Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
Nat Commun. 2024 Aug 26;15(1):7342. doi: 10.1038/s41467-024-51707-w.
Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.
乙酰胆碱通过广泛的胆碱能神经支配调节各种认知功能。然而，识别记忆背后特定的胆碱能亚群、回路和分子机制在很大程度上仍是未知的。在这里，我们发现，孤啡肽受体（Ngfr）阳性胆碱能神经元在脑桥被盖区/内侧基底前脑（nBM）-前额叶皮质（mPFC）的中缝核/斜角带核（MS）-海马通路选择性地参与了近因判断。神经生长因子受体（Ngfr）缺失减少了 SI/nBM-mPFC 回路中胆碱能神经元的兴奋性，但不减少 MS-海马通路中的胆碱能神经元兴奋性，导致近因判断受损，但不影响新物体和物体位置识别。在 Ngfr 神经元中表达 Ngfr 恢复了近因判断的缺陷。光纤光度测定显示，mPFC 中的乙酰胆碱释放不仅预测了物体的出现，还介导了物体的近因判断，而 Ngfr mPFC 中没有这种乙酰胆碱释放。在 ChAT-Cre 小鼠中，通过化学遗传学和光遗传学抑制 SI/nBM 投射到 mPFC，会减少 mPFC 中的乙酰胆碱释放，并使近因识别受损。胆碱能活性的损伤导致 GABA 能传入到 mPFC 锥体神经元的去极化转移，这是由于 KCC2 介导的氯离子梯度紊乱造成的。最后，增强乙酰胆碱信号转导会增加 KCC2 的水平，恢复 GABA 能驱动并挽救 Ngfr 小鼠的近因识别缺陷。因此，NGFR 依赖性的 SI/nBM-mPFC 胆碱能回路是近因识别记忆的基础。
