Regulation of nucleus accumbens neurons by sleep and circadian rhythm
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
批准号:
10217074
负责人:
Yanhua H Huang
金额:
$29.5万
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:
2020-07-15 至 2025-06-30
关键词:
AMPA ReceptorsAcuteAdenosineAdolescenceAdolescentAdolescent DevelopmentAffectAnhedoniaBehaviorBehavioralChronicCircadian DysregulationCircadian RhythmsCircadian desynchronyCognitiveCollaborationsCorpus striatum structureCuesDiurnal RhythmDopamineEmotionalEvaluationExhibitsFibrinogenGene MutationGlutamatesHigh School StudentHumanHyperactivityLeadMedialMediatingMembraneModelingMolecularMolecular GeneticsNeuronsNucleus AccumbensOutcomePharmaceutical PreparationsPhasePrefrontal CortexPublishingRattusRegulationResearch Project GrantsRewardsRiskRodent ModelSelf AdministrationSiteSleepSleep DeprivationSleep FragmentationsSleep disturbancesSubstance abuse problemSucroseSynapsesSynaptic TransmissionTeenagersTestingTimeVentral Striatumbasebehavior testbehavioral phenotypingcellular targetingcholinergiccircadiancircadian regulationcognitive controlcortico-limbic circuitsdrug rewarddrug seeking behaviordrug testinghuman datahuman imagingimaging studyinsightmolecular phenotypemotivated behaviorpostsynapticpreferencerelating to nervous systemresponsereward processingsubstance usetraittransmission process
中文摘要
项目摘要
青春期是开始使用和滥用药物的脆弱时期,在此期间,睡眠和昼夜节律
节律紊乱是普遍的。 人们越来越认识到,睡眠和昼夜节律的因果关系,
有力地调节奖励处理,但其潜在机制仍然知之甚少。可以睡
昼夜节律特征与奖赏回路功能有关吗? 睡眠和昼夜节律是否以及如何
中断导致青少年使用药物的脆弱性增加?中心的中心假设
青少年的发展作用于潜在的睡眠和昼夜节律特征,以改变体内平衡,
睡眠驱动、昼夜节律相位和昼夜节律排列,这反过来又影响皮质边缘系统功能,
物质使用风险(例如, 奖励和认知控制)。进一步假设,特定的操纵
青春期的睡眠和昼夜节律会影响奖赏反应和认知控制,
积极或消极的方向。 本研究项目(项目5)将侧重于啮齿动物模型,以确定
皮质-大脑边缘回路中的细胞和突触机制,通过这些机制睡眠和昼夜节律中断
改变奖励处理。具体地说,丘脑腹侧核(NAc)是腹侧核中的一个奖赏-兴奋处理“枢纽”,
纹状体对睡眠和昼夜节律的破坏都很敏感。例如,急性睡眠剥夺会减少
内侧前额叶皮层-小脑-小脑NAc中棘主神经元(MSNs)突触谷氨酸释放;慢性
睡眠片段增加NAc的胆碱能神经活动(初步结果);
在NAc中也观察到AMPA受体(AMPAR)水平和内在膜兴奋性的波动
MSNs和NAc中的昼夜节律基因突变导致MSNs中AMPAR传输的改变。所有这些
结果表明,NAc可能代表了睡眠和昼夜节律调节奖赏的会聚点
处理.因此,项目5将测试睡眠和昼夜节律靶向NAc方面的假设。
突触传递和神经调制来调节奖赏动机行为。 因此,目标1将使用
基因多样的远系繁殖大鼠,以确定是否自然发生的“早”和“晚”的时钟型,
与NAc MSNs中AMPAR传输的不同日变化相关。 这一目标将适应
这些大鼠的分子(项目3)和行为(项目4)表征。 目标2将决定是否
没有睡眠变化的昼夜节律中断改变了膜兴奋性的昼夜变化和/或
NAc MSNs中的突触后AMPAR水平。 目标3将确定急性和慢性睡眠的影响
限制腺苷和胆碱能传输的NAc,以及行为后果,在自然条件下,
或药物自我给药。项目5的预期成果将整合和扩展行为研究的结果,
(项目4)和分子遗传学(项目3)研究,它们将共同提供机制见解,
进一步开展人类研究(项目1和2)。
英文摘要
PROJECT SUMMARY
Adolescence is a vulnerable period for initiating substance use and abuse, during which time sleep and circadian
rhythm disruptions are pervasive. It is increasingly recognized that sleep and circadian rhythm causally, and
powerfully regulate reward processing, but the underlying mechanisms remain poorly understood. Could sleep
and circadian rhythm traits be related to reward circuit function? Whether and how do sleep and circadian
disruptions lead to increased vulnerability for substance use in adolescents? The central hypothesis of the Center
application is that adolescent development acts on underlying sleep and circadian traits to modify homeostatic
sleep drive, circadian phase, and circadian alignment, which in turn impact cortico-limbic functions critical to
substance use risk (e.g., reward and cognitive control). It is further hypothesized that specific manipulations of
sleep and circadian rhythms during adolescence will affect reward responsivity and cognitive control in either
positive or negative directions. This research project (Project 5) will focus on rodent models to determine the
cellular and synaptic mechanisms within the cortico-limbic circuit through which sleep and circadian disruptions
alter reward processing. Specifically, the nucleus accumbens (NAc) is a reward-processing “hub” in the ventral
striatum which is sensitive to both sleep and circadian disruptions. For example, acute sleep deprivation reduces
glutamate release at medial prefrontal cortex-to-NAc medium spiny principal neurons (MSNs) synapses;; chronic
sleep fragmentation increases cholinergic neural activity in the NAc (preliminary results);; robust diurnal
fluctuations in AMPA receptor (AMPAR) levels and intrinsic membrane excitability are also observed in the NAc
MSNs, and circadian gene mutation in the NAc leads to altered AMPAR transmission in MSNs. Together, these
results suggest that the NAc may represent a converging site for sleep and circadian rhythm to regulate reward
processing. Accordingly, Project 5 will test the hypothesis that sleep and circadian rhythm target aspects of NAc
synaptic transmission and neural modulation to regulate reward-motivated behaviors. Thus, Aim 1 will use
genetically diverse outbred rats to determine whether naturally occurring “early” and “late” chronotypes are
associated with different diurnal variation of AMPAR transmission in NAc MSNs. This aim will accommodate
molecular (Project 3) and behavioral (Project 4) characterizations of these rats. Aim 2 will determine whether
circadian disruptions without changes in sleep alter the diurnal variation of membrane excitability and/or
postsynaptic AMPAR levels in the NAc MSNs. Aim 3 will determine the effects of acute and chronic sleep
restrictions on adenosine and cholinergic transmission in the NAc, and the behavioral consequences in natural
or drug self-administration. The expected outcome of Project 5 will integrate and extend findings from behavioral
(Project 4) and molecular genetic (Project 3) studies, which together will provide mechanistic insights to inform
and further develop human studies (Projects 1&2).
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
-
批准号:10655471
-
项目类别:
-
资助金额:$30.06万
-
财政年份:2020
-
负责人:Yanhua H Huang
-
依托单位:
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
-
批准号:10442467
-
项目类别:
-
资助金额:$29.97万
-
财政年份:2020
-
负责人:Yanhua H Huang
-
依托单位:
Mechanistic studies of alcohol-sleep interactions
-
批准号:10687066
-
项目类别:
-
资助金额:$39.13万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Sleep regulates drug relapse and addiction
-
批准号:10548145
-
项目类别:
-
资助金额:$35.21万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Sleep regulates drug relapse and addiction
-
批准号:9912146
-
项目类别:
-
资助金额:$35.21万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Mechanistic studies of alcohol-sleep interactions
-
批准号:9912917
-
项目类别:
-
资助金额:$39.13万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Mechanistic studies of alcohol-sleep interactions
-
批准号:10019443
-
项目类别:
-
资助金额:$39.13万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Sleep regulates drug relapse and addiction
-
批准号:10092144
-
项目类别:
-
资助金额:$35.21万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Sleep regulates drug relapse and addiction
-
批准号:10350587
-
项目类别:
-
资助金额:$35.21万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
Mechanistic studies of alcohol-sleep interactions
-
批准号:10466827
-
项目类别:
-
资助金额:$39.13万
-
财政年份:2019
-
负责人:Yanhua H Huang
-
依托单位:
REM Sleep in Cocaine Relapse
-
批准号:9789241
-
项目类别:
-
资助金额:$19.56万
-
财政年份:2018
-
负责人:Yanhua H Huang
-
依托单位:
Synaptic Reorganization in Drug Addiction
-
批准号:8649371
-
项目类别:
-
资助金额:$34.57万
-
财政年份:2014
-
负责人:Yanhua H Huang
-
依托单位:
Synaptic Reorganization in Drug Addiction
-
批准号:9233066
-
项目类别:
-
资助金额:$34.65万
-
财政年份:2014
-
负责人:Yanhua H Huang
-
依托单位:
Synaptic Reorganization in Drug Addiction
-
批准号:8836511
-
项目类别:
-
资助金额:$34.13万
-
财政年份:2014
-
负责人:Yanhua H Huang
-
依托单位:
Dopamine Signaling and Synaptic Plasticity in the Nucleus Accumbens
-
批准号:9241442
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2014
-
负责人:Yanhua H Huang
-
依托单位:
Presynaptic Release of Endocannabinoids in the Nucleus Accumbens
-
批准号:8598574
-
项目类别:
-
资助金额:$19.06万
-
财政年份:2013
-
负责人:Yanhua H Huang
-
依托单位:
Presynaptic Release of Endocannabinoids in the Nucleus Accumbens
-
批准号:8699182
-
项目类别:
-
资助金额:$19.25万
-
财政年份:2013
-
负责人:Yanhua H Huang
-
依托单位:
Regulation of Nucleus Accumbens Neurons by Sleep Deprivation
-
批准号:8664823
-
项目类别:
-
资助金额:$24.21万
-
财政年份:2012
-
负责人:Yanhua H Huang
-
依托单位:
Regulation of Nucleus Accumbens Neurons by Sleep Deprivation
-
批准号:8495300
-
项目类别:
-
资助金额:$23.53万
-
财政年份:2012
-
负责人:Yanhua H Huang
-
依托单位:
Regulation of Nucleus Accumbens Neurons by Sleep Deprivation
-
批准号:8458391
-
项目类别:
-
资助金额:$25.05万
-
财政年份:2012
-
负责人:Yanhua H Huang
-
依托单位:
海外基金