Circuit-specific actions of endocannabinoids in stress and mood disorders
Circuit-specific actions of endocannabinoids in stress and mood disorders
批准号:
10689093
负责人:
Cecilia J Hillard
金额:
$38.5万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-11 至 2024-08-31
关键词:
2-arachidonylglycerolAcuteAffectAnatomyAnimalsAnti-Anxiety AgentsAntidepressive AgentsAnxietyAnxiety DisordersAttenuatedBehaviorBehavioralBrainBrain regionBuffersCNR1 geneCannabinoidsCannabisCell CountCellsChronicClassificationClinicalClinical ResearchDataDeep Brain StimulationDepressive disorderDiagonal Band NucleusDiseaseDisease remissionElectrophysiology (science)EndocannabinoidsEpithalamic structureEvolutionExposure toFrightG-Protein-Coupled ReceptorsGene ExpressionGlutamatesGoalsHabenulaHormonalHumanHyperactivityIn Situ HybridizationIndividualLateralLinkLiteratureMapsMedialMediatingMental DepressionMessenger RNAModelingMood DisordersMoodsNeuronsOutputPathway interactionsPatientsPhysiologicalPhysiologyPlayPopulation HeterogeneityPrevalenceRegulationReverse Transcriptase Polymerase Chain ReactionRodentRoleSignal TransductionSliceStressSynapsesSynaptic plasticityTechniquesTestingTranscription Factor AP-1anatomical tracingantagonistantidepressant effectanxiety-like behavioravoidance behaviorbehavioral phenotypingbehavioral responsebiological adaptation to stresscell typecholinergicconditioned fearendocannabinoid signalingendogenous cannabinoid systemgamma-Aminobutyric Acidgenetic manipulationknock-downlipoprotein lipasemood regulationmouse modelneuralneural circuitnonhuman primatenoveloptogeneticspreclinical studyreceptorresponserimonabantstress disorderstress managementstress reactivitytraumatic stresstreatment-resistant depressionvirus genetics
中文摘要
项目摘要/摘要
脑内大麻素(Ecb)系统可通过以下途径抑制对应激的行为和生理反应
激活大麻素受体1(CB1),这是大脑中最丰富的G蛋白偶联受体之一。
然而,欧洲央行介导的效应背后的不同神经回路仍未完全确定和
明白了。最近的研究已经确定缰核,一种在脊椎动物中保存的上皮性结构
进化,在编码啮齿动物的应激反应、回避行为和厌恶行为中发挥核心作用
非人类灵长类动物,其多动与焦虑样行为和情绪失调有关。
人类研究表明,抑郁症患者缰核体积和细胞数量减少
精神障碍和缰核深部脑刺激导致耐药个体缓解
抑郁症。因此,人类和动物研究都指出缰核在调节
与压力、反应能力和情绪有关的行为。在这项研究中,我们提供了第一个证据,即
内侧缰核(MHB)合成和释放ECB以抑制来自内侧隔核的突触输入
斜角带核(MSDB)。此外,我们还证明了这种ECB/CB1信号是钝化的
与应激诱导的焦虑样行为有关,MSDB中CB1受体的敲除足以
模仿应激诱导的行为表型。因此,这些结果与以前的文献联系在一起
MHB和MSDB的焦虑样行为,导致我们假设MSDB-ECB/CB1信号-
MHB途径是ECB减轻应激诱导的焦虑样行为的一种新机制
这种信号的失调可能会导致这种行为状态。提出了三个具体的测试目标
这些假设。我们在AIM I的第一个目标是对特定类型的细胞进行详细的评估
MSDB-MHB途径的连通性,因为对其解剖学和生理学知之甚少。在AIM II中,
我们将确定ECB如何调节这一回路,以及这种调节如何受到压力暴露的影响。在AIM
第三,我们将检验ECB在这一途径中的信号调节应激行为反应的假设。
成功完成概述的研究将推进我们理解神经的长期目标。
焦虑类行为背后的回路,ECB施加行为影响的具体机制,以及
欧洲央行信号的失调可能会导致焦虑和情绪相关的障碍。
英文摘要
Project Summary/Abstract
The brain endocannabinoid (eCB) system can dampen behavioral and physiological responses to stress via
activation of cannabinoid receptor 1 (CB1), one of the most abundant G protein-coupled receptors in the brain.
However, the distinct neural circuits which underlie eCB-mediated effects remain incompletely identified and
understood. Recent studies have identified the habenula, an epithalamic structure conserved across vertebrate
evolution, to play a central role in encoding stress reactivity, avoidance behavior, and aversion in rodents and
non-human primates, and its hyperactivity has been linked to anxiety-like behavior and mood dysregulation.
Human studies have shown that habenula volumes and cell numbers are reduced in patients with depressive
disorders, and deep brain stimulation of the habenula led to remission in an individual with treatment-resistant
depression. Thus, both human and animal studies point to a critical role for the habenula in regulating
behaviors relevant to stress responsivity and mood. In this study, we provide first evidence that neurons of the
medial habenula (MHb) synthesize and release eCBs to suppress synaptic input from the medial septum and
nucleus of the diagonal band (MSDB). Further, we show that this eCB/CB1 signaling is blunted in association
with stress-induced anxiety-like behavior, and that knockdown of CB1 receptors in the MSDB is sufficient to
mimic the stress-induced behavioral phenotype. Thus, these results, together with previous literature linking
the MHb and the MSDB to anxiety-like behavior, led us to hypothesize that eCB/CB1 signaling in the MSDB-
MHb pathway is a novel mechanism whereby eCBs attenuate stress-induced anxiety-like behavior, and that
dysregulation of this signaling can contribute to this behavioral state. Three Specific Aims are proposed to test
these hypotheses. Our first goal in Aim I will be to carry out a detailed assessment of the cell type-specific
connectivity of the MSDB-MHb pathway, as very little is known regarding its anatomy and physiology. In Aim II,
we will determine how eCBs regulate this circuit and how this regulation is affected by stress exposure. In Aim
III, we will test the hypothesis that eCB signaling in this pathway regulates behavioral responses to stress.
Successful completion of the outlined studies will advance our long-term objectives to understand the neural
circuits underlying anxiety-like behavior, the specific mechanisms whereby eCBs exert behavior effects, and
how dysregulation of eCB signaling may contribute to anxiety and mood-related disorders.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
2023 Cannabinoid Function in the CNS Gordon Research Conference and Gordon Research Seminar
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批准号:10683605
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项目类别:
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资助金额:$1.0万
-
财政年份:2023
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负责人:Cecilia J Hillard
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依托单位:
Mechanisms underlying the influence of stress on drug-seeking behavior
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批准号:10752220
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项目类别:
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资助金额:$58.62万
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财政年份:2023
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负责人:Cecilia J Hillard
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依托单位:
Studies of Cannabidiol in Neurodevelopment
-
批准号:10366030
-
项目类别:
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资助金额:$19.5万
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财政年份:2021
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负责人:Cecilia J Hillard
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依托单位:
Examining the impact of circulating endocannabinoid levels on neurocognition, mood, and early cannabis use in youth enrolled in the ABCD Study
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批准号:9916212
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项目类别:
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资助金额:$28.02万
-
财政年份:2019
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负责人:Cecilia J Hillard
-
依托单位:
Circuit-specific actions of endocannabinoids in stress and mood disorders
-
批准号:10477473
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2019
-
负责人:Cecilia J Hillard
-
依托单位:
Circuit-specific actions of endocannabinoids in stress and mood disorders
-
批准号:10238098
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2019
-
负责人:Cecilia J Hillard
-
依托单位:
Circuit-specific actions of endocannabinoids in stress and mood disorders
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批准号:10013295
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2019
-
负责人:Cecilia J Hillard
-
依托单位:
Examining the impact of circulating endocannabinoid levels on neurocognition, mood, and early cannabis use in youth enrolled in the ABCD Study
-
批准号:10019508
-
项目类别:
-
资助金额:$15.27万
-
财政年份:2019
-
负责人:Cecilia J Hillard
-
依托单位:
Circulating endocannabinoids in rats: Assay development and validation
-
批准号:9306814
-
项目类别:
-
资助金额:$7.7万
-
财政年份:2016
-
负责人:Cecilia J Hillard
-
依托单位:
CB2 Cannabinoid Receptors and Cocaine Action: Studies with Conditional Knock Outs
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批准号:9250114
-
项目类别:
-
资助金额:$19.25万
-
财政年份:2016
-
负责人:Cecilia J Hillard
-
依托单位:
Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking
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批准号:9059860
-
项目类别:
-
资助金额:$0.66万
-
财政年份:2014
-
负责人:Cecilia J Hillard
-
依托单位:
Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking
-
批准号:9271366
-
项目类别:
-
资助金额:$0.72万
-
财政年份:2014
-
负责人:Cecilia J Hillard
-
依托单位:
Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking
-
批准号:8797514
-
项目类别:
-
资助金额:$44.76万
-
财政年份:2014
-
负责人:Cecilia J Hillard
-
依托单位:
Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking
-
批准号:9053466
-
项目类别:
-
资助金额:$43.36万
-
财政年份:2014
-
负责人:Cecilia J Hillard
-
依托单位:
Role of ECS in Resilience & Psychopathology After Trauma
-
批准号:8935916
-
项目类别:
-
资助金额:$18.9万
-
财政年份:2014
-
负责人:Cecilia J Hillard
-
依托单位:
Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking
-
批准号:9259928
-
项目类别:
-
资助金额:$53.21万
-
财政年份:2014
-
负责人:Cecilia J Hillard
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依托单位:
Cannabinoid regulation of glycogen synthase kinase-3
-
批准号:8417028
-
项目类别:
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资助金额:$33.62万
-
财政年份:2010
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负责人:Cecilia J Hillard
-
依托单位:
Cannabinoid regulation of glycogen synthase kinase-3
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批准号:8620631
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项目类别:
-
资助金额:$35.02万
-
财政年份:2010
-
负责人:Cecilia J Hillard
-
依托单位:
Cannabinoid regulation of glycogen synthase kinase-3
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批准号:8038315
-
项目类别:
-
资助金额:$35.02万
-
财政年份:2010
-
负责人:Cecilia J Hillard
-
依托单位:
Cannabinoid regulation of glycogen synthase kinase-3
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批准号:8233541
-
项目类别:
-
资助金额:$35.02万
-
财政年份:2010
-
负责人:Cecilia J Hillard
-
依托单位:
海外基金