity, and protein synthesis may be upregulated by a period of environmental enrichment (Lichti et al, 2014; Novkovic et al, 2015; Sampedro-Piquero et al, 2014) including group 1 metabotropic glutamate receptors (mGluR1/5) (Melendez, Gregory, Bardo, & Kalivas, 2004). Indeed, the role of metabotropic glutamate receptor subtype 5 (mGluR5) in learning and memory is well established; mice lacking mGluR5 show impaired learning on the Morris water maze and contextual fear conditioning tasks (Lu et al, 1997), and the daily application of the mGluR5 antagonist 2-methyl-6-(phenylethyl)pyridine (MPEP) causes impairments in working and reference memory in rats (Manahan-Vaughan & Braunewell, 2005).…”