Optogenetic Stimulation of Serotonergic Neurons in the Raphe Magnus Prevents Seizure-Induced Respiratory Arrest in DBA/1 Mice
Abstract number :
1.071
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2021
Submission ID :
1825682
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Hua-Jun Feng, PhD - Massachusetts General Hospital and Harvard Medical School; Haiting Zhao, MD, PhD – Massachusetts General Hospital and Harvard Medical School; Zheren Tan, MD – Massachusetts General Hospital and Harvard Medical School; Christa Nehs, PhD – Anesthesia, Critical Care and Pain Medicine – Massachusetts General Hospital and Harvard Medical School; Carl Faingold, PhD – Pharmacology – Southern Illinois University School of Medicine; Ken Solt, MD – Anesthesia, Critical Care and Pain Medicine – Massachusetts General Hospital and Harvard Medical School
Rationale: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy. Studies show that seizure-induced respiratory arrest (S-IRA) is the major cause of death in SUDEP. Enhancing serotonin (5-HT) signaling prevents S-IRA, and selective activation of 5-HT neurons in the midbrain dorsal raphe suppresses S-IRA in animal models of SUDEP. However, it is unknown if medullary raphe nuclei contribute to S-IRA control. The present study selectively activated 5-HT neurons in the medullary raphe magnus (RM) using optogenetics and investigated the role of this nucleus in control of S-IRA in transgenic DBA/1 mice.
Methods: Channelrhodopsin (ChR2) was specifically expressed on 5-HT neurons in transgenic DBA/1 TPH2-ChR2 mice. These transgenic DBA/1 mice exhibit generalized seizures and S-IRA evoked by acoustic stimulation or pentylenetetrazole (PTZ), similarly to wild type DBA/1 mice. Transgenic DBA/1 mice were primed (3-4 daily acoustic stimulation). A fiberoptic cannula was implanted into RM. One week after surgery, S-IRA susceptibility was confirmed 24 hr prior to photostimulation (20 ms pulse duration, 20 Hz) using a diode blue light laser with an energy level of 9 mW. The effect of drug treatment and/or photostimulation on S-IRA incidence was examined, and video was digitally recorded for offline analysis. Differences in S-IRA incidence between treatments as well as between the treatment and control were compared using the Chi-square test.
Results: S-IRA incidence in transgenic DBA/1 mice evoked by acoustic stimulation at 24 hr prior to photostimulation (100%) was significantly reduced by photostimulation of 5-HT neurons in the RM at 9 mW for 30 min (8.3%, n = 24) (p < 0.001). However, photostimulation at the same parameters in littermates without ChR2 expression did not alter S-IRA (100%, n = 6). S-IRA incidence evoked by PTZ (75 mg/kg, i.p.) in transgenic DBA/1 mice was also reduced by RM photostimulation (9 mW, 30 min) to 20% (n = 5) vs. those without photostimulation (87.5%, n = 8) (
Basic Mechanisms