Serotonergic network mechanisms in postictal generalized EEG suppression
发作后广义脑电图抑制中的血清素网络机制
基本信息
- 批准号:10177965
- 负责人:
- 金额:$ 3.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAmericanAmygdaloid structureAnimalsArousalAttentionBrainBrain regionBreathingCause of DeathCell NucleusCessation of lifeChemicalsConsequentialismDataDepressed moodElectroencephalographyEpilepsyEtiologyFDA approvedFamiliarityFluorescent in Situ HybridizationFreedomFunctional disorderGene DeliveryGoalsHTR2A geneImmunohistochemistryImpairmentInjectionsIntractable EpilepsyInvestigationKnowledgeLifeMediatingMidbrain structureMusNeuronsNeurosciencesOrganPatientsPedunculopontine Tegmental NucleusPharmaceutical PreparationsPontine structurePublic HealthRegulationResearchResearch PersonnelResearch TechnicsRiskRisk FactorsRisk MarkerRoleSeizuresSelective Serotonin Reuptake InhibitorSerotoninSerotonin AntagonistsSerotonin Receptor 5-HT2ASignal TransductionSleepSolventsSourceStrokeStuporSystemTestingThree-Dimensional ImagingTrainingViralWakefulnesscholinergic neuronconventional therapydorsal raphe nucleusexpectationexperienceexperimental studyhigh riskmortalitynervous system disorderneurotransmissionnon rapid eye movementoptogeneticspreventreceptorresponsereuptakeserotonin receptorsudden unexpected death in epilepsy
项目摘要
Project Summary
One in twenty-six Americans will develop epilepsy during their lifetime. Unfortunately, one-third of epilepsy
patients will not achieve seizure freedom with conventional therapies. These patients are at greatest risk for
sudden unexpected death in epilepsy (SUDEP), the leading cause of death in patients with refractory epilepsy.
While the exact etiology of SUDEP is unknown, it is thought that cardiorespiratory dysfunction and arousal
impairment are involved. Suppression of EEG activity following a seizure, or post-ictal generalized EEG
suppression (PGES), may correlate with SUDEP risk. The origin of PGES is unknown, but during PGES
patients experience stupor and unresponsiveness. Serotonin (5-HT) is broadly implicated in SUDEP due to its
role breathing, sleep/wakefulness, and arousal. The dorsal raphe nucleus (DRN) is a key source of 5-HT
projections. DRN 5-HT activity is depressed by seizures. We hypothesize PGES may represent an
electrographic marker of impaired arousal consequent to seizure-induced DRN dysregulation. Our preliminary
data in mice indicate that systemic application of a selective serotonin reuptake inhibitor (SSRI) or direct
chemical or optogenetic stimulation of DRN 5-HT neurons prior to an induced seizure shortens PGES duration.
However, the specific network and receptor mechanisms underlying PGES are unknown. Our objective is to
identify a DRN network and 5-HT receptor mechanism that could be manipulated to reduce PGES and prevent
SUDEP. A potential downstream target is the pedunculopontine tegmental nucleus (PPT), a pontine region
involved in sleep-wake regulation, attention, EEG regulation, and arousal. Seizure-induced dysregulation of 5-
HT signaling may interfere with subcortical arousal networks, such as those involving the PPT, and produce
PGES. In Aim 1, to determine a role for a DRN PPT circuit in PGES, we will optogenetically stimulate and
inhibit DRN 5-HT terminals in the PPT prior to seizures induced by amygdala stimulation in amygdala kindled
mice during wake/NREM/REM and observe changes in PGES duration. Several 5-HT receptors have been
implicated in SUDEP and may be found on cholinergic neurons in the PPT. In Aim 2, we will utilize
immunolabeling-enabled three-dimensional imaging of solvent-cleared organs, RNAscope fluorescent in situ
hybridization, and immunohistochemistry to determine the identity of PPT neurons and 5-HT receptors
contacted by DRN 5-HT terminals. Then we will administer intracranial 5-HT antagonists into the PPT with or
without a selective serotonin reuptake inhibitory onboard, induce an amygdala-kindled seizure, and observe
effects on PGES. Participation in the proposed training plan and completion of the proposed experiments will
advance the applicant’s neuroscience training. It will also elucidate the DRN-PPT circuit and determine its role
in PGES. By manipulating 5-HT circuitry, we may discover ways to eliminate PGES and consequentially
prevent death in high risk epilepsy patients.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alexandra Petrucci其他文献
Alexandra Petrucci的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 3.18万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 3.18万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 3.18万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 3.18万 - 项目类别:
Studentship