5/8: INIA Stress and Chronic Alcohol Interactions: Stress-induced Dysregulation of Prefrontal Cortex Circuitry and Plasticity in Alcohol Dependence

5/8：INIA 压力和慢性酒精相互作用：压力引起的前额皮质回路失调和酒精依赖的可塑性

• 批准号: 10090537
• 负责人: PATRICK J. MULHOLLAND
• 金额: $ 33.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090537
• 关键词: Abstinence; Address; Adult; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Behavioral; Bioinformatics; Biosensor; Brain; Brain Diseases; Chronic; Chronic stress; Clinical Research; Cognition; Cognitive deficits; Collaborations; Coupled; Data; Development; Drug Targeting; Electrophysiology (science); Ethanol; Ethanol dependence; Exposure to; Feasibility Studies; Female; Fiber; Funding; Genes; Glutamates; Heavy Drinking; Impaired cognition; Impairment; Inbred Strains Mice; Individual; Knowledge; Label; Long-Term Potentiation; Macaca; Maintenance; Medial; Mediating; Monkeys; Morphology; Mus; Neurons; Nucleus Accumbens; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Photometry; Potassium Channel; Prefrontal Cortex; Public Health; Publishing; Recombinant Inbred Strain; Relapse; Rewards; Rodent; Role; Self Administration; Short-Term Memory; Signal Transduction; Stress; Structure; Swimming; System; Testing; Time; Treatment outcome; Validation; Viral; alcohol abuse therapy; alcohol exposure; alcohol use disorder; biological adaptation to stress; cognitive function; computing resources; drinking; drug efficacy; efficacy testing; experimental study; flexibility; functional adaptation; glutamatergic signaling; in vivo; male; motivated behavior; nerve supply; neuroadaptation; neuromechanism; neuronal patterning; new therapeutic target; novel; novel therapeutics; preclinical study; prevent; protein K; relapse risk

PROJECT SUMMARY Alcohol use disorder is a major public health issue associated with altered activation of brain stress systems, cognitive deficits, and escalated alcohol drinking. The prefrontal cortex (PFC) is a key structure involved in executive cognitive function and imposing inhibitory control over reward-motivated behaviors. Altered stress responsivity is implicated in the development and maintenance of excessive alcohol drinking, and both chronic ethanol and stress negatively impact PFC function. Cognitive deficits in individuals with alcohol use disorder are thought to hinder successful treatment and contribute to increased risk for relapse. Preclinical studies show that chronic ethanol exposure produces an exaggerated stress response in the PFC that mediates cognitive impairments and escalated ethanol drinking. In the current funding period, we identified chronic ethanol- sensitive proteins and K+ channel genes in the PFC and nucleus accumbens (NAc) of mice and monkeys. We also identified predictive relationships between candidate K+ channel genes and drinking in ethanol-dependent BXD recombinant inbred strains of mice, and pharmacological validation showed that positive modulation of a KCa2 channels significantly reduces escalated drinking in stressed, dependent mice. Moreover, we demonstrated that chronic stress elevates drinking only in ethanol dependent mice and enhances the magnitude of the early component of long-term potentiation (LTP) in the mouse PFC. In addition to the enhanced LTP we observed in the stressed mice, our preliminary data shows that glutamatergic signaling in the PFC is enhanced in macaques following chronic ethanol self-administration. While it is known that chronic ethanol and stress exposure elicit maladaptive plasticity in the PFC, the underlying neural mechanisms and the adaptations in the PFC circuitry induced by ethanol-stress interactions remain poorly understood. To address this gap in our knowledge, we propose three specific aims that will test the overarching hypothesis that disruption of PFC circuitry and plasticity underlies the excessive drinking and cognitive impairments produced by chronic stress and ethanol dependence. Studies in Aim 1 will test the hypothesis that chronic ethanol self- administration and interactions between ethanol dependence and stress produce functional adaptations in the PFC of monkeys and mice. Aim 2 will test the efficacy of drugable proteogenetic targets to reduce escalated drinking in stressed dependent male and female mice. Finally, studies in Aim 3 will test the hypothesis that ethanol dependence and chronic stress produce aberrant signaling in PFC circuitry that contributes to escalated drinking and cognitive impairments. In addition to identifying drugable targets, the findings from these studies will provide data on the temporal aspects of circuit-specific, functional, and morphological adaptations produced by chronic stress and ethanol in the mouse and monkey PFC.

项目总结

项目成果

Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses.

针对新兴和重新出现病毒生命周期的各个阶段的小分子病毒抑制剂的发展。

• DOI: 10.1007/s11684-017-0589-5
• 发表时间: 2017-12
• 期刊: Frontiers of medicine
• 影响因子: 8.1
• 作者: Wang X;Zou P;Wu F;Lu L;Jiang S
• 通讯作者: Jiang S

A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses.

基于肽的病毒灭活剂可抑制怀孕小鼠和胎儿的寨卡病毒感染

• DOI: 10.1038/ncomms15672
• 发表时间: 2017-07-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yu Y;Deng YQ;Zou P;Wang Q;Dai Y;Yu F;Du L;Zhang NN;Tian M;Hao JN;Meng Y;Li Y;Zhou X;Fuk-Woo Chan J;Yuen KY;Qin CF;Jiang S;Lu L
• 通讯作者: Lu L

Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations.

靶向gp41的HIV-1融合抑制剂的合理改进：创新设计的具有替代构象的Ile-Asp-Leu尾

• DOI: 10.1038/srep31983
• 发表时间: 2016-09-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zhu Y;Su S;Qin L;Wang Q;Shi L;Ma Z;Tang J;Jiang S;Lu L;Ye S;Zhang R
• 通讯作者: Zhang R

Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy.

HIV融合抑制剂AP3的药理和结构特性优于恩夫韦肽：凸显人工肽策略的优势

• DOI: 10.1038/srep13028
• 发表时间: 2015-08-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zhu X;Zhu Y;Ye S;Wang Q;Xu W;Su S;Sun Z;Yu F;Liu Q;Wang C;Zhang T;Zhang Z;Zhang X;Xu J;Du L;Liu K;Lu L;Zhang R;Jiang S
• 通讯作者: Jiang S