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

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

Lisa N Miller et al. eNeuro.

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.

Keywords: dentate gyrus; learning; memory; neurogenesis; trace eyeblink conditioning.

Figures

Figure 1.
Figure 1.
Trace eyeblink conditioning in mice. A, EMG activity from an animal trained on tEBC (bottom trace), depicting a well timed CR. The timing of the CS (whisker vibration) and US (air puff) presentation are shown at the top of the panel. B, C, Learning curves for the male (B) and female (C) control and experimental groups. Average percentage CRs are shown for each day, where “H” refers to days of habituation and “T” refers to days of training. Error bars represent the SEM. Post hoc t tests were used to test statistical differences for each day of training (*p < 0.05; **p < 0.01).
Figure 2.
Figure 2.
Measuring neurogenesis in the adult brain. A, B, Sample images of DCX expression in DG in sections from a male control animal (A) and a male experimental animal (B). C, Zoomed in views of DCX+ cells from A and B (left and right, respectively). D, Quantification of the number of DCX+ cells within the granule cell layer, expressed as the number of cells per cubic micrometer. The male experimental group (n = 13) showed a significant decrease relative to the male control group (n = 11; **p < 0.01). There was no significant difference between the female experimental group (n = 5) and the female control group (n = 6; p > 0.05). Error bars represent the SEM. Scale bars: B, 100 µm; C, 50 µm.
Figure 3.
Figure 3.
The amount of neurogenesis is correlated with learning in male mice. A, C, The number of DCX+ cells per micrometer of DG is positively correlated with the average percentage of CRs across all 10 d of training for males (A; r = 0.574, p = 0.0027), but not females (C; r = −0.025, p = 0.943). B, D, The number of DCX+ cells per cubic micrometer of DG is negatively correlated with the number of trials it took to show six CRs within a sliding block of 10 trials for males (B; r = −0.519, p = 0.0121), but not for females (D; r = 0.102, p = 0.77).

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