Pituitary adenylate cyclase-activating polypeptide 27 in the paraventricular thalamus and its projections: Role in ethanol drinking
室旁丘脑中的垂体腺苷酸环化酶激活多肽 27 及其预测:在乙醇饮用中的作用
基本信息
- 批准号:10597976
- 负责人:
- 金额:$ 33.88万
- 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:2020-04-10 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgonistAlcohol consumptionAmygdaloid structureAnatomyAnteriorAnxietyAttentionBehaviorBehavioralBrainBrain regionCell NucleusCellsDevelopmentEatingEthanolExcisionGenesGeneticGenetic TechniquesKnock-outLimbic SystemMental DepressionMicroinjectionsMusNeuronsNeuropeptidesNucleus AccumbensPACAP38Pathway interactionsPeptidesPharmacotherapyPlayProtein IsoformsPublic HealthPublishingRattusRestRoleStructure of paraventricular nucleus of thalamusStructure of terminal stria nuclei of preoptic regionTestingThalamic structurealcohol abuse therapyalcohol use disorderantagonistdepressive symptomsdrinkingdrinking behavioremotional behaviorexperimental studyinnovationinsightinterdisciplinary approachoverexpressionpharmacologicpituitary adenylate cyclase activating polypeptideselective expressionsmall hairpin RNA
项目摘要
PROJECT SUMMARY
The neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has previously been shown
through genetic knockout to suppress ethanol intake, but the brain regions and protein isoforms through which
this occurs remain to be identified. While the more highly expressed of the two PACAP isoforms, PACAP38, is
found to affect a range of behaviors, including anxiety and depression, our recent studies focus attention on
the more selectively-expressed PACAP27, which appears to have few such associations. We have found
PACAP27 to be significantly more dense than PACAP38 in neurons of a key node of the limbic system, the
paraventricular nucleus of the thalamus (PVT), which has a major role in pharmacologically-relevant ethanol
drinking. Moreover, these PACAP27-containing neurons are particularly dense in the posterior (p) subregion of
the PVT, and we have previously shown that activation of the pPVT can decrease ethanol drinking. Thus,
building on published and preliminary results, we hypothesize that PACAP27 in neurons of the PVT,
specifically in the pPVT, suppresses ethanol intake (Aim 1); and these effects are exerted through PACAP27
projections to the nucleus accumbens shell (NAcSh) (Aim 2). To test this, Aim 1 investigates the specific
hypothesis that expression of PACAP in cells of the pPVT functions to inhibit ethanol drinking, with minimal
effects on anxiety- and depressive-like behavior. To accomplish this, the proposed experiments will use an
overexpression AAV or an shRNA silencing AAV approach to (1) determine the effects of increasing PACAP
expression in the pPVT on ethanol drinking, (2) assess the effects of decreasing endogenous PACAP
expression in the pPVT on ethanol drinking, and (3) investigate the effects of increasing PACAP expression in
the pPVT on emotional behavior. Next, Aim 2 investigates the hypothesis that PACAP27 from the pPVT
suppresses ethanol drinking through projections to the NAcSh. Thus, the proposed experiments will use
anatomical, immunohistochemical, pharmacological, and chemogenetic techniques, to (1) identify the primary
projections of PACAP27 from the pPVT, (2) determine the effects on ethanol intake of PACAP agonists and
antagonists in the major projection region(s), and (3) establish if the effects of PACAP27 on ethanol intake are
due to direct projections from the pPVT. Together, these proposed studies should benefit public health by
offering insight into an understudied peptide isoform with few known behavioral effects, which could ultimately
lead to innovative drug therapies for treating alcohol use disorder.
项目总结
神经肽,垂体腺苷环化酶激活多肽(PACAP),已被发现
通过基因敲除来抑制酒精摄取,但大脑区域和蛋白质亚型通过
这种情况的发生还有待确定。而两种PACAP亚型中表达较高的PACAP38是
发现会影响一系列行为,包括焦虑和抑郁,我们最近的研究集中在
PACAP27的表达更有选择性,似乎几乎没有这样的关联。我们发现了
在边缘系统的一个关键节点的神经元中,PACAP27的密度明显高于PACAP38,
丘脑室旁核(PVT),在与药物相关的乙醇中起主要作用
喝酒。此外,这些含有PACAP27的神经元尤其密集在后(P)亚区。
PVT,我们之前已经证明激活pPVT可以减少酒精饮用量。因此,
根据已发表的初步结果,我们假设PACAP27在PVT的神经元中,
具体地说,在pPVT中,抑制乙醇摄入(Aim 1);这些影响是通过PACAP27施加的
向伏隔核外壳投射(NAcSh)(目标2)。为了测试这一点,Aim 1调查了特定的
假设PACAP在pPVT细胞中的表达具有抑制酒精饮酒的功能,最低限度
对焦虑和抑郁样行为的影响。为了实现这一点,拟议的实验将使用
过表达AAV或shRNA沉默AAV的方法:(1)确定增加PACAP的效果
饮酒后pPVT的表达;(2)评估降低内源性PACAP的作用
饮酒后pPVT中PACAP的表达,以及(3)研究PACAP在大鼠体内的表达。
情绪行为的PPVT。接下来,Aim 2调查了来自pPVT的PACAP27的假设
通过向NAcSh的投射抑制酒精的饮用。因此,拟议的实验将使用
解剖学、免疫组织化学、药理学和化学遗传学技术,以(1)确定主要的
PACAP27从pPVT的投射,(2)确定PACAP激动剂和
主投射区域的拮抗剂(S),以及(3)确定PACAP27对酒精摄取的影响是否
由于pPVT的直接投影。总之,这些拟议的研究应该会通过以下方式使公共卫生受益
提供了对一种未被充分研究的多肽亚型的洞察力,但几乎没有已知的行为影响,这最终可能
导致治疗酒精使用障碍的创新药物疗法。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A little night(PA)CAP: pituitary adenylate cyclase-activating polypeptide mediates behavioral effects of alcohol withdrawal.
小夜(PA)CAP:垂体腺苷酸环化酶激活多肽介导酒精戒断的行为效应。
- DOI:10.1038/s41386-020-00922-2
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Pirino,BreanneE;Barson,JessicaR
- 通讯作者:Barson,JessicaR
Expression and Distribution of Neuropeptide-Expressing Cells Throughout the Rodent Paraventricular Nucleus of the Thalamus.
- DOI:10.3389/fnbeh.2020.634163
- 发表时间:2020
- 期刊:
- 影响因子:3
- 作者:Curtis GR;Oakes K;Barson JR
- 通讯作者:Barson JR
Pituitary adenylate cyclase-activating polypeptide (PACAP) in the paraventricular nucleus of the thalamus: Influence on binge-type eating in male and female mice.
丘脑室旁核中的垂体腺苷酸环化酶激活多肽(PACAP):对雄性和雌性小鼠暴饮暴食的影响。
- DOI:10.21203/rs.3.rs-4145128/v1
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Curtis,GenevieveR;Carpenter,BrodyA;Pirino,BreanneE;Hawks,Annie;Li,George;Barson,JessicaR
- 通讯作者:Barson,JessicaR
Inactivation of the thalamic paraventricular nucleus promotes place preference and sucrose seeking in male rats.
- DOI:10.1007/s00213-022-06160-2
- 发表时间:2022-08
- 期刊:
- 影响因子:3.4
- 作者:Gargiulo, Andrew T.;Badve, Preeti S.;Curtis, Genevieve R.;Prino, Breanne E.;Barson, Jessica R.
- 通讯作者:Barson, Jessica R.
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Jessica Rose Barson其他文献
Jessica Rose Barson的其他文献
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{{ truncateString('Jessica Rose Barson', 18)}}的其他基金
Mechanisms of rostrocaudal differences in accumbal kappa opioid receptor effects on ethanol drinking
伏卡帕阿片受体颈尾差异对乙醇饮酒的影响机制
- 批准号:
10210667 - 财政年份:2021
- 资助金额:
$ 33.88万 - 项目类别:
Mechanisms of rostrocaudal differences in accumbal kappa opioid receptor effects on ethanol drinking
伏卡帕阿片受体颈尾差异对乙醇饮酒的影响机制
- 批准号:
10627808 - 财政年份:2021
- 资助金额:
$ 33.88万 - 项目类别:
Mechanisms of rostrocaudal differences in accumbal kappa opioid receptor effects on ethanol drinking
伏卡帕阿片受体颈尾差异对乙醇饮酒的影响机制
- 批准号:
10425399 - 财政年份:2021
- 资助金额:
$ 33.88万 - 项目类别:
Pituitary adenylate cyclase-activating polypeptide 27 in the paraventricular thalamus and its projections: Role in ethanol drinking
室旁丘脑中的垂体腺苷酸环化酶激活多肽 27 及其预测:在乙醇饮用中的作用
- 批准号:
10380126 - 财政年份:2020
- 资助金额:
$ 33.88万 - 项目类别:
Paraventricular thalamic nucleus: Role of orexin and opioids in ethanol intake
丘脑室旁核:食欲素和阿片类药物在乙醇摄入中的作用
- 批准号:
8585016 - 财政年份:2012
- 资助金额:
$ 33.88万 - 项目类别:
Paraventricular thalamic nucleus: Role of orexin and opioids in ethanol intake
丘脑室旁核:食欲素和阿片类药物在乙醇摄入中的作用
- 批准号:
9049646 - 财政年份:2012
- 资助金额:
$ 33.88万 - 项目类别:
Paraventricular thalamic nucleus: Role of orexin and opioids in ethanol intake
丘脑室旁核:食欲素和阿片类药物在乙醇摄入中的作用
- 批准号:
8424767 - 财政年份:2012
- 资助金额:
$ 33.88万 - 项目类别:
Paraventricular thalamic nucleus: Role of orexin and opioids in ethanol intake
丘脑室旁核:食欲素和阿片类药物在乙醇摄入中的作用
- 批准号:
9259889 - 财政年份:2012
- 资助金额:
$ 33.88万 - 项目类别:
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