7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
批准号:
10247815
负责人:
Lisa M Savage
金额:
$27.36万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-09-01 至 2025-08-31
关键词:
ATAC-seqAcetylcholineAdolescenceAdolescentAdultAlcohol consumptionAlcoholsAlzheimer&aposs DiseaseAnimal ModelAnxietyAttentionBehaviorBehavioralBrainBrain InjuriesCellsCholinergic FibersChromatinClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCognitionCognitiveComplementComplexCoupledDataDecision MakingDevelopmentDissectionEpigenetic ProcessEthanolExerciseExercise TherapyFunctional disorderGenesGoalsGrowth Factor GeneImpaired cognitionImpairmentMaintenanceMapsMedialMediatingMediator of activation proteinModelingMonkeysNGFR ProteinNGFR geneNerve DegenerationNerve Growth FactorsNeurodegenerative DisordersNeuroimmuneNeuronsNucleus Basalis MagnocellularisPathologicPathologyPatternPhenotypePrefrontal CortexProcessProsencephalonRattusRecoveryResearchReversal LearningRodent ModelRoleShort-Term MemorySignaling MoleculeSiteSourceStructureTechniquesTestingViraladolescent alcohol exposureadolescent binge drinkingagedalcohol exposurebasal forebrainbasal forebrain cholinergic neuronsbasecholinergiccholinergic neuroncognitive functionconnectomedensitydesigner receptors exclusively activated by designer drugsdiscountingdrinkingearly adolescenceeffective therapyepigenetic regulationepigenetic silencingflexibilityfrontal lobegene therapyhuman modelinnovationknock-downnerve supplynestin proteinneuroimagingneuron lossphenotypic biomarkerrestorationtoolunderage drinking
中文摘要
C7/8 UO1:Lisa Savage和Ryan Vetreno
青少年酒精对基底前脑-皮质投射环路破坏的恢复
项目摘要
青春期大量饮酒与大脑结构的持续变化有关,
连接性和成人皮质调节的认知功能。持续观察到严重的病理变化
在青少年狂欢酒精暴露的啮齿动物模型中(青少年间歇性乙醇;AIE)是一种减少
皮质神经生长因子(NGF)的抑制,胆碱能表型的抑制,以及长期
功能性胆碱能基底前脑神经元(CBFN)数量。胆碱能投射神经元
在基底核内,大细胞复合体(NBM)向额叶皮质提供乙酰胆碱(ACh),
包括内侧前额叶皮质(MPFC)和眶前叶皮质(OFC)。行为刺激的外流
AIE后,mPFC和OFC中的ACh都被钝化,认知和行为能力下降
灵活性。我们最近的数据表明,AIE诱导的CBFN的丢失是由于表观遗传沉默所致
胆碱能表型标记物,但运动,可能通过NGF机制,可以逆转这些
表观遗传学改变和挽救胆碱能神经元。这表明AIE最初由一个
减少胆碱能神经元表型的表达,而不是神经元细胞死亡。因此,
应探讨AIE后CFBN病理恢复的机制。我们最重要的假设是
AIE诱导皮质投射部位NGF减少导致胆碱能表观遗传沉默
皮质-NBM胆碱能神经再支配的表型与NBM、退缩和/或功能障碍
连接体,导致皮质胆碱能张力减退和认知功能障碍。然而,适当地,
AIE后基于NGF的定时治疗(运动、NGF基因治疗、CRISPR/dCas9-P300编辑)将
通过激活胆碱能基因来重振胆碱能前脑回路,这将挽救
大脑皮层ACh和恢复AIE诱导的皮质依赖行为损伤。我们的目标是绘制地图和
抢救AIE后出现的胆碱能前脑和皮质环路病理(目标1),恢复认知
通过运动、NGF基因治疗或选择性胆碱能神经元化学刺激发挥功能(目的
2),并通过CRISPR/dCas9编辑,确定NGF缺陷在AIE诱导的表观遗传学中的核心作用
胆碱能表型基因沉默(目标3)。越来越多的证据支持药物的神经保护作用
NGF作为抢救正在经历神经变性的脆弱CBFN的一个疗程,我们有强有力的证据
AIE诱导的胆碱能病理是可以逆转的。对胆碱能机制的认识
神经元的恢复将有助于开发更有效的治疗认知功能障碍的方法
与酒精相关的脑损伤和其他神经退行性疾病有关。
英文摘要
C7/8 UO1: Lisa Savage & Ryan Vetreno
Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
Project Summary
Heavy alcohol consumption during adolescence is associated with persistent changes in brain structure,
connectivity, and adult cortical-mediated cognitive function. Critical pathological changes consistently observed
in rodent models of adolescent binge ethanol exposure (Adolescent Intermittent Ethanol; AIE) are a reduction
of cortical nerve growth factor (NGF), suppression of the cholinergic phenotypes, and a long-term decrease in
the number of functional cholinergic basal forebrain neurons (CBFNs). The cholinergic projection neurons
within the nucleus basalis magnocellularis complex (NbM) provide acetylcholine (ACh) to the frontal cortex,
including the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Behaviorally-stimulated efflux of
ACh in both the mPFC and OFC are blunted following AIE, and there is a loss of cognitive and behavioral
flexibility. Our recent data demonstrate that AIE-induced loss of CBFNs is due to epigenetic silencing of
cholinergic phenotypic markers, but exercise, potentially through a NGF mechanism, can reverse these
epigenetic changes and rescue cholinergic neurons. This demonstrates that AIE is initially marked by a
reduction of the expression of cholinergic neuronal phenotypes, rather than neuronal cell death. Thus,
mechanisms should be explored to recover CFBN pathology following AIE. Our overarching hypothesis is that
AIE-induced reductions of NGF in cortical projection sites leads to epigenetic silencing of cholinergic
phenotypes with the NbM, retraction and/or dysfunctional re-innervation of the cortical-NbM cholinergic
connectome, causing blunting of cortical cholinergic tone and cognitive dysfunction. However, appropriately
timed NGF-based therapies (exercise, NGF gene therapy, CRISPR/dCas9-P300 editing) following AIE will
reinvigorate cholinergic forebrain circuitry through the revitalization of cholinergic genes, which will rescue
cortical ACh and recover AIE-induced impairments in cortical-dependent behaviors. Our goals are to map and
rescue cholinergic forebrain and cortical circuit pathology seen following AIE (Aim 1), restore cognitive
functioning by exercise, NGF-gene therapy, or selective chemogenetic stimulation of cholinergic neurons (Aim
2), and identify the central role of NGF deficits, through CRISPR/dCas9 editing, in AIE-induced epigenetic
silencing of cholinergic phenotype genes (Aim 3). Mounting evidence supports the neuroprotective effects of
NGF as a course to rescue vulnerable CBFNs undergoing neurodegeneration, and we have strong evidence
that AIE-induced cholinergic pathology can be reversed. Understanding the mechanisms of cholinergic
neuronal recovery will aid in the development of more effective therapies to treat cognitive dysfunction
associated with alcohol-related brain damage and other neurodegenerative disorders.
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会议论文
7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
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批准号:10831641
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项目类别:
-
资助金额:$15.29万
-
财政年份:2020
-
负责人:Lisa M Savage
-
依托单位:
7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
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批准号:10688064
-
项目类别:
-
资助金额:$27.36万
-
财政年份:2020
-
负责人:Lisa M Savage
-
依托单位:
7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits
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批准号:10473730
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项目类别:
-
资助金额:$27.36万
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财政年份:2020
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负责人:Lisa M Savage
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依托单位:
Cortical Biobehavioral Disruption after Thiamine Deficiency and Chronic Alcohol
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批准号:8900087
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项目类别:
-
资助金额:$4.28万
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财政年份:2014
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负责人:Lisa M Savage
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依托单位:
Cortical Biobehavioral Disruption after Thiamine Deficiency and Chronic Alcohol
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批准号:8696330
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项目类别:
-
资助金额:$37.34万
-
财政年份:2014
-
负责人:Lisa M Savage
-
依托单位:
Exercise recovers cholinergic dysfunction through neurotrophin modulation
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批准号:8768919
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项目类别:
-
资助金额:$22.15万
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财政年份:2014
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负责人:Lisa M Savage
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依托单位:
Exercise recovers cholinergic dysfunction through neurotrophin modulation
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批准号:8846694
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项目类别:
-
资助金额:$18.72万
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财政年份:2014
-
负责人:Lisa M Savage
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依托单位:
Cortical Biobehavioral Disruption after Thiamine Deficiency and Chronic Alcohol
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批准号:9210578
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项目类别:
-
资助金额:$41.79万
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财政年份:2014
-
负责人:Lisa M Savage
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依托单位:
Administrative Supplement: Cortical Biobehavioral disruption after thiamine deficiency and chronic alcohol
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批准号:9234793
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项目类别:
-
资助金额:$10.0万
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财政年份:2014
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负责人:Lisa M Savage
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依托单位:
Main Research Component 2: Binge-type alcohol exposure during adolescence alters the septohippocampal circuit during advanced aging
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批准号:10686844
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项目类别:
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资助金额:$28.37万
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财政年份:2009
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负责人:Lisa M Savage
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依托单位:
Main Research Component 2: Binge-type alcohol exposure during adolescence alters the septohippocampal circuit during advanced aging
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批准号:10470011
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项目类别:
-
资助金额:$29.39万
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财政年份:2009
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负责人:Lisa M Savage
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依托单位:
Main Research Component 2: Binge-type alcohol exposure during adolescence alters the septohippocampal circuit during advanced aging
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批准号:10227930
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项目类别:
-
资助金额:$29.62万
-
财政年份:2009
-
负责人:Lisa M Savage
-
依托单位:
Main Research Component 2: Binge-type alcohol exposure during adolescence alters the septohippocampal circuit during advanced aging
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批准号:10006504
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项目类别:
-
资助金额:$29.7万
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财政年份:2009
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负责人:Lisa M Savage
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依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7227783
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项目类别:
-
资助金额:$22.18万
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财政年份:2006
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负责人:Lisa M Savage
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依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7146428
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项目类别:
-
资助金额:$25.69万
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财政年份:2006
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负责人:Lisa M Savage
-
依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7631362
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项目类别:
-
资助金额:$22.71万
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财政年份:2006
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负责人:Lisa M Savage
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依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7435324
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项目类别:
-
资助金额:$22.71万
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财政年份:2006
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负责人:Lisa M Savage
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依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7807103
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项目类别:
-
资助金额:$22.48万
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财政年份:2006
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负责人:Lisa M Savage
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依托单位:
The Role of Acetylcholine Dysfunction in Diencephalic Amnesia
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批准号:7869463
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项目类别:
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资助金额:$12.62万
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财政年份:2006
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负责人:Lisa M Savage
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依托单位:
THIAMINE DEFICIENCY IN AGED RATS--PATHOLOGY AND BEHAVIOR
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批准号:2255447
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项目类别:
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资助金额:$3.7万
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财政年份:1996
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负责人:Lisa M Savage
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依托单位:
海外基金