title: Impaired Serotonergic Brainstem Function during and after Seizures.
abstract: Impaired breathing, cardiac function, and arousal during and after seizures are important causes of morbidity and mortality. Previous work suggests that these changes are associated with depressed brainstem function in the ictal and post-ictal periods. Lower brainstem serotonergic systems are postulated to play an important role in cardiorespiratory changes during and after seizures, whereas upper brainstem serotonergic and other systems regulate arousal. However, direct demonstration of seizure-associated neuronal activity changes in brainstem serotonergic regions has been lacking. Here, we performed multiunit and single-unit recordings from medullary raphe and midbrain dorsal raphe nuclei in an established rat seizure model while measuring changes in breathing rate and depth as well as heart rate. Serotonergic neurons were identified by immunohistochemistry. Respiratory rate, tidal volume, and minute ventilation were all significantly decreased during and after seizures in this model. We found that population firing of neurons in the medullary and midbrain raphe on multiunit recordings was significantly decreased during the ictal and post-ictal periods. Single-unit recordings from identified serotonergic neurons in the medullary raphe revealed highly consistently decreased firing during and after seizures. In contrast, firing of midbrain raphe serotonergic neurons was more variable, with a mixture of increases and decreases. The markedly suppressed firing of medullary serotonergic neurons supports their possible role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depressed population activity of several neuronal pools in the upper brainstem and forebrain. These findings have important implications for preventing morbidity and mortality in people living with epilepsy.
  
  
  CONCLUSIONS
  Seizures often cause impaired breathing, cardiac dysfunction, and loss of consciousness. The brainstem and, specifically, brainstem serotonin neurons are thought to play an important role in controlling breathing, cardiac function, and arousal. We used an established rat seizure model to study the overall neuronal activity in the brainstem as well as firing of specific serotonin neurons while measuring cardiorespiratory function. Our results demonstrated overall decreases in brainstem neuronal activity and marked downregulation of lower brainstem serotonin neuronal firing in association with decreased breathing and heart rate during and after seizures. These findings point the way toward new treatments to augment brainstem function and serotonin, aiming to prevent seizure complications and reduce morbidity and mortality in people living with epilepsy.
authors.affiliation: Departments of Neurology, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Departments of Neurology.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Buchanan
authors.affiliation: Departments of Neurology.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Motelow
authors.affiliation: Departments of Neurology.
authors.forename: John
authors.identifier: http://orcid.org/0000-0002-8025-1525
authors.initials: J
authors.lastname: Andrews
authors.affiliation: Departments of Neurology.
authors.forename: Petr
authors.initials: P
authors.lastname: Vitkovskiy
authors.affiliation: Departments of Neurology.
authors.forename: William C
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Departments of Neurology.
authors.forename: Florian
authors.initials: F
authors.lastname: Serout
authors.affiliation: Departments of Neurology.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Gummadavelli
authors.affiliation: Departments of Neurology.
authors.forename: Adam
authors.initials: A
authors.lastname: Kundishora
authors.affiliation: Departments of Neurology.
authors.forename: Moran
authors.initials: M
authors.lastname: Furman
authors.affiliation: Departments of Neurology, Department of Neurosurgery, Jinling Hospital, School of Medicine Nanjing University, Nanjing Jiangsu 210002, China, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Bo
authors.affiliation: Departments of Neurology and Molecular Physiology and Biophysics, and Veterans Affairs Medical Center, Iowa City, Iowa 52246.
authors.forename: George B
authors.identifier: http://orcid.org/0000-0001-5696-1554
authors.initials: GB
authors.lastname: Richerson
authors.affiliation: Departments of Neurology, Neuroscience, and Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, hal.blumenfeld@yale.edu.
authors.forename: Hal
authors.initials: H
authors.lastname: Blumenfeld
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000209:etiology; D009474:Neurons / Q000502:physiology*; D010991:Plethysmography; D011903:Raphe Nuclei / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration; D012120:Respiration Disorders / Q000209:etiology; D012640:Seizures / Q000150:complications / Q000473:pathology*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D012701:Serotonin
keywords: SUDEP; brainstem; consciousness; respiratory; serotonin; temporal lobe epilepsy