Hamilton G F, Majdak P, Miller D S, Bucko P J, Merritt J R, Krebs C P, Rhodes J S
Department of Psychology, The Beckman Institute, 405N Mathews Ave, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Brain Plast. 2015;1(1):83-95. doi: 10.3233/BPL-150011.
New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and "hybrid vigor"). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice ( = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice ( = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.
成年海马体中会持续产生新的神经元，但其功能仍是个谜。巢蛋白胸苷激酶（nestin-TK）转基因方法已被用于选择性和条件性减少神经发生，以测试新神经元在学习、记忆和运动表现中的功能意义。在此，我们在混合遗传背景下探究了nestin-TK模型（以增加杂合性和“杂种优势”）。将转基因C57BL/6J（B6）与129S1/SvImJ（129）杂交，产生杂交后代（F1），其基因组的B6一半携带由修饰的巢蛋白启动子调控的单纯疱疹病毒胸苷激酶（TK）转基因。在给予外源性缬更昔洛韦的情况下，表达TK的新神经元会发生凋亡。雌性B6 nestin-TK小鼠（n = 80）被评估神经发生减少情况作为阳性对照。雄性和雌性F1 nestin-TK小鼠（n = 223）被用于确定神经发生减少对莫里斯水迷宫（MWM）和转棒试验的影响。所有小鼠接受溴脱氧尿苷（BrdU）注射以标记分裂细胞，并给予缬更昔洛韦或对照饲料，有或没有转轮，持续30天。F1和B6背景均显示神经发生减少约50%，这种差异并未损害在MWM上的学习和记忆或转棒试验表现。跑步增强了神经发生和转棒试验表现，但对MWM没有影响，这表明F1背景可能不适合研究运动对MWM的促认知作用。可能需要更大程度地减少神经发生才能观察到行为影响。或者，新神经元可能在学习中不发挥关键作用，或者现有神经元中的补偿机制可能掩盖了缺陷。需要使用这些及其他选择性减少神经发生的模型进行进一步研究，以确定成年海马体神经发生在行为中的功能意义。
