Letsinger Ayland C, Nacer Samir A, Stevanovic Korey D, Larson Gary J, DeFilipp Jemma S, Cushman Jesse D, Yakel Jerrel L
Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, United States.
Social & Scientific Systems, Inc., a DLH Holdings Corp. Company, Durham, NC, United States.
Front Neurosci. 2023 Sep 7;17:1244118. doi: 10.3389/fnins.2023.1244118. eCollection 2023.
Neurogenesis within the dentate gyrus is thought to play an important role in cognitive processes such as reversal learning and pattern separation. The α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed early in newly formed granule cells of the dentate gyrus, though its role in neurogenesis and related cognitive function is not fully understood.
To better characterize relevant function of α7 nAChRs, we performed unbiased stereology to quantify hippocampal granule cells, pyramidal cells, and total volume and used a touchscreen operant spatial discrimination/reversal task to test pattern separation in a global α7 nAChR knockout mouse line.
The knockout resulted in an ≈22% reduction in granule cells and a ≈ 20% reduction in pyramidal cells in both sexes, with no change in total hippocampal volume. However, the knockout impaired performance in the touchscreen task for males only. The sex-dependent difference in behavioral, but not stereological, results suggest a divergence in the structure-function relationship in males versus females. Detailed analyses revealed males were more biased by the initial reversal contingency relative to females indicating a potential source of the sex-specific interaction with the loss of α7 nAChRs.
These findings argue that the α7 nAChR plays a critical role in hippocampal development, not just granule cell neurogenesis, and plays a sex-dependent role in cognitive function.
齿状回内的神经发生被认为在诸如逆向学习和模式分离等认知过程中发挥重要作用。α7烟碱型乙酰胆碱受体（α7 nAChR）在齿状回新形成的颗粒细胞中早期表达，但其在神经发生及相关认知功能中的作用尚未完全明确。
为更好地表征α7 nAChRs的相关功能，我们采用无偏立体学方法对海马颗粒细胞、锥体细胞及总体积进行定量，并使用触屏操作性空间辨别/逆向任务来测试全球α7 nAChR基因敲除小鼠品系中的模式分离。
基因敲除导致两性颗粒细胞减少约22%，锥体细胞减少约20%，海马总体积无变化。然而，基因敲除仅损害了雄性小鼠在触屏任务中的表现。行为学结果而非立体学结果中的性别差异表明，雄性与雌性在结构-功能关系上存在差异。详细分析显示，相对于雌性，雄性在初始逆向偶然性方面的偏差更大，这表明α7 nAChRs缺失导致的性别特异性相互作用存在潜在来源。
这些发现表明，α7 nAChR在海马发育中起关键作用，不仅在颗粒细胞神经发生中起作用，而且在认知功能中起性别依赖性作用。
