Troppoli Timothy A, Yang Chun, Katsuki Fumi, Uygun David S, Lin Ilyan, Aguilar David, Spratt Tristan, Basheer Radhika, McNally James M, Chan C Savio, McKenna James T, Brown Ritchie E
bioRxiv. 2023 Nov 11:2023.11.09.566065. doi: 10.1101/2023.11.09.566065.
Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1 neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1 neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1 neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1 neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1 neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1 neurons in stress responsiveness, the anatomical projections of BF Npas1 neurons and the effect of activating them suggest a possible role for BF Npas1 neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF.
We characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1 neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1 neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1 neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.
在此，我们描述了一组新的基底前脑（BF）神经元，它们表达神经元PAS结构域1（Npas1），这是一种与神经精神疾病相关的发育转录因子。对Npas1-cre-2A-tdTomato小鼠进行免疫组织化学染色显示，BF Npas1神经元与研究充分的小白蛋白或胆碱能神经元不同。在GAD67-GFP基因敲入小鼠中进行的Npas1染色证实，绝大多数Npas1神经元是γ-氨基丁酸能（GABAergic）的，在vGlut1-cre-tdTomato或vGlut2-cre-tdTomato小鼠中与谷氨酸能神经元的共定位极少。Npas1神经元的密度很高，是相邻胆碱能、小白蛋白或谷氨酸能神经元的5至6倍。顺行示踪确定了BF Npas1神经元向参与睡眠-觉醒控制、动机行为和嗅觉的脑区有显著投射，如外侧下丘脑、外侧缰核、伏隔核壳、腹侧被盖区和嗅球。在光照（非活动）期对BF Npas1神经元进行化学遗传激活，可使觉醒量增加，睡眠潜伏期延长2至3小时，这是由于长觉醒时段增加和短非快速眼动（NREM）睡眠时段增加所致。非快速眼动慢波（0 - 1.5赫兹）和西格玛波（9 - 15赫兹）功率以及睡眠纺锤波密度、振幅和持续时间均降低，这与在几种神经精神疾病中的发现相似。结合先前有关BF Npas1神经元参与应激反应的研究结果，BF Npas1神经元的解剖投射以及激活它们的效果表明，BF Npas1神经元在动机驱动的觉醒和应激性失眠中可能发挥作用。鉴定出BF GABA能神经元的这一主要亚群将有助于研究它们在睡眠障碍、痴呆和其他涉及BF的神经精神疾病中的作用。
我们对小鼠中一组表达神经元PAS结构域1（Npas1）的基底前脑（BF）神经元进行了表征描述，Npas1是一种与神经精神疾病相关的发育转录因子。BF Npas1神经元是GABA能神经元的一个主要亚群，与胆碱能、小白蛋白或谷氨酸能神经元不同且数量更多。BF Npas1神经元靶向参与觉醒、动机和嗅觉的脑区。在光照（非活动）期激活BF Npas1神经元会因长觉醒时段增加而使觉醒增加和睡眠潜伏期延长。非快速眼动睡眠慢波和纺锤波减少，这与在几种神经精神疾病中的发现相似。鉴定出BF GABA能促觉醒神经元的这一主要亚群将有助于研究它们在失眠、痴呆和其他涉及BF的疾病中的作用。
