Anterior Insula Projections for Alcohol Drinking/Anxiety Interactions in Female and Male Rats

雌性和雄性大鼠饮酒/焦虑相互作用的前岛叶预测

• 批准号: 10608759
• 负责人: Frederic Woodward Hopf
• 金额: $ 53.56万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608759
• 关键词: Address; Agreement; Alcohol abuse; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Anterior; Anxiety; Behavior; Behavioral; Cells; Clinical; Data; Devices; Electrophysiology (science); Emotional; Female; Goals; Health; Heavy Drinking; Human; Implant; Individual; Insula of Reil; Intake; Link; Measures; Mediating; Mediator; Medical; Methods; Mood Disorders; Motivation; Neurons; Nucleus Accumbens; Output; Pattern; Prevalence; Probability; Property; Rattus; Rodent; Role; Sex Differences; Testing; Woman; Work; addiction; alcohol comorbidity; alcohol use disorder; anxiety-like behavior; chronic alcohol ingestion; comorbidity; compulsion; drinking; economic cost; experimental study; in vivo; male; men; negative affect; neuropsychiatry; new therapeutic target; novel; optogenetics; personalized medicine; rapid detection; response; sex; social

Abstract Alcohol Use Disorder (AUD) extracts substantial medical, social, and economic costs, and compulsion-like alcohol drinking (CLAD), where intake persists despite negative consequences, can be a particular obstacle to treatment. Also concerning is that problem drinking in women has risen dramatically, and women can have greater alcohol problems. However, mechanisms underlying sex differences remain poorly understood, although anxiety-like states can strongly contribute to alcohol drinking, and women have greater prevalence of mood disorders and AUD/anxiety comorbidity. Also, our rat studies suggest that females have greater persistence in responding for alcohol, as well as greater anxiety-like responding. Thus, to help develop better, personalized therapies, it is essential to understand sex differences and similarities in mechanisms underlying excessive drinking and comorbidity with anxiety. Alcohol intake is likely driven by its salient motivational properties, and anterior insula (aINS) is a critical regulator of responding to important situations and regulating accompanying emotional states. We find that specific aINS projections (including aINS-Nucleus Accumbens, NAcb) promote male CLAD, with little impact on alcohol-only drinking (AOD); in agreement, compulsion-like responding for alcohol in women and men with AUD activates a similar aINS circuit. However, very little is known about specific aINS mechanisms for alcohol drinking in females, or overcoming higher challenge more generally. Also, global aINS inhibition reduces AOD, but the underlying aINS projection(s) remain completely undiscovered. Here, we address the overarching hypothesis that different aINS circuits drive CLAD vs AOD, and, especially, that particular aINS circuits mediate both CLAD and anxiety-like behavior (ALB) in higher-anxiety individuals, which is especially cogent in females. Aim 1 uses projection-specific optogenetic inhibition to examine particular aINS projections for AOD and CLAD: aINS-NAcb and aINS- amygdala for CLAD, and aINS-posterior insula (pINS) for AOD. aINS-pINS projection is large, and pINS inhibition decreases drinking, but aINS-pINS is nearly unstudied in rodent. Also, to best understand how aINS outputs regulate behavior, it is critical to identify actual activity patterns within specific aINS projections. Thus, Aim 2 uses cutting edge in vivo electrophysiology recording methods with “opto-tagging” to identify firing patterns within specific aINS projections, especially predicted higher activity in females that underlies greater persistence for alcohol. Finally, Aim 3 examines potential sex differences in the relation between ALB and alcohol drinking, aINS encoding of these behaviors, and the impact of optogenetic inhibition of specific aINS projections on both ALB and drinking. We predict that higher ALB rats will have greater aINS encoding of both ALB and drinking, and greater optogenetic inhibition of ALB and intake, particularly in females. If successful, we will discover key aINS projection mechanisms that drive AOD, CLAD, ALB, and their interrelations, including important sex differences, which may open novel, sex-specific AUD treatments.

抽象的 酒精使用障碍（AUD）提取了大量的医疗，社会和经济成本，以及强迫症 饮酒（外壳），进气持续存在的负面后果，可能是特殊的障碍 治疗。还担心的是，女性饮酒的问题急剧增加，女性可以 更大的酒精问题。但是，性别差异的基础机制仍然很少理解， 尽管类似焦虑的状态可以强烈促进饮酒，而女性的患病率更高 情绪障碍和AUD/焦虑合并症。另外，我们的大鼠研究表明，女性的研究更大 持续反应酒精以及更大的焦虑般的反应。为了帮助更好地发展 个性化疗法，必须了解性别差异和基本机制的相似之处 动画过多的饮酒和合并症。酒精摄入量可能是由其显着动机驱动的 特性和前绝缘（AINS）是应对重要情况和调节的关键调节剂 参加情绪状态。我们发现特定的AINS项目（包括Ains-Nucleus Accumbens， NACB）促进雄性外壳，对仅酒精饮酒的影响很小（AOD）；同意，类似于强迫 在具有AUD的男性和男性中为酒精做出反应会激活类似的AINS电路。但是，很少 知道女性中饮酒的特定AINS机制，或克服更高的 更广泛地挑战。同样，全球AIN抑制会减少AOD，但基础AINS投影 保持完全未被发现。在这里，我们解决了不同Ains电路的总体假设 驱动包装与AOD，尤其是该特定的ains循环介导了外壳和类似动画的行为 （ALB）在较高焦虑的个体中，这在女性中尤为明智。 AIM 1使用特定于投影 光遗传学抑制以检查AOD和clad的特定AINS项目：ains-nacb和ains- Amygdala用于外壳，Ains-Posterior Insula（PIN）用于AOD。 ains-pins投影很大，销钉 抑制作用下降饮酒，但在啮齿动物中几乎没有研究Ains-Pins。另外，要最好地了解Ains 输出调节行为，至关重要的是确定特定AINS项目中的实际活动模式。那， AIM 2在体内电生理记录方法中使用尖端和“ to tagging”来识别射击 特定AINS项目中的模式，尤其是预测女性的较高活动，而女性则是更大的基础 酒精的持久性。最后，AIM 3考试在ALB和 饮酒，编码这些行为的AIN以及特定AIN的光遗传学抑制的影响 对ALB和饮酒的预测。我们预测，较高的Alb大鼠将具有更大的AIN编码 ALB和饮酒，以及对Alb和摄入量的较高的光学抑制作用，尤其是在女性中。如果成功， 我们将发现驱动AOD，Clad，Alb及其相互关系的关键AINS投影机制 包括重要的性别差异，这些性别差异可能打开新颖的，性别特定的AUD治疗。