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Increases in broadband cortical electroencephalogram (EEG) power in the gamma band (30-80 Hz) range have been observed in schizophrenia patients and in mouse models of schizophrenia. They are also seen in humans and animals treated with the psychotomimetic agent ketamine. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. Here we report that tonic optogenetic manipulation of an ascending arousal system bidirectionally tunes cortical broadband gamma power, allowing on-demand tests of the effect on cortical processing and behavior. Constant, low wattage optogenetic stimulation of basal forebrain (BF) neurons containing the calcium-binding protein parvalbumin (PV) increased broadband gamma frequency power, increased locomotor activity, and impaired novel object recognition. Concomitantly, task-associated gamma band oscillations induced by trains of auditory stimuli, or exposure to novel objects, were impaired, reminiscent of findings in schizophrenia patients. Conversely, tonic optogenetic inhibition of BF-PV neurons partially rescued the elevated broadband gamma power elicited by subanesthetic doses of ketamine. These results support the idea that increased cortical broadband gamma activity leads to impairments in cognition and behavior, and identify BF-PV activity as a modulator of this activity. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity.

Sleep-wake scoring is a time-consuming, tedious but essential component of clinical and pre-clinical sleep research. Sleep scoring is even more laborious and challenging in rodents due to the smaller EEG amplitude differences between states and the rapid state transitions which necessitate scoring in shorter epochs. Although many automated rodent sleep scoring methods exist, they do not perform as well when scoring new data sets, especially those which involve changes in the EEG/EMG profile. Thus, manual scoring by expert scorers remains the gold-standard. Here we take a different approach to this problem by using a neural network to accelerate the scoring of expert scorers. Sleep-Deep-Net (SDN) creates a bespoke deep convolution neural network model for individual electroencephalographic or local-field-potential records via transfer learning of GoogleNet, by learning from a small subset of manual scores of each EEG/LFP record as provided by the end-user. SDN then automates scoring of the remainder of the EEG/LFP record. A novel REM scoring correction procedure further enhanced accuracy. SDN reliably scores EEG and LFP data and retains sleep-wake architecture in wild-type mice, in sleep induced by the hypnotic zolpidem, in a mouse model of Alzheimer's disease and in a genetic knock-down study, when compared to manual scoring. SDN reduced manual scoring time to 1/12. Since SDN uses transfer learning on each independent recording, it is not biased by previously scored existing data sets. Thus, we find SDN performs well when used on signals altered by a drug, disease model or genetic modification., Competing Interests: Competing interests: Authors declare no competing interests.

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., Significance Statement: 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.