IMPACT OF NOREPINEPHRINE ON ADULT NEUROGENESIS

Endogenous regeneration of neuronal tissue by adult neurogenesis provides a promising treatment strategy for neurodegenerative diseases. Interestingly, adult neuronal stem cells are located along the entire ventricular system, however, their proliferative activity appears to be repressed by many factors. This study aims to determine whether norepinephrine (NE), which originates from the locus coeruleus (LC), acts as regulator of neural stem cell activity and adult neurogenesis.

Therefore, we established an inducible, conditional knockout mouse model (icKO), based on a floxed dopamine-β-hydroxylase (DbH) gene and the tamoxifen-inducible CreERT2 driven by Camk2a promoter. IcKO verification was done by DbH staining. LC neuron integrity was verified by NET and DAT staining. Six and twelve weeks after knockout induction, adult neurogenesis was verified by EdU, BrdU, Pax6, and Nestin staining. In addition, changes in behavior related to cognition, anxiety, and hedonia were examined.

Tamoxifen-treated mice displayed a significant loss of DbH expression in the LC and showed elevated body temperature and food intake. Further, the number of BrdU⁺ and EdU⁺ cycling cells in the dentate gyrus and third ventricle was significantly enhanced in icKO mice. While behavioral tests revealed no changes in cognition or hedonia, the icKO mice from both cohorts showed increased anxiety as they spent more time in safer zones.

Together, we established the first inducible knockout mouse model for NE reduction. Our results indicate a modulatory role of NE in adult neurogenesis, and our model provides a valuable tool for future studies investigating the suppressive effect of NE on adult stem cells.