The role of brainstem projecting extended amygdala neurons in sudden unexpected death in epilepsy

脑干投射扩展杏仁核神经元在癫痫猝死中的作用

• 批准号: 10718024
• 负责人: William Paul Nobis
• 金额: $ 51.24万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718024
• 关键词: Acute; Amygdaloid structure; Apnea; Arousal; Brain Stem; Breathing; Cause of Death; Cell Nucleus; Central Sleep Apnea; Cessation of life; Chronic; Clinical; DBA/1 Mouse; Data; Development; Disease; Electric Stimulation; Electrocardiogram; Electrocorticogram; Electroencephalography; Electrophysiology (science); Epilepsy; Evaluation; FOS gene; Fiber; Foundations; Functional disorder; Future; Genetic; Genetic Recombination; Goals; Human; Hypoventilation; Impairment; Intervention; Intractable Epilepsy; Light; Maps; Medial; Mediating; Mediator; Mission; Modeling; Monitor; Mus; Myocardial dysfunction; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurons; Neurosciences; Opioid; Opsin; Outcome; Outcome Study; Output; Patients; Pharmacologic Substance; Photometry; Physiologic Monitoring; Physiologic pulse; Pontine structure; Population; Pre-Clinical Model; Prosencephalon; Public Health; Research; Respiration Disorders; Risk; Role; Seizures; Structure; Structure of terminal stria nuclei of preoptic region; Sudden Death; Synapses; System; Techniques; Testing; Time; Translating; Ventilatory Depression; Viral; Whole Body Plethysmography; Work; audiogenic seizure; clinical translation; critical period; high risk; improved; in vivo; innovation; mortality; mouse model; nervous system disorder; neural circuit; neurophysiology; neuroregulation; novel; novel therapeutics; optogenetics; parabrachial nucleus; patch clamp; prevent; preventable epilepsy; respiratory; risk stratification; selective expression; sudden unexpected death in epilepsy; tool

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Currently, it is impossible to predict or prevent SUDEP. However, SUDEPs that have occurred in monitored settings were characterized by hypoventilation and apnea prior to cardiac dysfunction, implicating seizure-related respiratory dysfunction as a critical factor. Human intracranial data suggests the amygdala as a forebrain structure that may be important for respiratory control and involved in seizure-related respiratory dysfunction. Understanding the neural circuit mechanisms involving amygdalar structures that underlies seizure-related respiratory dysfunction that leads to hypoventilation and death is critical to advancing SUDEP prevention options, which currently do not exist. Our long-term goal is to identify the neural circuits underlying seizure-related respiratory dysfunction to predict and prevent sudden death. The main objective of the proposed project is to delineate brainstem projecting extended amygdalar neurons involved in seizure-related respiratory dysfunction and arrest. Preliminary data in a mouse model of SUDEP show that the extended amygdalar structure the bed nucleus of the stria terminalis (BNST) represents a potential mediator underlying seizure-related respiratory dysfunction. Our hypothesis is that BNST activation during seizures contributes to seizure-related respiratory dysfunction, respiratory arrest, and death via downstream activation in the parabrachial nucleus (PBN) of the pons. This hypothesis will be tested via the following specific aims in a model of SUDEP: (1) Characterize the role of BNST and BNSTPBN activation in respiratory dysfunction in a model of SUDEP. (2) Determine the effect of acute BNST inhibition on seizure-induced respiratory dysfunction in a model of SUDEP. In Aim 1, we will use a viral approach to selectively identify and dissect BNST neurons activated by seizures as well as determine the relationship between BNST activation and respiratory dysfunction during seizures. In Aim 2, we will use in vivo optogenetic inactivation of the BNST to determine the critical period of activity for respiratory depression and potential intervention. At the successful completion of the proposed research, the expected outcomes are characterization of seizure-activated BNST-brainstem circuitry and the temporal relationship of BNST activation to seizure-related respiratory dysfunction to determine sufficiency and the timepoint necessary for acute BNST activation in this effect. The proposed research is conceptually innovative through its focus on BNST circuitry in terms of SUDEP pathophysiology and technically innovative through the use of cutting-edge systems neuroscience techniques applied to SUDEP including fiber photometry, virally-mediated Targeted Recombination in Active Populations (TRAP) and in vivo optogenetics. These results are expected to have a significant impact on our current understanding of alterations of forebrain respiratory circuits that lead to SUDEP and will provide a strong basis for future development of novel therapeutics and clinical targets for neuromodulation to prevent SUDEP.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Currently, it is impossible to predict or prevent SUDEP. However, SUDEPs that have occurred in monitored settings were characterized by hypoventilation and apnea prior to cardiac dysfunction, implicating seizure-related respiratory dysfunction as a critical factor. Human intracranial data suggests the amygdala as a forebrain structure that may be important for respiratory control and involved in seizure-related respiratory dysfunction. Understanding the neural circuit mechanisms involving amygdalar structures that underlies seizure-related respiratory dysfunction that leads to hypoventilation and death is critical to advancing SUDEP prevention options, which currently do not exist. Our long-term goal is to identify the neural circuits underlying seizure-related respiratory dysfunction to predict and prevent sudden death. The main objective of the proposed project is to delineate brainstem projecting extended amygdalar neurons involved in seizure-related respiratory dysfunction and arrest. Preliminary data in a mouse model of SUDEP show that the extended amygdalar structure the bed nucleus of the stria terminalis (BNST) represents a potential mediator underlying seizure-related respiratory dysfunction. Our hypothesis is that BNST activation during seizures contributes to seizure-related respiratory dysfunction, respiratory arrest, and death via downstream activation in the parabrachial nucleus (PBN) of the pons. This hypothesis will be tested via the following specific aims in a model of SUDEP: (1) Characterize the role of BNST and BNSTPBN activation in respiratory dysfunction in a model of SUDEP. (2) Determine the effect of acute BNST inhibition on seizure-induced respiratory dysfunction in a model of SUDEP. In Aim 1, we will use a viral approach to selectively identify and dissect BNST neurons activated by seizures as well as determine the relationship between BNST activation and respiratory dysfunction during seizures. In Aim 2, we will use in vivo optogenetic inactivation of the BNST to determine the critical period of activity for respiratory depression and potential intervention. At the successful completion of the proposed research, the expected outcomes are characterization of seizure-activated BNST-brainstem circuitry and the temporal relationship of BNST activation to seizure-related respiratory dysfunction to determine sufficiency and the timepoint necessary for acute BNST activation in this effect. The proposed research is conceptually innovative through its focus on BNST circuitry in terms of SUDEP pathophysiology and technically innovative through the use of cutting-edge systems neuroscience techniques applied to SUDEP including fiber photometry, virally-mediated Targeted Recombination in Active Populations (TRAP) and in vivo optogenetics. These results are expected to have a significant impact on our current understanding of alterations of forebrain respiratory circuits that lead to SUDEP and will provide a strong basis for future development of novel therapeutics and clinical targets for neuromodulation to prevent SUDEP.