Frequency-specific medial septal nucleus deep brain stimulation improves spatial memory in MK-801-treated male rats

Nancy C. Zepeda; Lindsey M. Crown; Sasha Medvidovic; Wooseong Choi; Megha Sheth; Matthew Bergosh; Raymond Gifford; Caroline Folz; Phillip Lam; Gengxi Lu; Robert Featherstone; Charles Y. Liu; Steven J. Siegel; Darrin J. Lee

Neurobiology of Disease (Aug 2022)

Frequency-specific medial septal nucleus deep brain stimulation improves spatial memory in MK-801-treated male rats

Nancy C. Zepeda,
Lindsey M. Crown,
Sasha Medvidovic,
Wooseong Choi,
Megha Sheth,
Matthew Bergosh,
Raymond Gifford,
Caroline Folz,
Phillip Lam,
Gengxi Lu,
Robert Featherstone,
Charles Y. Liu,
Steven J. Siegel,
Darrin J. Lee

Affiliations

Nancy C. Zepeda: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Lindsey M. Crown: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Sasha Medvidovic: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Wooseong Choi: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Megha Sheth: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Matthew Bergosh: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Raymond Gifford: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Caroline Folz: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Phillip Lam: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Gengxi Lu: Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90033, USA
Robert Featherstone: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Charles Y. Liu: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90033, USA; USC Neurorestoration Center, Keck School of Medicine of USC, Los Angeles, USA
Steven J. Siegel: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Darrin J. Lee: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90033, USA; USC Neurorestoration Center, Keck School of Medicine of USC, Los Angeles, USA; Corresponding author at: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, 1200 North State Street, Suite 3300, Los Angeles, CA 90033.

Journal volume & issue: Vol. 170
p. 105756

Abstract

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Background: Few treatments exist for the cognitive symptoms of schizophrenia. Pharmacological agents resulting in glutamate N-methyl-d-aspartate (NMDA) receptor hypofunction, such as MK-801, mimic many of these symptoms and disrupt neural activity. Recent evidence suggests that deep brain stimulation (DBS) of the medial septal nucleus (MSN) can modulate medial prefrontal cortex (mPFC) and hippocampal activity and improve spatial memory. Objective: Here, we examine the effects of acute MK-801 administration on oscillatory activity within the septohippocampal circuit and behavior. We also evaluate the potential for MSN stimulation to improve cognitive behavioral measures following MK-801 administration. Methods: 59 Sprague Dawley male rats received either acute intraperitoneal (IP) saline vehicle injections or MK-801 (0.1 mg/kg). Theta (5–12 Hz), low gamma (30–50 Hz) and high frequency oscillatory (HFO) power were analyzed in the mPFC, MSN, thalamus and hippocampus. Rats underwent MSN theta (7.7 Hz), gamma (100 Hz) or no stimulation during behavioral tasks (Novel object recognition (NOR), elevated plus maze, Barnes maze (BM)). Results: Injection of MK-801 resulted in frequency-specific changes in oscillatory activity, decreasing theta while increasing HFO power. Theta, but not gamma, stimulation enhanced the anxiolytic effects of MK-801 on the elevated plus maze. While MK-801 treated rats exhibited spatial memory deficits on the Barnes maze, those that also received MSN theta, but not gamma, stimulation found the escape hole sooner. Conclusions: These findings demonstrate that acute MK-801 administration leads to altered neural activity in the septohippocampal circuit and impaired spatial memory. Further, these findings suggest that MSN theta-frequency stimulation improves specific spatial memory deficits and may be a possible treatment for cognitive impairments caused by NMDA hypofunction.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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