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.
Highlights
Torromino et al (2019) found the cross-regional communication between hippocampus and the ventral striatum to play a critical role in spatial memory formation in mice after water maze training
Similar gene expression profiles in the striatum and hippocampus have been found in NOS-1 knockdown animals which show impairments of spatial learning and memory including the holeboard test
Upregulated genes were related to gamma-Aminobutyric acid (GABA) ergic signaling and the glucocorticoid receptor (GR)
Summary
Striatal involvement in spatial learning is well-documented (Luine and Hearns, 1990; Lavoie and Mizumori, 1994; McDonald and White, 1994; Packard and Teather, 1997; Gengler et al, 2005). Torromino et al (2019) found the cross-regional communication between hippocampus and the ventral striatum to play a critical role in spatial memory formation in mice after water maze training. Because of the small body of literature regarding age and cognition related effects upon gene expression in the striatum, we combined both aspects in the present study. We compared young males with aged ones and divided the latter into bad (OMB) and good (OMG) performers, similar as in the study of De Risi et al (2020) in mice. This approach provides information about age effects and should reveal mechanisms of cognitive maintenance during aging. The here presented results may be of interest for other researchers in the field
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