Normalization of the accumbal cell type-specific transcriptomic signatures and anxiety-like behaviour following treatment with a mitochondrial booster in outbred rats

The nucleus accumbens (NAc), a central hub in reward processing, intricately modulates emotional behaviours, including anxiety. A compound derived from the metabolization of polyphenols by the microbiota, mitobooster (MB) has been previously shown to improve mitochondrial function by promoting turnover of the dysfunctional mitochondria. In this study, we aimed to understand the effect of MB treatment in outbred rats that show high anxious-like behaviour. First, animals were grouped by their trait anxiety based on the amount of time spent in the open arms in the elevated plus maze test, and these results were corroborated by the open field/novel object test. Then, the nucleus accumbens of the high-, low-anxious (HA and LA), and HA rats treated with MB (HAUA) were collected, homogenized, and subjected to snRNA-seq in the 10x Chromium Platform. Our analysis revealed distinct transcriptional signatures associated with HA and LA rats. Notably, across many cell types ranging from the medium spiny neurons (MSNs) to glia, MB treatment resulted in the widespread normalization of genes differentially expressed in HA vs LA, to LA-like levels. Furthermore, in silicoanalysis revealed several mitochondrial and dendrite arborization-related pathways co-dysregulated in the MSNs of HA and reverted in HAUA. Together, our data underscore the robust transcriptional changes in the NAc of the HA rats upon MB treatment and implicates several cellular pathways in the mitigation of the anxiety-like behaviour.