Abstract
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.
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Acknowledgements
We would like to dedicate this paper to Dr Robert W. McCarley, who passed away on May 27th, 2017. The authors are deeply grateful for his support and his encouragement to test the ideas presented in this study, which were informed by his studies of patients with schizophrenia. The work was supported by grants from VA Biomedical Laboratory and Clinical Science Research and Development Service Awards: VA CDA IK2BX002130 (JMM), IK2BX004905 (DSU), and Merit Awards I01BX004500 (JMM), I01 BX004673 (REB), I01BX001356 (REB), I01 CX001443 (KMS), I01BX002774 (RES), NIH support from R01-MH039683 (REB), R01-MH093540 (KMS), R21-NS079866 (REB), R21-NS093000 (REB), T32-MH016259 (DDA), T32-HL007901(FLS, FK & DSU), F32-MH119838 (FLS), and P01-HL095491(RES), and the SURE fellowship program, Stonehill College (LKR). JMM, JTM, DSU, KMS, and REB are Research Health Scientists at VA Boston Healthcare System. The contents of this work do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
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The authors declare that they have no conflict of interest. JTM received partial salary compensation and funding from Merck MISP (Merck Investigator Sponsored Programs) but has no conflict of interest with this work.
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McNally, J.M., Aguilar, D.D., Katsuki, F. et al. Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia. Mol Psychiatry 26, 3461–3475 (2021). https://doi.org/10.1038/s41380-020-0840-3
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DOI: https://doi.org/10.1038/s41380-020-0840-3
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