Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation

Abstract

Cholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviors. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin releasing factor, opioids, insulin and leptin, which can influence animal behavior by signaling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridization on mouse striatal tissue to characterize the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1), and corticotropin releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the striatum, we found that female mice have more Chat mRNA-expressing neurons than males. At the population level, we observed a sexually dimorphic distribution of Esr1- and Crhr1-expressing ChIs in the ventral striatum that demonstrates an antagonistic correlational relationship, which is abolished by ovariectomy. Only in the NAc did we find a significant population of ChIs that co-express Crhr1 and Esr1. At the cellular level, Crhr1 and Esr1 transcript levels were negatively correlated only during estrus, indicating that changes in sex hormones levels can modulate the interaction between Crhr1 and Esr1 mRNA levels. Together, these data provide evidence for the unique expression and interaction of Esr1 and Crhr1 in ventral striatal ChIs, warranting further investigation into how these transcriptomic patterns might underlie important functions for ChIs at the intersection of stress and reproductive behaviors.

Oxytocin receptor function regulates neural signatures of pair bonding and fidelity in the nucleus accumbens

“…We recently demonstrated that loss of Oxtr unmasks sex differences in gene expression in the NAc that are not found in wild-type animals 20 . Thus, the absence of Oxtr signaling during development may also contribute to the differences we observed in patterns of activity in the NAc between male and female Oxtr 1-/- voles 51–57 . Alternatively, or in combination, such sex differences in the NAc may arise from Oxtr-regulated inputs to this region that differ between males and females 3,4,58–61,67–69 .…”