Indiana CTSI Predoctoral Training Award PHS (NCCR) Grant No: TL1RR02575

1. MTP Steady-State Auditory Evoked Potentials in the Neonatal VentralHippocampal Lesion Rat Model of Schizophrenia PLF Jenifer L. Vohs, CTSI Predoctoral Fellow1 Sandra L. Morzorati, PhD2 R. Andrew Chambers, MD2 Brian F. O’Donnell, PhD1 Giri P. Krishnan1 1Indiana University, Dept. Psychological and Brain Sciences 2Indiana University School of Medicine, Psychiatry RESULTS BACKGROUND • Disrupted synchronization of neural processes is considered a potential mechanism of schizophrenia • Patients with schizophrenia have specific synchronization disturbances within the gamma frequency range (30-80 Hz) • By stimulating neural networks at a given frequency, steady-state auditory evoked potentials (SSAEPs) are elicited in the EEG • SSAEPs enable the examination of the functional state of neural circuits supporting synchronization • The neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia provides a valuable tool to test potential mechanisms of the disorder, but must be characterized to ensure it is an appropriate model for the implemented paradigm • This is the first study to characterize SSAEP disturbances in the NVHL rat model of schizophrenia Mean Trial Power (MTP) across frequency of stimulation. SHAM N = 8 NVHL N = 7 10 Hz RESULTS 20 Hz • MTP: Effect of frequency (F(6,78)= 8.16, pη2 = .39, p < .001) & group X frequency interaction (F(6,78)= 3.20, pη2 = .20, p = .007); follow-up effects at 50 (F(1,15)= 5.11, pη2 = .28, p = .04) and 70 (F(1,15)= 8.71, pη2 = .40, p = .01) Hz • PLF: Effect of frequency (F(6,78)= 6.28, pη2 = .33, p < .001) & group X frequency interaction (F(6,78)= 3.67, pη2 = .22, p = .003); follow-up effects of group at 50 (F(1,15)= 3.41, pη2 = .23, p = .05) & 70 (F(1,15)= 8.27, pη2 = .39, p = .01) Hz 30 Hz 40 Hz CONCLUSIONS 50 Hz • The gamma frequency band deficit observed in NVHL rats is similar to gamma deficit observed in patients with schizophrenia. • Reduced gamma band activity in NVHL rats suggests developmental lesioning of the ventral hippocampi alters the response characteristics of neural networks in the rat temporal cortex. • SSAEPs in the NVHL model provide a viable assay to test potential mechanisms of parallel disturbances in human schizophrenia. • Future studies of SSAEPs in the NVHL model, which examine mechanistic hypotheses and explain observed disturbances, should be performed. • Characterization of the mechanisms underlying NVHL disturbances will further understanding of schizophrenia etiology and may suggest novel treatment approaches for patients with the disorder. 70 Hz METHODS 0 • Animals. • Post natal day 7, male pups received either excitotoxic ibotenic acid lesions bilaterally to ventral hippocampi, or sham lesions • Weaned and housed normally in temperature-controlled room, 12:12 hr light/dark cycle, food and water available ad libitum • EEG Surgery. • At adulthood (~350 g), stainless steel screw electrodes were stereotaxically implanted epidurally over the temporal cortex (from bregma: 4.5 mm posterior, 4 mm ventral), cerebellum (ground) and frontal sinus (reference) • Data Collection & Processing. • SSAEPs were elicited via the presentation of auditory stimuli (10s train of clicks, 1 ms duration) at 10, 20, 30, 40, 50, 70, and 80 Hz • EEG was collected (band pass .1 - 300 Hz) and digitized (1,000 Hz) • Time-frequency analyses were performed to examine the magnitude of response with mean trial power (MTP); and degree of phase synchronization (consistency of response) with phase locking factor (PLF) 80 Hz 50 Frequency (Hz) 100 0 250 500 750 • SSAEP frequency response curve of sham and NVHL rats, using mean trial power (MTP) and phase locking factor (PLF). * * 0 250 500 750 * * • Note: 50 Hz is the frequency of maximal response (peak frequency in response curve) in sham, but not NVHL, rats. • NVHL rats have reduced power and phase consistency at 50 & 70 Hz compared to sham rats (p < .05), using both measures. FUNDING Histology from NVHL and sham rats. • Indiana CTSI Predoctoral Training Award • PHS (NCCR) Grant No: TL1RR02575 • Orvis Fund Intercampus IUMS Psychiatry Training Grant at IUPUI Sham NVHL Phase Consistency (PLF) Cortex Ventral Hippocampus SHAM NVHL 50 Hz Thalamus Lesion 0 • NVHL rats that did not meet criteria for successful hippocampal (or sham) lesions were excluded from further analyses (Chambers et al., 1996, 2002). 70 Hz Frequency (Hz) 50 100 0 250 500 750 0 250 500 750