Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence

内侧前额叶皮质胶质生成和酒精依赖

• 批准号: 10733568
• 负责人: Chitra D Mandyam
• 金额: $ 40.52万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733568
• 关键词: Abstinence; Acute; Adherens Junction; Adult; Alcohol consumption; Alcohol dependence; Alcoholism; American; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Biological Assay; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Brain; Brain region; CD31 Antigens; Cadherins; Cell Separation; Cells; Chronic; Clinical Research; Collaborations; Cues; Data; Electrophysiology (science); Endothelial Cells; Endothelium; Ethanol; Ethanol dependence; Female; Foundations; Functional disorder; Funding; Future; Gene Expression; Glutamates; Health; Immune response; Inflammatory; Inflammatory Response; Infusion procedures; Inhalation; Medial; Modeling; Neuronal Plasticity; Neurons; Patients; Peptides; Prefrontal Cortex; Proteins; Psychopathology; Public Health; Publishing; Rattus; Relapse; Research Institute; Rodent Model; Role; Self Administration; Surveys; Synaptic plasticity; Testing; Therapeutic Agents; Translational Research; Withdrawal; Work; alcohol seeking behavior; alcohol use disorder; angiogenesis; blood-brain barrier disruption; cadherin 5; chemokine; cytokine; diagnostic criteria; drinking; drinking behavior; functional plasticity; gliogenesis; hippocampal pyramidal neuron; male; novel marker; pharmacologic; prolonged abstinence; relapse prevention; sex; sexual dimorphism; stem; therapy design; transcriptome; transcriptome sequencing; vapor

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.

项目摘要/摘要 复发被定义为长时间禁欲后饮酒的恢复， 代表着酒精中毒的普遍公共卫生关注。 治疗范围 严重的酒精使用障碍（AUD）是对大脑造成的脆弱性因素的识别。 增强对乙醇饮用的复发； 与乙醇饮酒行为相关。 我们已经使用了慢性间歇性伊特醇蒸气吸入（CIE）乙醇依赖性的模型 证明雌性大鼠CIE期间乙醇自我给药的增加预示着更高的复发 与男性相比，在强迫节制期间触发乙醇饮酒 此外，我们已经表明，复发期间的饮酒与特异性细胞的增加有关 两性中MPFC中的血管生成肽PECAM -1，表明血脑屏障（BBB）不稳定性。 用抗增密剂治疗性别和复发降低的PECAM-1表达 雌性老鼠喝埃塞霍醇。 为了进一步了解BBB不稳定性和功能障碍的基础机制，我们已经开始研究 为了通过富含冲突细胞的富集分离内皮细胞。 测序最初介绍了从伊特罗莫尔幼稚的成年女性分离的细胞的内皮转录组和 雄性大鼠。 血管生成和研究型细胞稳定性，而雄性的细胞较高基因表达 与免疫反应有关。 分析MPFC在乙醇中幼稚的成年雄性大鼠大鼠较高表达和抗 与女性相比，炎性细胞因子和趋化因子支持性二态性。 在控制的MPFC中，内皮转录和免疫反应，乙醇幼稚的条件 并开放有关在伊特醇依赖期间发生变化的问题。 为了进一步支持BBB的不稳定性，我们表明粘附蛋白cadherin5（CDH5，VE- 在埃塞哥雌性和雌性大鼠的MPFC中，钙粘着蛋白）发生了显着改变。 证明在急性戒断期间，CDH5增加，在戒酒期间显着降低， 与乙醇饮酒相比，与乙醇的复发相比，在两性中都增加了 除了MPFC的吸收性变化外，电生理研究表明突触发生了改变 因此 CDH5在禁欲中的作用在促进两性乙醇饮酒中的复发中的作用通过改变你 MPFC中的内皮转录组，pro和抗炎反应和神经元 假设将通过3个特定目标进行检验。

项目成果

The Interplay between the Hippocampus and Amygdala in Regulating Aberrant Hippocampal Neurogenesis during Protracted Abstinence from Alcohol Dependence.

• 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

SCH23390 Reduces Methamphetamine Self-Administration and Prevents Methamphetamine-Induced Striatal LTD.

• 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

Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction-Like Behavior.

• DOI: 10.3233/bpl-150007
• 发表时间: 2015-10-09
• 期刊: Brain plasticity (Amsterdam, Netherlands)
• 作者: Somkuwar SS;Staples MC;Fannon MJ;Ghofranian A;Mandyam CD
• 通讯作者: Mandyam CD

Dietary restriction reduces hippocampal neurogenesis and granule cell neuron density without affecting the density of mossy fibers.

• 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

Synaptic Plasticity and its Modulation by Alcohol.

• DOI: 10.3233/bpl-190089
• 发表时间: 2020-12-29
• 期刊: Brain plasticity (Amsterdam, Netherlands)
• 作者: Avchalumov Y;Mandyam CD
• 通讯作者: Mandyam CD