Spectral components of abnormal spontaneous gamma activity in schizophrenia and translational mouse models - spontaneous activity in the gamma band (~30-100 HZ) of the electroencephalogram has been…

This federal Project Grant award from the National Institute of Mental Health (NIMH), under the Mental Health Research Grants program (CFDA 93.242), provides $128,000.00 to the Boston VA Research Institute, Inc. to investigate the spectral components of abnormal spontaneous gamma activity in schizophrenia and translational mouse models. The research aims to better understand the neural mechanisms underlying spontaneous gamma activity, which has been used as an index of excitation-inhibition balance in studies of neuropsychiatric disorders. The project will analyze whether alterations in spontaneous gamma activity in schizophrenia are primarily due to changes in gamma bursts or other aspects of the power spectrum. This 2-year project, scheduled to run from April 1, 2025 to March 31, 2027, will build upon the researchers' prior findings that increased spontaneous gamma activity in schizophrenia was most closely related to increased power of gamma bursts.

Spectral components of abnormal spontaneous gamma activity in schizophrenia and translational mouse models - spontaneous activity in the gamma band (~30-100 HZ) of the electroencephalogram has been related to the balance of excitation to inhibition (e/i) in the cortex (sohal & rubenstein, 2019). Manipulations of e/i balance by means such as optogenetic stimulation of pyramidal cells or inhibitory interneurons (e.g., yizhar ET AL., 2011), and blockade of n-methyl-d-aspartate receptors (nmdars) on parvalbumin-expressing inhibitory interneurons (e.g., carlén ET AL., 2012) or pyramidal cells (tatard-leitman ET AL., 2015), have been shown to alter the degree of spontaneous gamma activity (SGA). As such, SGA has come to be used as an index of e/i balance in studies of neuropsychiatric disorders (e.g., hirano ET AL., 2015; picard ET AL., 2019). However, the neural mechanisms underlying SGA have received relatively little focus. Recent research has suggested that some kinds of neural activity that appear to be constant across time and/or frequency are actually composed of brief bursts of oscillations that occur at different times and frequency bands across trials (e.g., jones, 2016). Furthermore, there is evidence that these oscillatory bursts play functional roles in information processing (e.g., lundqvist ET AL., 2016). However, the extent to which alterations in SGA are due to changes in gamma bursts or other aspects of the power spectrum are unknown. Previously we reported that SGA was increased in individuals with schizophrenia (SZ) compared to healthy controls during auditory steady-state stimulation (hirano ET AL., 2015). Further analyses revealed that increased SGA in SZ was most closely related to the increased power of gamma bursts (spencer ET AL., 2023). Thus, alterations in SGA could reflect changes in particular aspects of gamma-generating circuits, which might be attributable to specific neural circuit abnormalities and information processing mechanisms. We will analyze previously collected data from humans and mice in our laboratories to further investigate how components of SGA might be altered in SZ and in optogenetic and pharmacological manipulation of cortical e/i balance in mice. Our specific aims are: aim 1: to determine if increased SGA in the ketamine and BF optogenetic models is due to the same changes in SGA components as increased SGA in SZ. We will decompose SGA in the mouse baseline state during ketamine administration and BF PV stimulation into burst parameters and spectral slope. We predict that increased SGA will be primarily associated with increased gamma burst power and not other measures. Aim 2: to determine if cognitive deficits in SZ and in mice during BF PV neuron stimulation are similarly associated with increased SGA and gamma burst power. We will decompose SGA in human visual oddball task data and in the novel object recognition task (nort) in mice. We predict that reduced performance in the oddball task in SZ and in the nort in mice during BF PV neuron stimulation will be associated with increased SGA, primarily because of increased gamma burst power.