Abstract

A neural signature of temperament: unique and shared features in the hippocampus and nucleus accumbens of selectively bred rats that differ in exploration, anxiety, and addiction

Hebda-Bauer EK, Hagenauer MH, Khalil H, Watson SJ, Palmer AA, Li J, Akil H
53rd Annual Meeting of the Society for Neuroscience. 2024.

Selective breeding of rats for high and low propensity to explore a novel environment has produced two rat lines with highly divergent behaviors: bred Low Responders (bLR) are extremely inhibited and anxious in a novel environment, whereas bred High Responders (bHR) are exploratory and sensation-seeking. These traits map onto temperament extremes predictive of externalizing and internalizing psychiatric disorders and model two paths to drug use. Examining gene regulation in hippocampus (HPC) and nucleus accumbens (NAcc)--two brain areas involved in temperament, stress reactivity, and reward processing--in the bHR/bLR model will help elucidate molecular correlates of individual differences in vulnerability to psychiatric and addictive behaviors. We performed RNAseq/ATACseq in NAcc (N=40) and RNAseq in HPC (N=24) from two generations of adult male and female bHR and bLR animals. Selective breeding produced a robust molecular phenotype, showing greater differential gene expression associated with bHR/bLR lineage than with sex. This differential gene expression is more pronounced in NAcc (N=1,820 genes, FDR<0.05) obtained from a later generation than HPC (N=144 genes, FDR<0.05). Gene set enrichment analysis revealed both unique and common gene sets between brain areas when comparing bHRs to bLRs. In bHRs, neurons are enriched in HPC, while oligodendrocytes are enriched in NAcc; growth/proliferation pathways are upregulated in HPC, while phospholipid metabolic processes are upregulated in NAcc. In bLRs, microglia-related pathways are enriched in both brain areas, plus energy regulation, mitochondria, and immune-related pathways. In contrast, metabolism pathways are upregulated in HPC, while secretory pathways are upregulated in NAcc of bLRs. Regions of differentially accessible chromatin between bHRs and bLRs are being identified in NAcc. Notably, increased gene expression of synuclein gamma (Sncg) in bLRs vs bHRs (FDR=0.017) is coupled with increased chromatin accessibility (p<0.006) in NAcc. The correlation between Sncg gene expression and the ATAC-Seq peak height (R2=0.61, p=4.688e-09) reveals a dichotomy among the bLRs such that half show similar gene regulation to that of the bHRs while the other half show a higher gene expression and chromatin accessibility. Implications of this bimodal distribution of Sncg among the bLRs will be explored further. In addition to gene regulation differences in the NAcc, our findings elucidate common and unique gene expression patterns in two brain areas involved in shaping temperament differences contributing to externalizing and internalizing behaviors inherent in psychiatric disorders.