Dynamic changes in Ccn3 expression across the limbic forebrain through the mouse estrous cycle and during lactation

Cellular communication network factor 3 (CCN3), also known as nephroblastoma overexpressed (NOV), is an adipocytokine that has recently been suggested to be secreted selectively by hypothalamic arcuate nucleus kisspeptin (ARN^KISS) neurons to protect bone density during lactation. Using RNAscope hybridization, we have examined the expression of Ccn3 transcripts in the forebrain of male mice and female mice across the estrous cycle and during lactation. Transcripts for Ccn3 are highly expressed in the cerebral cortex, hippocampus, subthalamic nucleus, and amygdala in both sexes. Lower levels of Ccn3 mRNA were detected within the hypothalamus of females but not males. During lactation (day 11), a substantial 6-fold increase in the numbers of cells expressing Ccn3 mRNA was found in the arcuate and dorsomedial nuclei of the hypothalamus as well as the posterodorsal division of the medial amygdala. Approximately 50% of cells expressing Ccn3 in the ARN during lactation also contained Kiss1 transcripts. An increase in Ccn3 mRNA expression in ARN^KISS neurons also occurred during proestrus. These observations demonstrate that multiple limbic brain regions and cell types coordinately up-regulate their expression of Ccn3 during lactation in the mouse.