Striatal transcriptome changes linked to drug‐induced repetitive behaviors. (23rd March 2021)

• Record Type: Journal Article
• Authors: Crittenden, Jill R.; Gipson, Theresa A.; Smith, Anne C.; Bowden, Hilary A.; Yildirim, Ferah; Fischer, Kyle B.; Yim, Michael; Housman, David E.; Graybiel, Ann M.
• Is Part Of: European journal of neuroscience. Volume 53:Number 8(2021)
• Page Start: 2450
• Page End: 2468
• Publication Date: 2021-03-23
• Subjects: amphetamine -- restricted repetitive behavior -- sensitization -- stereotypy -- tolerance; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.15116
• Languages: English
• ISSNs: 0953-816X

Abstract

Abstract: Disruptive or excessive repetitive motor patterns (stereotypies) are cardinal symptoms in numerous neuropsychiatric disorders. Stereotypies are also evoked by psychomotor stimulants such as amphetamine. The acquisition of motor sequences is paralleled by changes in activity patterns in the striatum, and stereotypies have been linked to abnormal plasticity in these reinforcement‐related circuits. Here, we designed experiments in mice to identify transcriptomic changes that underlie striatal plasticity occurring alongside the development of drug‐induced stereotypic behavior. We identified three schedules of amphetamine treatment inducing different degrees of stereotypy and used bulk RNAseq to compare striatal gene expression changes among groups of mice treated with the different drug‐dose schedules and vehicle‐treated, cage‐mate controls. Mice were identified as naïve, sensitized, or tolerant to drug‐induced stereotypy. All drug‐treated groups exhibited expression changes in genes that encode members of the extracellular signal‐regulated kinase (ERK) cascades known to regulate psychomotor stimulant responses. In the sensitized group with the most prolonged stereotypy, we found dysregulation of 20 genes that were not changed in other groups. Gene set enrichment analysis indicated highly significant overlap with genes regulated by neuregulin 1 (Nrg1). Nrg1 is known to be a schizophrenia and autism susceptibility gene that encodes a ligand for Erb‐B receptors, which are involved in neuronal migration, myelination, and cell survival, including that of dopamine‐containing neurons. Stimulant abuse is a risk factor for schizophrenia onset, and these two disorders share behavioral stereotypy phenotypes. Our results raise the possibility that drug‐induced sensitization of the Nrg1 signaling pathway might underlie these links. Abstract : This study used RNAseq to identify striatal gene expression changes associated with extreme repetitive behaviors. Heat plots show upregulation (red) and downregulation (blue) of genes in the striatum of mice after one amphetamine treatment (few repetitive behaviors), 7 days of daily amphetamine treatments (prolonged repetitive behaviors), or 21 days of daily amphetamine treatments (diminished repetitive behaviors), relative to saline‐treated controls. Each column shows results from one mouse.