Striatal Transcriptome Reveals Differences Between Cognitively Impaired and Unimpaired Aged Male Rats

Abstract

Cognitive processes require striatal activity. The underlying molecular mechanisms are widely unknown. For this reason the striatal transcriptome of young (YM), aged cognitively impaired (OMB), and unimpaired (OMG) male rats was analyzed. The global comparison of transcripts reveal a higher number of differences between OMG and YM as compared to OMB and YM. Hierarchical clustering detects differences in up- and down-regulated gene clusters in OMG and OMB when compared to YM. In OMG we found more single genes to be specifically regulated in this group than in OMB when compared to young. These genes were considered as cognition specific, whereas genes shared in OMG and OMB were considered as age specific. OMB specific up-regulated genes are related to negative control of cell differentiation and transcription (Hopx), to phagocytosis (Cd202) and cell adhesion (Pcdhb21), whereas down-regulated genes are related to associative learning, behavioral fear response and synaptic transmission (Gabra5). OMG specific up-regulated genes are in the context of maintenance of transcription and estrogen receptor signaling (Padi2, Anxa3), signal transduction [Rassf4, Dock8)], sterol regulation (Srebf1), and complement activity (C4a, C4b). Down-regulated genes are related to lipid oxidation reduction processes (Far2) and positive regulation of axon extension (Islr2). These relations were supported by pathway analysis, which reveals cholesterol metabolism processes in both aged group and cholesterol biosynthesis specifically in OMG; adipogenesis and focal adhesion in OMB. In OMG glucuronidation, estrogen metabolism, inflammatory responses and TGF beta signaling where detected as specific for this group. Signal transduction of the sphingosine-1-phospate-receptor (S1P) receptor was the main pathway difference in the comparison of OMB and OMG with downregulated genes in the first group. This difference could also be observed in the OMB vs. YM comparison but not in the OMG vs. YM analysis. Thus, an up-regulation of cognition related genes could be observed in OMG compared to OMB rats. The S1P pathway discriminated between OMB and OMG as well as between OMB and OMG. Since this pathway has been described as essential for cognitive processes in the striatum of mice, it may, among steroid hormone signaling, significantly contribute to the maintenance of cognitive processes in OMG.

The effects of ruminant milk treatments on hippocampal, striatal, and prefrontal cortex gene expression in pigs as a model for the human infant

“…In the hippocampus and striatum, genes related to synaptic vesicle cycle, glutamatergic, GABAergic, serotonergic, and adrenergic transmission, and neurotrophin signaling were most affected by the ruminant milk treatments. Other studies have shown that lower gene expression levels in the hippocampus and striatum associated with these processes were implicated in behavior changes involving memory impairment in rodent models ( Mathew et al, 2010 ; Tellez et al, 2012 ; Xie et al, 2015 ; Ramos-Miguel et al, 2017 ; Korz et al, 2021 ). However, the present study did not ascertain any functional relevance of these changes, i.e., whether the level of changes in gene expression between milk treatments was sufficient to change brain function.…”