Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence
Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence
批准号:
10733568
负责人:
Chitra D Mandyam
金额:
$40.52万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
未结题
起止时间:
2012-09-25 至 2028-08-31
关键词:
AbstinenceAcuteAdherens JunctionAdultAlcohol consumptionAlcohol dependenceAlcoholismAmericanAngiogenesis InhibitorsAnti-Inflammatory AgentsBiological AssayBlood - brain barrier anatomyBlood brain barrier dysfunctionBrainBrain regionCD31 AntigensCadherinsCell SeparationCellsChronicClinical ResearchCollaborationsCuesDataElectrophysiology (science)Endothelial CellsEndotheliumEthanolEthanol dependenceFemaleFoundationsFunctional disorderFundingFutureGene ExpressionGlutamatesHealthImmune responseInflammatoryInflammatory ResponseInfusion proceduresInhalationMedialModelingNeuronal PlasticityNeuronsPatientsPeptidesPrefrontal CortexProteinsPsychopathologyPublic HealthPublishingRattusRelapseResearch InstituteRodent ModelRoleSelf AdministrationSurveysSynaptic plasticityTestingTherapeutic AgentsTranslational ResearchWithdrawalWorkalcohol seeking behavioralcohol use disorderangiogenesisblood-brain barrier disruptioncadherin 5chemokinecytokinediagnostic criteriadrinkingdrinking behaviorfunctional plasticitygliogenesishippocampal pyramidal neuronmalenovel markerpharmacologicprolonged abstinencerelapse preventionsexsexual dimorphismstemtherapy designtranscriptometranscriptome sequencingvapor
中文摘要
项目总结/文摘
英文摘要
Project summary/Abstract
Relapse defined as the resumption of alcohol drinking following a prolonged period of abstinence,
represents a prevalent and significant public health concern in alcoholism. Relapse is a major impediment to
treatment efforts. One promising approach for reducing high propensity for relapse in subjects with moderate
to severe alcohol use disorder (AUD) is the identification of vulnerability factors in the brain that contribute to
enhanced relapse to ethanol drinking; the medial prefrontal cortex (mPFC) is one of the key brain regions
implicated in relapse to ethanol drinking behaviors.
We have used the chronic intermittent ethanol vapor inhalation (CIE) model of ethanol dependence to
demonstrate that increased ethanol self-administration during CIE in female rats predicts higher relapse to
ethanol drinking triggered by ethanol contextual cues during forced abstinence compared with males. In
addition, we have shown that drinking during relapse is associated with increases in endothelial cell specific
angiogenesis peptide PECAM-1 in the mPFC in both sexes, indicating blood-brain barrier (BBB) instability.
Treatment with an anti-angiogenic agent normalized PECAM-1 expression in both sexes and reduced relapse
to ethanol drinking in female rats.
To further understand the mechanisms underlying BBB instability and dysfunction, we have begun studies
to isolate endothelial cells from the mPFC via endothelial cell enrichment assay. We have performed RNA
sequencing to initially profile endothelial transcriptome of cells isolated from ethanol naïve adult female and
male rats. Our results show that endothelial cells in females have higher expression of genes associated with
angiogenesis and endothelial cell stability, whereas cells from males have higher expression of genes
associated with immune responses. We have published findings from cytokine and chemokine multiplex
analyses to show that the mPFC in ethanol naïve adult male rats has higher expression of pro- and anti-
inflammatory cytokines and chemokines compared with females. These findings support sexual dimorphism in
the endothelial transcriptome and immune responses in the mPFC under control, ethanol naïve conditions
and open questions on how they are altered during ethanol dependence.
In further support of BBB instability, we show that adherens junction protein cadherin5 (Cdh5, VE-
cadherin) is significantly altered in the mPFC in ethanol dependent female and male rats. Specifically we
show that Cdh5 is increased during acute withdrawal, significantly decreased during prolonged abstinence,
and increased following relapse to ethanol drinking compared to ethanol naïve controls in both sexes. In
addition to the endothelial changes in the mPFC, electrophysiological studies demonstrate altered synaptic
plasticity in ethanol dependent female and male rats. Therefore, in the renewal application we hope to define
the role of Cdh5 during abstinence in promoting relapse to ethanol drinking in both sexes via altering the
endothelial transcriptome, pro- and anti-inflammatory responses and neuronal plasticity in the mPFC. Our
hypotheses will be tested via 3 Specific Aims.
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DOI:
10.3390/ijms21186491
发表时间:
2020-09-05
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Avchalumov Y, Trenet W, Piña-Crespo J, Mandyam C]
通讯作者:
Mandyam C
DOI:
10.3233/bpl-150007
发表时间:
2015-10-09
期刊:
Brain plasticity (Amsterdam, Netherlands)
影响因子:
--
作者:
[Somkuwar SS, Staples MC, Fannon MJ, Ghofranian A, Mandyam CD]
通讯作者:
Mandyam CD
DOI:
10.3389/fpsyt.2013.00061
发表时间:
2013
期刊:
Frontiers in psychiatry
影响因子:
4.7
作者:
[Mandyam CD]
通讯作者:
Mandyam CD
DOI:
10.3233/bpl-190089
发表时间:
2020-12-29
期刊:
Brain plasticity (Amsterdam, Netherlands)
影响因子:
--
作者:
[Avchalumov Y, Mandyam CD]
通讯作者:
Mandyam CD
DOI:
10.1016/j.brainres.2017.02.028
发表时间:
2017-05-15
期刊:
Brain research
影响因子:
2.9
作者:
[Staples MC, Fannon MJ, Mysore KK, Dutta RR, Ongjoco AT, Quach LW, Kharidia KM, Somkuwar SS, Mandyam CD]
通讯作者:
Mandyam CD
共 29 条
Caveolins, Striatal Toxicity and Methamphetamine Addiction
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批准号:9348473
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项目类别:
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资助金额:$0.0万
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财政年份:2017
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负责人:Chitra D Mandyam
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依托单位:
Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence
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批准号:9121372
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项目类别:
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资助金额:$25.03万
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财政年份:2016
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:9276837
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项目类别:
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资助金额:$0.91万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:9066260
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项目类别:
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资助金额:$0.98万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:8686809
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项目类别:
-
资助金额:$29.85万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:8506181
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项目类别:
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资助金额:$29.85万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:9281714
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项目类别:
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资助金额:$24.19万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:9043006
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项目类别:
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资助金额:$22.3万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:8856810
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项目类别:
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资助金额:$0.91万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Methamphetamine and adult hippocampal neurogenesis
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批准号:9480122
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项目类别:
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资助金额:$0.76万
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财政年份:2013
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负责人:Chitra D Mandyam
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依托单位:
Medial prefrontal cortical gliogenesis and alcohol dependence
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批准号:8237688
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项目类别:
-
资助金额:$30.34万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Medial prefrontal cortical gliogenesis and alcohol dependence
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批准号:8549933
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项目类别:
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资助金额:$30.84万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Medial prefrontal cortical gliogenesis and alcohol dependence
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批准号:8901841
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项目类别:
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资助金额:$32.17万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence
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批准号:9753067
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项目类别:
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资助金额:$32.06万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Medial prefrontal cortical gliogenesis and alcohol dependence
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批准号:8718945
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项目类别:
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资助金额:$32.17万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence
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批准号:10468061
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项目类别:
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资助金额:$32.06万
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财政年份:2012
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负责人:Chitra D Mandyam
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依托单位:
Regulation of Adult Neurogenesis by Methamphetamine
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批准号:8101237
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项目类别:
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资助金额:$16.43万
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财政年份:2007
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负责人:Chitra D Mandyam
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依托单位:
Regulation of Adult Neurogenesis by Methamphetamine
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批准号:7315180
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项目类别:
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资助金额:$15.2万
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财政年份:2007
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负责人:Chitra D Mandyam
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依托单位:
Regulation of Adult Neurogenesis by Methamphetamine
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批准号:7881579
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项目类别:
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资助金额:$16.1万
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财政年份:2007
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负责人:Chitra D Mandyam
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依托单位:
Regulation of Adult Neurogenesis by Methamphetamine
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批准号:7859976
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项目类别:
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资助金额:$0.82万
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财政年份:2007
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负责人:Chitra D Mandyam
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依托单位:
海外基金