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

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 bi-directionally 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.

Network asynchrony underlying increased broadband gamma power

“…Increased spontaneous broadband gamma oscillations have also been demonstrated in other mouse models of PV neuron dysfunctions (del Pino et al, 2013;Cho et al, 2015), and in individuals with schizophrenia (Mathalon and Sohal, 2015;Grent-'t-Jong et al, 2018). Further, administration of NMDAR antagonists such as ketamine (Pinault, 2008;Hakami et al, 2009;Kulikova et al, 2012;Caixeta et al, 2013;Picard et al, 2019;Lopes-Aguiar et al, 2020;Mahdavi et al, 2020;McNally et al, 2020), or MK-801 (Carlén et al, 2012;Molina et al, 2014;Hudson et al, 2020), is associated with increased power in spontaneous broadband gamma oscillations in both anesthetized and awake rodents, and also in humans (Rivolta et al, 2015). Importantly, lack of NMDAR in PV neurons blunts this response (Carlén et al, 2012;Picard et al, 2019;Hudson et al, 2020), confirming that cortical PV interneurons are a central target of NMDAR antagonists.…”

Basal forebrain parvalbumin neurons modulate vigilant attention

“…However, the role of other neurochemically defined BF subtypes is unknown. Recent work has shown that one population of BF GABAergic neurons containing the calcium-binding protein parvalbumin (PV) control cortical fast oscillations and arousals from sleep [16][17][18][19] but their role in awake behavior is unclear. Thus, here we test the hypothesis that BF-PV neurons modulate vigilant attention in mice.…”

“…After establishing stable baseline performance (<10% change in mean session reaction time across three consecutive sessions), mice (N=6) were tested under each of three conditions: ChR2 (1s, 5mW continuous BF-PV excitation beginning 0.5s prior to cue light onset; Bilateral, brief and continuous low-wattage BF-PV excitation was used to enhance activity of BF-PV neurons without attempting to drive specific firing rate frequencies. Moreover, brief excitation closely timed to stimulus onset was used since prolonged (>30s) continuous BF-PV excitation disrupts performance in other tasks 18 .…”

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

“…EEG epochs were extracted around the investigation time, and gamma power (25-58Hz) was examined immediately after investigation onset vs a 4s "baseline" (0-4s pre-stimulus). This frequency range was selected because our preliminary data and previous studies [28] identified investigation-induced increases in 25-58Hz power, and this frequency range may signify top-down predictive coding in spatial working memory tasks [29]. Grand averages were taken across all epochs from all animals for each respective genotype after normalization.…”