Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia

• Published in: Molecular psychiatry 2021-07, Vol.26 (7), p.3461-3475
• Main Authors: McNally, James M., Aguilar, David D., Katsuki, Fumi, Radzik, Leana K., Schiffino, Felipe L., Uygun, David S., McKenna, James T., Strecker, Robert E., Deisseroth, Karl, Spencer, Kevin M., Brown, Ritchie E.
• Format: Article
• Language: English
• Subjects: 631/1647; 631/378; 631/443; 64/60; Animal models; Animals; Arousal; Auditory stimuli; Basal forebrain; Basal Forebrain - metabolism; Behavioral Sciences; Biological Psychology; Brain; Calcium-binding protein; Cerebral cortex; Cognition; Complications and side effects; Drug therapy; EEG; Electric properties; Electroencephalography; Forebrain; Health aspects; Humans; Ketamine; Locomotor activity; Medicine; Medicine & Public Health; Mental disorders; Methods; Mice; Neurons; Neurosciences; Optogenetics; Parvalbumin; Parvalbumins - metabolism; Pattern recognition; Pharmacotherapy; Physiological aspects; Psychiatry; Schizophrenia; Schizophrenia - genetics
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-020-0840-3

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.