Genetic Ablation of Neural Progenitor Cells Impairs Acquisition of Trace Eyeblink Conditioning

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 used nestin-HSV-TK 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 4 weeks, mice were trained on trace eyeblink conditioning, 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.

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning

“…Doublecortin is associated with levels of neurogenesis, which has a well-documented role in learning (Miller, Weiss, and Disterhoft 2019;Dalla et al 2009;Deng, Aimone, and Gage 2010). Levels of doublecortin were significantly lower in intact microdrive females and dummy drive females compared to headbolt females.…”

Sex Differences in the Spatial Behavior Functions of Adult-Born Neurons in Rats

“…To date, sex differences in function have gone largely undetected because few studies have compared male and female animals that have altered neurogenesis. In our recent analysis of the literature ( Knudson et al, 2022 ), we counted only four functional studies that have reported data by sex or included sex as a variable in their statistical analyses ( Huckleberry et al, 2018 ; Seib et al, 2018 ; Miller et al, 2019 ; Cope et al, 2020 ). Very recently, two studies have identified functional differences in male and female rodents that lack adult neurogenesis.…”

Discerning state estimation and sensory gating, two presumptive predictive signals in mouse barrel cortex

“…5A). Layering information was extracted from the CSD data based on the well corroborated fact that the CSD signal at a fixed latency of 5-10 ms after a pulse-like whisker deflection is known to show two sinks, one centered on L4, the other on the border of L5 and L6 (=L5/6) 25,26 . We did not find any depth profile of the specific ranking of stimulus types.…”