The role of medial prefrontal cortex CRF signaling in binge-like ethanol intake

内侧前额叶皮质 CRF 信号在暴饮暴食乙醇摄入中的作用

• 批准号: 9396186
• 负责人: Stacey Robinson
• 金额: $ 5.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396186
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Animals; Anxiety; Attention; Behavior; Bilateral; Biochemical; Blood; Brain; CRF receptor type 1; CRH gene; Cannulations; Clozapine; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Dangerousness; Darkness; Development; Diabetes Mellitus; Emotional; Ethanol; Ethanol dependence; Expenditure; Female; Goals; Health; Healthcare; Heart Diseases; Heavy Drinking; Human; Immunohistochemistry; Injection of therapeutic agent; Internal Ribosome Entry Site; Investigation; Lead; Link; Literature; Lobotomies; Maintenance; Medial; Mediating; Microinjections; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; National Research Service Awards; Neurobiology; Neurons; Neuropeptides; Oxides; Pattern; Pharmacogenetics; Pharmacology; Play; Prefrontal Cortex; Public Health; Research; Research Training; Rewards; Risk Factors; Rodent; Role; Signal Transduction; Site; Stress; System; Technical Expertise; Techniques; Technology; Testing; Time; Transgenic Mice; Transgenic Organisms; United States; Viral; Viral Vector; Water; Western Blotting; Withdrawal; Work; alcohol abuse therapy; alcohol behavior; alcohol exposure; alcohol response; alcohol seeking behavior; behavioral pharmacology; binge drinking; career; corticotropin releasing factor-binding protein; cost; design; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; executive function; experimental study; frontal lobe; insight; interest; male; mouse model; neglect; neural circuit; neuromechanism; receptor; response; therapeutic target

Project Summary/Abstract Alcohol dependence is a widespread public health concern with limited treatment options available. A growing body of evidence supports binge intake of ethanol as a significant risk factor for the development of ethanol dependence. Additionally, this form of excessive ethanol intake is associated with negative health effects, such as heart disease and diabetes, and represents a significant portion of the financial burden induced by alcohol use within the United States. Our lab and others have extensively demonstrated the neuropeptide corticotropin releasing factor (CRF) plays an important role in modulating binge ethanol consumption. Further, alterations in the CRF system are known to play an important role in ethanol-related behaviors both following the development of ethanol-dependence and into withdrawal. Dissecting the specific role of CRF in binge drinking behavior in non-ethanol dependent animals therefore enables the discovery of treatments for this risky pattern of behavior and, further, provides important insights into initial ethanol related alterations of a system critically involved in the development and maintenance of ethanol-dependence. The role of CRF in ethanol-related behaviors within the extended amygdala has been the focus of numerous investigations. However, the role of CRF within regions critical to entraining these limbic regions and coordinating reward-directed/inhibiting inappropriate behaviors has gone essentially neglected. This proposal focuses on addressing this hole in the literature by examining the role of CRF within the medial prefrontal cortex (mPFC) in modulating binge ethanol consumption. The proposed studies will employ biochemical, pharmacogenetic, transgenic, and behavioral pharmacological approaches. The well-validated model of binge-like ethanol intake in rodents ‘drinking in the dark’ (DID) will be used throughout these experiments. For Aim 1, I will use the DID paradigm and immunohistochemistry and western blot techniques to assess whether 1 or 3-weeks of DID alter components of the mPFC CRF system (CRF, CRF receptor 1 and 2 (CRF1R/CRF2R), CRF-binding protein). For Aim 2, I will use designer receptor technology (viral injection of Cre-dependent DREADDs) along with CRH-IRES-Cre transgenic mice in the DID model to (1) determine whether ‘silencing’ CRF neurons (via activation of inhibitory DREADDs) in the mPFC decreases binge-like ethanol intake and associated blood ethanol concentrations (BECs) and (2) assess whether activation of CRF neurons (via excitatory DREADDs) in the in the mPFC decreases binge-like ethanol intake and associated BECs. For Aim 3, I will use behavioral pharmacology and site-specific microinjections to assess the relative contribution of the CRF1R and CRF2R receptors within the mPFC in modulating binge-like ethanol intake in the DID paradigm. Results from this project will advance our understanding of the neural mechanisms underlying binge-like ethanol intake, as well as characterize the potential for specific components of the mPFC CRF system to serve as a therapeutic target for treatment of alcohol dependence.

项目摘要/摘要 酒精依赖是普遍的公共卫生问题，有限的治疗选择。成长 证据体支持乙醇作为乙醇发展的重要危险因素 依赖。此外，这种过多的乙醇摄入形式与负面的健康影响有关 作为心脏病和糖尿病，代表着酒精诱导的财务燃烧的很大一部分 在美国境内使用。我们的实验室和其他实验室已经广泛证明了神经肽皮质激素 释放因子（CRF）在调节暴饮暴食乙醇消耗中起着重要作用。此外，改变 众所周知，CRF系统在开发之后都在与乙醇相关的行为中起重要作用 乙醇依赖并撤离。剖析CRF在暴饮暴食行为中的特定作用 因此，非乙醇依赖性动物可以发现这种风险的行为模式的治疗方法 此外，还为与乙醇相关的最初相关的变化提供了重要的见解 乙醇依赖性的发展和维护。 CRF在乙醇相关行为中的作用 扩展的杏仁核一直是许多调查的重点。但是，CRF在区域内的作用 对于参加这些边缘区域和协调奖励指导/抑制不当行为至关重要 本质上被忽略了。该建议重点是通过检查文献中的这个漏洞 CRF在内侧前额叶皮层（MPFC）中的作用在调节暴饮暴食消耗中。 拟议的研究将采用生化，药物遗传学，转基因和行为药理学 方法。啮齿动物“黑暗中的饮酒”中的狂欢般的乙醇摄入量的验证模型将是 在这些实验中使用。对于AIM 1，我将使用DID范式和免疫组织化学以及 蛋白质印迹技术评估MPFC CRF系统的1个或3周的DID DID改变组件 （CRF，CRF受体1和2（CRF1R/CRF2R），CRF结合蛋白）。对于AIM 2，我将使用设计器受体 DID中的技术（病毒注射CRE依赖性恐惧deardds）以及CRH-IRES-CRE转基因小鼠 模型（1）确定MPFC中的“沉默” CRF神经元（通过激活抑制性恐惧）是否 降低贝格样乙醇摄入量和相关的血乙醇浓度（BEC）和（2）评估是否是否 MPFC中的CRF神经元激活CRF神经元（通过兴奋性恐惧）的激活降低了Benge样乙醇的摄入量 和关联的BEC。对于AIM 3，我将使用行为药理学和特定地点的微型注射来评估 MPFC内CRF1R和CRF2R受体在调节暴饮暴食样乙醇中的相对贡献 在DID范式中摄入。该项目的结果将提高我们对神经机制的理解 基本的Benge样乙醇摄入量，并表征了MPFC特定成分的潜力 CRF系统是治疗酒精依赖性的治疗靶标。