Abstract
Adult-born neurons are believed to play a role in memory formation by providing enhanced plasticity to the hippocampus. Past studies have demonstrated that reduction of neurogenesis impairs associative learning, but these experiments used irradiation or neurotoxic substances, which may have had unintended off-target effects. Therefore, to investigate the role of these adult-born neurons more precisely, we utilized C57BL/6-Tg(Nes-TK*,-EGFP)145Sker transgenic mice (Nes-TK) to selectively ablate newborn neurons. Nes-TK mice were fed a chow infused with valganciclovir to induce the ablation of neural progenitor cells. After being on this diet for four weeks, subjects were trained on trace eyeblink conditioning (tEBC), a hippocampus-dependent temporal associative memory task. Following the completion of training, brain sections from these animals were stained for doublecortin, a marker for immature neurons, to quantify levels of neurogenesis. We found that male transgenic mice on valganciclovir had significantly decreased amounts of doublecortin relative to male control animals, indicating a successful reduction in levels of neurogenesis. In conjunction with this reduction in neurogenesis, the male transgenic mice on valganciclovir learned at a significantly slower rate than male control mice. The female Nes-TK mice on valganciclovir showed no significant decrease in neurogenesis and no behavioral impairment relative to female control mice. Ultimately, the results are consistent with, and expand upon, prior studies that demonstrated that adult-born neurons are involved in the formation of associative memories. This study also provides a foundation to continue to explore the physiological role of newborn neurons with in vivo recordings during behavioral training.
Significance Statement Newborn neurons in the adult brain have been shown to be involved in associative learning, but many prior studies illustrating this point used neurotoxins or irradiation to ablate newborn neurons, which may have had unintended off-target effects. Therefore, we utilized a transgenic mouse model to eliminate adult-born neurons in a more controlled, precise manner. Ultimately, we demonstrate that reduction of neurogenesis leads to an impairment in learning in males, and that levels of neurogenesis are associated with rate of learning and overall performance on trace eyeblink conditioning.
Footnotes
Authors report no conflict of interest.
This study was supported by the NIH though grants RF1 AG017139 and R37 AG008796 to JFD. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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