Neuronal PAS domain 1 identifies a major subpopulation of wakefulness- promoting GABAergic neurons in the basal forebrain

• 成果类型: Article
• 署名作者: Troppoli, Timothy A.; Yang, Chun; Katsuki, Fumi; Uygun, David S.; Lin, Ilyan; Aguilar, David D.; Spratt, Tristan; Basheer, Radhika; Mcnally, James M.; Chan, C. Savio; Mckenna, James T.; Brown, Ritchie E.
• 署名单位: Harvard University; Harvard University Medical Affiliates; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Boston Healthcare System; Harvard University; Harvard Medical School; Northwestern University; Feinberg School of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11161
• DOI: 10.1073/pnas.2321410121
• 发表日期: 2024-05-21
• 关键词: parvalbumin neurons; globus-pallidus; activation; afferents; thalamus; circuit; npas1

摘要

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (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, five to six 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 period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow - wave and sigma 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.