Optogenetic Modulation of Hippocampal Oscillations Following Early-Life Seizures Ameliorates Spatial Cognition and Hippocampal Rhythms
Abstract number :
3.04
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1825674
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Francisco Velasquez, BS - University of Vermont College of Medicine; Michelle Kloc, PhD - Postdoctoral Fellow, Neurological Sciences, University of Vermont College of Medicine; Conor Dickson, BS - Technician, Neurological Sciences, University of Vermont College of Medicine; Barry Jeremy, PhD - Assistant Professor, Neurological Sciences, University of Vermont College of Medicine; Gregory Holmes, MD - Professor, University of Vermont College of Medicine
Rationale: There is increasing human and animal evidence that in the epileptic encephalopathies abnormal brain rhythms can contribute to cognitive dysfunction. Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Early-life seizures (ELS) are associated with long-term deficits in spatial cognition and hippocampal oscillatory activity. Here we asked whether optogenetic stimulation following ELS can modify hippocampal connectivity and spatial cognition.
Methods: Male rat pups (n=20) were subjected to 50 flurothyl-induced seizures over 5 days between P10-15 and were then injected with a viral vector expressing channelrhodopsin (ChR2) into the medial septum (MS) followed by implants of hippocampal and MS electrodes and an optogenetic probe. During the critical period of spatial memory from P22-25 half of the ELS rats received 5 hrs of active blue light (BL; 465 nm) stimulation at 7 Hz per day while the other half received inactive yellow light (YL). Spatial cognition was assessed in the active avoidance task at P50 and EEGs were evaluated for power, coherence and phase locking following the testing.
Results: Non-selective optogenetic stimulation of the MS in weanling rats following ELS resulted in precisely regulated hippocampal oscillations with exact 1:1 entrainment of stimulation to hippocampal EEG. Rats receiving BL stimulation performed better than the rats receiving YL with fewer entrances into the shock zone (p=0.003). Peak frequency of theta was higher in the BL (7.84) than the YL (6.29). While there were no significant differences in relative or total power between groups, coherences in the delta, theta, slow gamma and medium gamma were significantly higher in rats receiving BL than YL. No cell loss was measured between the BL-stimulated and YL-stimulated in either the MS or hippocampus.
Conclusions: MS optogenetic stimulation of 7 Hz following ELS resulted in increased hippocampal connectivity and improved performance in a spatial memory task compared to non-stimulated rats. While the cognitive deficits were not totally reversed by stimulation, these finding indicate that post-ELS modification of hippocampal rhythms may be a new therapeutic modality.
Funding: Please list any funding that was received in support of this abstract.: This work was supported by the NIH Grants NS108765 andNS108296. The project was supported by NIH Grant Numbers 5 P30RR032135 from the COBRE Program of the National Center for Research Resources and 8 P30 GM103498 from the National Institute of General Medical Sciences.
Basic Mechanisms