Dentate neurogenesis mediates cognitive flexibility via modulation of the hippocampal longitudinal-axis network

Adult neurogenesis provides the hippocampus with significant neuroplasticity, supporting its involvement in complex functions, including cognitive flexibility. However, it remains unclear how these relatively sparse newborn neurons (NBNs) affect brain activity and regulate behavior. In this study, we silenced young NBNs (2-5 weeks old) non-invasively in a newly generated transgenic mouse model (NBN-TeTX) in which tetanus toxin is expressed in NBNs and confirmed their contribution to cognitive flexibility using the Morris water maze reversal learning and an operant learning Go/NoGo task. fMRI during the NoGo task revealed altered activity across the hippocampal longitudinal networks in the NBN-TeTX mice, while restingstate fMRI indicated that NBNs also contributed to inverse dorso-ventral inter-hippocampal correlations. Further investigation of the dentate gyrus excitation-inhibition circuits revealed that silencing young NBNs reduced parvalbumin (PV) expression in inhibitory basket cells but increased c-Fos expression in excitatory mossy cells, suggesting that NBNs contribute to local signal-to-noise ratio maintenance. This plasticity in the hippocampal longitudinal-axis network mediated by young NBNs may contribute to cognitive flexibility. Highlights ### Competing Interest Statement The authors have declared no competing interest.