Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Abstract

Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.

Altered Expression of Genes Associated with Major Neurotransmitter Systems in the Reward-Related Brain Regions of Mice with Positive Fighting Experience

“…Intracellular signal transduction is crucial for the STR participation in motor and behavioral functions as well as all types of addiction. Via correlation analysis, we have succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons’ gene pathways in winners [ 47 , 88 ] with hyperactive behavior revealed by us before [ 72 ] in chronically aggressive mice.…”

Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts

“…The studies on the neurological mechanisms of aggression along with the depression state attract specific attention in psychiatry. Aggression is coupled with an addiction-like state associated with a withdrawal (deprivation) phenomenon [ 1 , 2 , 3 , 4 ].…”

“…The major body of the DS comprises GABAergic medium spiny neurons (MSNs), acting synchronously in the response to phasic dopamine [ 9 ]. In particular, we have earlier used RNA-seq transcriptome data sampled from the DS of mice in experiments with chronic social conflicts and showed distinct coordinately expressed gene cluster profiles corresponding to D1- and D2-MSNs in different phases [ 4 , 10 ]. The major mechanism of MSN cellular signal processing is the cAMP-mediated (de)phosphorylation signaling cascades incorporating multiple phosphoproteins [ 7 , 11 , 12 ].…”

“…Using the same data on the social conflict model of repeated aggression-exposed mice with positive (winning) experience (A20), consequent aggression deprived (AD) mice, and control groups (see Methods), we recently assessed the differentially expressed genes (DEGs [ 4 ]) emphasizing the expression profile specifics of each group. The unexpected straight outcome of the study shows that while the A20 group differed from the control by over 1000 DEGs, the AD group (14 days of deprivation span after A20 group protocol) expression profile was quite similar to that of the control (62 DEGs [ 4 ]). The control vs.…”

Advances of Brain Transcriptomics

“…As a continuation of these studies, we include a report by the same group of authors on changes in the level of gene expression in the dorsal striatum in aggressive (winners) and aggression-deprived (AD) male mice [ 6 ]. Earlier work by the authors showed that AD mice displayed a higher aggressive behavior score compared with the aggressive group.…”