The neural circuitry of seizure-induced apnea and SUDEP

癫痫发作引起的呼吸暂停和 SUDEP 的神经回路

• 批准号: 10719519
• 负责人: Ian Christopher Wenker
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719519
• 关键词: Acute; Address; Apnea; Benchmarking; Brain; Brain Mapping; Brain Stem; Breathing; Bypass; Cardiac; Cause of Death; Cell Nucleus; Cessation of life; Chromosome Mapping; Clonic Seizure; Data; Development; Electrophysiology (science); Elements; Epilepsy; Experimental Designs; FOXP2 gene; Failure; Generations; Genetic; Heart Arrest; In Vitro; Individual; Injections; Interruption; Maps; Midbrain structure; Modeling; Motor Seizures; Mus; Muscle; Mutant Strains Mice; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Fibers; Neurons; Nodal; Patients; Pattern; Phase; Pontine structure; Prevention strategy; Prosencephalon; Recovery; Refractory; Research; Respiratory Failure; Risk Factors; Role; SCN8A gene; Seizures; Site; Slice; Structure; Sudden Death; Techniques; Testing; Tonic Seizures; Vagus nerve structure; Work; afferent nerve; hindbrain; in vivo; mouse model; mutant; neural; neural circuit; neuronal circuitry; neuronal excitability; novel; optogenetics; parabrachial nucleus; patch clamp; prevent; receptor; recruit; respiratory; selective expression; sudden unexpected death in epilepsy; ventilation

Sudden Unexpected Death in Epilepsy (SUDEP) accounts for up to 17% of all epilepsy-related deaths, and 50% for those refractory to treatment. There is increasing evidence that apnea (respiratory arrest) is the primary cause of death from SUDEP. We have shown in a number of mouse models - including PTZ injection, rapid kindling (prelim. data), and mouse models harboring Scn8a mutations identified from SUDEP patients - that sudden death is due to seizure-induced apnea (SIA) that occurs during tonic seizures, minutes prior to terminal asystole. As it pertains to this proposal, we have also made four other important observations: 1) artificial ventilation can prevent death and suppressed cardiac activity does not increase likelihood of fatality; 2) tonic contraction of breathing muscles represents a likely mechanism of SIA; 3) inhibition of cortical seizure activity does not impact SIA; and 4) inhibition of the inspiratory oscillator does not reduce apnea (prelim. data), suggesting seizure spread bypasses homeostatic elements of respiratory control circuitry. CENTRAL HYPOTHESIS: [AIM 1] Increased midbrain and pontine excitability is both necessary and sufficient to produce SIA, [AIM 2] the parabrachial/kölliker fuse (PB/KF) nucleus in the pons represents a key nodal point for SIA generation, and [AIM 3] that brainstem nuclei, like the PB/KF and PAG are recruited specifically during SIA, which we will explore using electrophysiology and genetic mapping. AIM 1: We have previously used chemogenetics to demonstrate that cortical ictal activity is not required for SIA and we now propose that hyperexcitability of the pons and midbrain drive SIA and SUDEP. We will use chemogenetics to inhibit different parts of the brainstem of Scn8a mutant mice to test their necessity for SIA and SUDEP. Additionally, we will test sufficiency of these regions by selectively expressing an Scn8a mutation that increases neuronal excitability. Using the rapid kindling model, we will also perform patch clamp recordings to test whether increased neuronal excitability in these regions occurs concurrently with the development of SIA. AIM 2: The parabrachial/kölliker fuse nucleus PB/KF in the Pons is a key nodal point for descending forebrain input and projects past the inspiratory oscillator, and is modulated by the vagus nerve. In this aim, we will photoinhibit the Foxp2-positive PB/KF neurons to regain normal breathing pattern during SIA, photostimulate P2ry1-positive vagal afferent nerve fibers to interrupt inspiration during SIA, and determine if PB/KF and Npy2r-positive vagal neuron photostimulation rescues postictal breathing in our PTZ SUDEP mouse model. AIM 3: We have demonstrated that tonic seizures with SIA and clonic seizures without SIA can occur in the very same mouse, both in Scn8a mutant and rapid kindling models (prelim. data) and that certain mid- and hindbrain structures are activated during SIA. We will determine the neuronal circuitry activated specifically during SIA and SUDEP using in vivo electrophysiology and TRAP2 identification of activated neurons.

癫痫猝死（SUDEP）占所有癫痫相关死亡的17%