Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry
项目 7/8:INIA 压力和慢性酒精相互作用:代谢动态平衡和纹状体回路改变的跨物种研究
基本信息
- 批准号:10590709
- 负责人:
- 金额:$ 48.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcetatesAcidsAffectAlcohol consumptionAlcoholic beverage heavy drinkerAlcoholsAminobutyric AcidsAnxietyBehaviorBiochemicalBrainBrain regionCellsCerebrumChronicChronic stressCitric Acid CycleCorpus striatum structureCouplingDataDevelopmentDiagnosisElectrophysiology (science)EthanolExperimental DesignsFutureGeneticGlucoseGlutamatesHeavy DrinkingHomeostasisHumanImpaired cognitionInterneuronsLightMacaca mulattaMagnetic Resonance SpectroscopyMeasurementMeasuresMetabolicMetabolismMethodsMonitorMouse StrainsMusNeuronsNeurotransmittersParvalbuminsPathway interactionsPatternPolydipsiaPopulationPrimatesProceduresRecombinantsRecording of previous eventsResearchResearch PersonnelRisk FactorsRoleScheduleSeveritiesSliceStressSwimmingTechniquesTimeValidationWorkalcohol effectalcohol exposurealcohol use disorderallostasisblood glucose regulationbrain circuitrybrain dysfunctionbrain metabolismchronic alcohol ingestioncognitive functiondrinkingdrinking behaviorexperimental studyflexibilityfrontal lobegenetic manipulationglucose metabolismhuman subjectimprovedin vivometabolic abnormality assessmentmetabolomicsneuralneural circuitneuroadaptationneurochemistryneuroimagingneuromechanismneuroregulationnonhuman primatepreservationputamenrestoration
项目摘要
PROJECT SUMMARY
Chronic heavy ethanol drinking and stress are associated with impaired cognitive flexibility, reflected in habitual
and compulsive drinking. This proposal seeks to improve our understanding of the neural basis of these effects
by combining ex vivo slice electrophysiological studies with non-invasive magnetic resonance spectroscopy
(MRS) measurements on mouse and nonhuman primate (NHP) subjects over the course of experimental
drinking procedures common across the INIA-Stress consortium. Electrophysiological recordings of brain slices
have demonstrated that establishment of habitual behaviors, including heavy drinking, involve and increase in
the excitatory to inhibitory tone of neural input (the E/I ratio) to medium spiny neurons (MSNs) of the mouse
dorsolateral striatum (DLS), which in primates is termed the putamen. Specialized MRS techniques for
quantifying -aminobutyric acid (GABA) and glutamate within specific brain regions have led researchers to
propose that the glutamate/GABA ratio reflects E/I, in the context of chronic stress, however the MRS
approach has yet to be validated with direct comparisons to electrophysiological recordings. In Aims 1 and 2,
we propose to use electrophysiology and MRS to study mice undergoing chronic intermittent ethanol exposure,
combined with forced swim stress (CIE-FSS mice). Our experiments will expand our understanding of striatal
neurocircuit adaptations to stress and ethanol exposure by using chemogenetic and recombinant mouse
strains to characterize changes in cortical (excitatory) and parvalbumin-expressing interneuron (inhibitory)
input to DLS MSNs. In the same mice, metabolic allostasis will be characterized with dynamic MRS methods
that monitor cerebral glucose metabolism and neurotransmitter synthesis to estimate the neural tricarboxcylic
acid cycle rate (VTCA) in real time, to provide a biochemical context for interpreting glutamate/GABA ratios,
which will also be measured in these mice. In Aim 3, parallel chemogenetic manipulations and
electrophysiological recordings will be performed in NHP subjects following schedule-induced polydipsia and
open-access drinking. These measures will be directly compared to MRS determinations of glutamate/GABA
and VTCA within the putamen. Together, these results will support the development of non-invasive strategies to
measure stress and ethanol-induced changes in striatal neurocircuitry associated with the establishment of
heavy drinking behaviors. The cross-species approach will contribute reliability to the conclusions to be drawn,
and enhance the translatability of this work to future application in human subjects.
项目概要
长期大量饮酒和压力与认知灵活性受损有关,这反映在习惯性行为中
和强迫性饮酒。该提案旨在提高我们对这些效应的神经基础的理解
通过将离体切片电生理学研究与非侵入性磁共振波谱相结合
在实验过程中对小鼠和非人类灵长类动物 (NHP) 受试者进行 (MRS) 测量
INIA-Stress 联盟中常见的饮酒程序。脑切片的电生理记录
已经证明,习惯行为的养成,包括酗酒,会涉及并增加
小鼠中型多棘神经元 (MSN) 的神经输入的兴奋性与抑制性音调(E/I 比)
背外侧纹状体(DLS),在灵长类动物中被称为壳核。专门的 MRS 技术
定量特定大脑区域内的 γ-氨基丁酸 (GABA) 和谷氨酸使研究人员
提出在慢性应激的情况下,谷氨酸/GABA 比率反映了 E/I,但是 MRS
该方法尚未通过与电生理记录的直接比较来验证。在目标 1 和 2 中,
我们建议使用电生理学和 MRS 来研究经历慢性间歇性乙醇暴露的小鼠,
结合强迫游泳应激(CIE-FSS 小鼠)。我们的实验将扩大我们对纹状体的理解
使用化学遗传学和重组小鼠的神经回路适应压力和乙醇暴露
表征皮质(兴奋性)和表达小清蛋白的中间神经元(抑制性)变化的菌株
输入到 DLS MSN。在同一只小鼠中,代谢失衡将通过动态 MRS 方法进行表征
监测大脑葡萄糖代谢和神经递质合成,以估计神经三羧基
实时酸循环率 (VTCA),为解释谷氨酸/GABA 比率提供生化背景,
这也将在这些小鼠中进行测量。在目标 3 中,并行化学遗传学操作和
电生理记录将在 NHP 受试者中进行日程诱发的烦渴和
开放饮酒。这些测量结果将直接与谷氨酸/GABA 的 MRS 测定进行比较
和壳核内的 VTCA。总之,这些结果将支持非侵入性策略的开发
测量与建立相关的纹状体神经回路的压力和乙醇诱导的变化
大量饮酒行为。跨物种方法将有助于得出结论的可靠性,
并增强这项工作未来在人类受试者中的应用的可转化性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Verginia Carmella Cuzon Carlson其他文献
Verginia Carmella Cuzon Carlson的其他文献
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{{ truncateString('Verginia Carmella Cuzon Carlson', 18)}}的其他基金
Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry
项目 7/8:INIA 压力和慢性酒精相互作用:代谢动态平衡和纹状体回路改变的跨物种研究
- 批准号:
10409985 - 财政年份:2022
- 资助金额:
$ 48.63万 - 项目类别:
Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI
子宫内 MRI 发现胎儿酒精引起的大脑生长异常的功能后果
- 批准号:
10398204 - 财政年份:2021
- 资助金额:
$ 48.63万 - 项目类别:
Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI
子宫内 MRI 发现胎儿酒精引起的大脑生长异常的功能后果
- 批准号:
10590615 - 财政年份:2021
- 资助金额:
$ 48.63万 - 项目类别:
Gestational ethanol effects on dorsal striatal function and associated behaviors
妊娠期乙醇对背侧纹状体功能和相关行为的影响
- 批准号:
8810270 - 财政年份:2014
- 资助金额:
$ 48.63万 - 项目类别:
Gestational ethanol effects on dorsal striatal function and associated behaviors
妊娠期乙醇对背侧纹状体功能和相关行为的影响
- 批准号:
9042902 - 财政年份:2014
- 资助金额:
$ 48.63万 - 项目类别:
Gestational ethanol effects on dorsal striatal function and associated behaviors
妊娠期乙醇对背侧纹状体功能和相关行为的影响
- 批准号:
8838018 - 财政年份:2014
- 资助金额:
$ 48.63万 - 项目类别:
In utero ethanol exposure & development of GABAergic cortical interneurons
子宫内乙醇暴露
- 批准号:
7321656 - 财政年份:2006
- 资助金额:
$ 48.63万 - 项目类别:
In utero ethanol exposure & development of GABAergic cortical interneurons
子宫内乙醇暴露
- 批准号:
7222441 - 财政年份:2006
- 资助金额:
$ 48.63万 - 项目类别:
7/8: INIA Stress and Chronic Alcohol Interactions: Stress and Ethanol Self Administration in Monkeys
7/8:INIA 压力和慢性酒精相互作用:猴子的压力和乙醇自我管理
- 批准号:
10090536 - 财政年份:2002
- 资助金额:
$ 48.63万 - 项目类别:
Translational examination of alcohol-associated epigenetic signatures: from primates to rodents
酒精相关表观遗传特征的转化检查:从灵长类动物到啮齿类动物
- 批准号:
10056068 - 财政年份:1996
- 资助金额:
$ 48.63万 - 项目类别:
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