Project 4_Bruchas : Circuit-level Approaches for Dissecting Approach/Avoidance Behaviors Mediated by Nociceptin Systems in Mice
项目 4_Bruchas:用于解剖小鼠伤害感受素系统介导的接近/回避行为的电路级方法
基本信息
- 批准号:10601138
- 负责人:
- 金额:$ 48.16万
- 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:2020-04-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectiveAnatomyAnhedoniaAnimalsAnteriorAnxietyAnxiety DisordersAutopsyAversive StimulusBehaviorBehavioralBiologicalBiological AssayBiological ProcessBrain regionCalciumCell CommunicationCell NucleusCellsCharacteristicsChronic stressCollaborationsComplexComputer ModelsCorpus striatum structureCre driverCuesDataDecision MakingDepressive disorderDiseaseDopamineDorsalExcisionExposure toFiberFunctional disorderG Protein-Coupled Receptor SignalingGeneticGoalsHabenulaHeterogeneityHumanImageIndividualInternal Ribosome Entry SiteInvestigationLinkMajor Depressive DisorderMedialMediatingMental DepressionMidbrain structureModelingMood DisordersMotivationMusNegative ValenceNeuronsNeuropeptidesNociceptionORL1 receptorOpioidOrganismPathway interactionsPhotometryPlayPopulationProcessPsychopathologyRegulationResearchRewardsRoleSpecificityStimulusStressSucroseSuicideSystemTail SuspensionTechniquesTestingVentral Tegmental AreaViralacute stressantagonistanxious behaviorapproach avoidance behavioravoidance behaviorbehavioral responsecell typecingulate cortexdepressive symptomsdopamine systemdopaminergic neuronefficacious treatmentexperimental studyimprovedin vivoinsightinterpeduncular nucleusmesolimbic systemmotivated behaviormouse modelnegative affectneuralneural circuitneurobiological mechanismnociceptinnonhuman primatenoveloptogeneticspharmacologicpreferenceprepronociceptinreceptorresponsestressorsynergism
项目摘要
Project Summary
The overall goal of Project 4 is to determine how the nociceptin/receptor system modulates the mesolimbic
dopamine (DA) system and behavioral responses associated with stress, aversion, and motivated behaviors.
We recently identified a population of paranigral ventral tegmental area (pnVTA) nociceptin (PNOC+) neurons
that constrain motivated behavior and regulate the motivation for natural reward seeking. These PNOC+ pnVTA
neurons are engaged during motivation, as well as carry a negative valence when activated. Our extensive body
of preliminary findings strongly implicate these neurons in regulating motivated behaviors, stress responsivity,
and avoidance behavior. Working in close collaboration with the other Projects (in particular, Projects 1 and 3),
Project 4 will use newly developed mouse model for accessing endogenous nociception circuits and focus on
the neurobiological mechanisms of how the prepronociceptin system engages the dopamine system to regulate
motivation – a key component of depressive disorders, including those outlined in this center project. The
research aims of this 5-year project are: (1) to determine the anatomical and functional characteristics of
nociceptin expressing neurons within the ventral midbrain and identify behavioral conditions (acute vs chronic
stress, motivation and Approach-Avoidance) that are modulated by this system; (2) to identify and characterize
pnVTA nociceptin neurons and their afferents involved in motivated behavior that drive negative affective
behavior. The project will use novel and validated mouse cre-driver models that allow unparalleled access to
PNOC+ neurons in the VTA, combined with optogenetic, chemogenetic, calcium imaging, viral tracing, and
behavior to uncover circuit mechanisms that underlie how these neurons are regulated by aversive stimuli. This
project directly synergizes with the other projects outlined in this Conte Center, in two key ways: 1) using novel
cutting-edge mouse models, it will allow to dissect the role of prepronociceptin system in motivation, and 2) it will
comprehensively examine the role of nociceptin circuits in dopamine-dependent behaviors, with direct relevance
to motivational states, avoidance, and stress-induced negative affect. Results from Project 4 will: (1) directly
inform post-mortem analyses probing nociception neurons in the pnVTA of individuals with MDD who died by
suicide (Project 1); (2) synergize with pharmacological challenges used to test the hypothesis that nociceptin
receptor antagonism will normalize neural substrates underlying approach/avoidance behaviors in humans with
MDD and anxiety disorders (Project 1); and (3) integrate with studies using PNOC-IRES-cre mice to determine
how specific populations of nociceptin neurons (striatal vs VTA) regulate motivation, anhedonia, and
approach/avoidance decision making (Project 3). Data emerging from Project 4’s aims, together with the three
other projects and the Computational Modeling Core will fundamentally enhance our understanding of the
nociceptin/NOPR system in motivation and depressive/anxious behaviors, and identify novel treatment targets.
项目摘要
项目4的总体目标是确定伤害感受素/受体系统如何调节中脑边缘系统,
多巴胺(DA)系统和行为反应与压力,厌恶和动机行为。
我们最近发现了一个黑质旁腹侧被盖区(pnVTA)的伤害感受素(PNOC+)神经元群体
约束动机行为并调节自然奖励寻求的动机。这些PNOC+ pnVTA
神经元在动机期间参与,并且在激活时携带负价。我们庞大的身体
的初步研究结果强烈暗示这些神经元在调节动机行为,压力反应,
和回避行为。与其他项目(特别是项目1和3)密切合作,
项目4将使用新开发的小鼠模型来评估内源性伤害感受回路,并专注于
前原感受肽系统如何参与多巴胺系统调节的神经生物学机制
动机-抑郁症的一个关键组成部分,包括在这个中心项目概述。的
本课题的研究目标是:(1)确定大鼠大脑皮层的解剖和功能特征,
腹侧中脑内表达伤害感受素的神经元,并识别行为状况(急性与慢性
压力、动机和回避);(2)识别和表征
pnVTA伤害感受素神经元及其传入参与驱动负性情感的动机性行为
行为该项目将使用新颖和有效的鼠标cre-driver模型,允许无与伦比的访问,
VTA中的PNOC+神经元,结合光遗传学,化学遗传学,钙成像,病毒示踪,
行为,揭示电路机制,这些神经元是如何调节厌恶刺激。这
该项目直接协同与其他项目概述了这个康特中心,在两个关键方面:1)使用新的
尖端的小鼠模型,它将允许解剖前原感受素系统在动机中的作用,2)它将
全面研究伤害感受素回路在多巴胺依赖性行为中的作用,
动机状态、回避和压力引起的负面影响。项目4的结果将:(1)直接
通知尸检分析探测MDD死亡的个体的pnVTA中的伤害感受神经元,
自杀(项目1);(2)协同药理学的挑战,用于测试的假设,伤害感受素
受体拮抗作用将使人类接近/回避行为的神经基质正常化,
MDD和焦虑症(项目1);(3)与使用PNOC-IRES-cre小鼠的研究相结合,以确定
特定群体的伤害感受素神经元(纹状体与腹侧被盖区)如何调节动机、快感缺乏和
接近/回避决策(项目3)。项目4的目标中出现的数据,以及三个
其他项目和计算建模核心将从根本上提高我们对
Nociceptin/NOPR系统在动机和抑郁/焦虑行为中的作用,并确定新的治疗靶点。
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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Michael R. Bruchas其他文献
A cluster of neuropeptide S neurons regulates breathing and arousal
一群神经肽 S 神经元调节呼吸和觉醒
- DOI:
10.1016/j.cub.2023.11.018 - 发表时间:
2023-12-18 - 期刊:
- 影响因子:7.500
- 作者:
Christopher Caleb Angelakos;Kasey S. Girven;Yin Liu;Oscar C. Gonzalez;Keith R. Murphy;Kim J. Jennings;William J. Giardino;Larry S. Zweifel;Azra Suko;Richard D. Palmiter;Stewart D. Clark;Mark A. Krasnow;Michael R. Bruchas;Luis de Lecea - 通讯作者:
Luis de Lecea
Recapitulating phenotypes of alcohol dependence via overexpression of emOprk1/em in the ventral tegmental area of non-dependent TH::Cre rats
通过在非依赖性 TH::Cre 大鼠腹侧被盖区中过表达 emOprk1/em 来概括酒精依赖的表型
- DOI:
10.1016/j.neuropharm.2023.109457 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:4.600
- 作者:
Gaetan Lepreux;Grace E. Shinn;Gengze Wei;Azra Suko;George Concepcion;Sunil Sirohi;Bok Soon Go;Michael R. Bruchas;Brendan M. Walker - 通讯作者:
Brendan M. Walker
Circuit dynamics of <em>in vivo</em> dynorphn release in the nucleus accumbens
- DOI:
10.1016/j.alcohol.2017.02.258 - 发表时间:
2017-05-01 - 期刊:
- 影响因子:
- 作者:
Ream Al-Hasani;Jenny M. Wong;Jordan G. McCall;Omar S. Mabrouk;Gavin Schmitz;Kirsten Porter-Stransky;Julio M. Bernardi;Brandon Aragona;Robert T. Kennedy;Michael R. Bruchas - 通讯作者:
Michael R. Bruchas
An integrated microfluidic and fluorescence platform for probing emin vivo/em neuropharmacology
一种用于探究体内神经药理学的集成微流控和荧光平台
- DOI:
10.1016/j.neuron.2025.03.017 - 发表时间:
2025-05-21 - 期刊:
- 影响因子:15.000
- 作者:
Sean C. Piantadosi;Min-Kyu Lee;Mingzheng Wu;Huong Huynh;Raudel Avila;Catalina A. Zamorano;Carina Pizzano;Yixin Wu;Rachael Xavier;Maria Stanslaski;Jiheon Kang;Sarah Thai;Youngdo Kim;Jinglan Zhang;Yonggang Huang;Yevgenia Kozorovitskiy;Cameron H. Good;Anthony R. Banks;John A. Rogers;Michael R. Bruchas - 通讯作者:
Michael R. Bruchas
Dynorphin modulates reward-seeking actions through a pallido-amygdala cholinergic circuit
强啡肽通过苍白球 - 杏仁核胆碱能回路调节寻求奖赏的行为
- DOI:
10.1016/j.neuron.2025.03.018 - 发表时间:
2025-06-04 - 期刊:
- 影响因子:15.000
- 作者:
Qingtao Sun;Mingzhe Liu;Wuqiang Guan;Xiong Xiao;Chunyang Dong;Michael R. Bruchas;Larry S. Zweifel;Yulong Li;Lin Tian;Bo Li - 通讯作者:
Bo Li
Michael R. Bruchas的其他文献
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{{ truncateString('Michael R. Bruchas', 18)}}的其他基金
Optopharmacology and Sensors for Dissecting Opioid Action In Vivo
用于剖析阿片类药物体内作用的光药理学和传感器
- 批准号:
10268988 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Optopharmacology and Sensors for Dissecting Opioid Action In Vivo
用于剖析阿片类药物体内作用的光药理学和传感器
- 批准号:
10040355 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Optopharmacology and Sensors for Dissecting Opioid Action In Vivo
用于剖析阿片类药物体内作用的光药理学和传感器
- 批准号:
10867978 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Optopharmacology and Sensors for Dissecting Opioid Action In Vivo
用于剖析阿片类药物体内作用的光药理学和传感器
- 批准号:
10471283 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Project 4_Bruchas : Circuit-level Approaches for Dissecting Approach/Avoidance Behaviors Mediated by Nociceptin Systems in Mice
项目 4_Bruchas:用于解剖小鼠伤害感受素系统介导的接近/回避行为的电路级方法
- 批准号:
10383688 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Next-gen Opto-GPCRs: spatiotemporal simulation of neuormodulator signaling
下一代 Opto-GPCR:神经调节信号传导的时空模拟
- 批准号:
9815886 - 财政年份:2018
- 资助金额:
$ 48.16万 - 项目类别:
Next-gen Opto-GPCRs: spatiotemporal simulation of neuromodulator signaling
下一代 Opto-GPCR:神经调节信号传导的时空模拟
- 批准号:
9213972 - 财政年份:2016
- 资助金额:
$ 48.16万 - 项目类别:
Decoding Locus Coeruleus Neural Circuits and Signaling in Negative Affect
解码蓝斑神经回路和负面情绪中的信号传导
- 批准号:
9357671 - 财政年份:2016
- 资助金额:
$ 48.16万 - 项目类别:
Decoding Locus Coeruleus Neural Circuits and Signaling In Negative Affect
解码蓝斑神经回路和消极情绪中的信号传导
- 批准号:
10518981 - 财政年份:2016
- 资助金额:
$ 48.16万 - 项目类别:
Decoding Locus Coeruleus Neural Circuits and Signaling In Negative Affect
解码蓝斑神经回路和负面情绪中的信号传导
- 批准号:
10676944 - 财政年份:2016
- 资助金额:
$ 48.16万 - 项目类别:
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