Immune-reward interactions: Contributions of the endocannabinoid system

免疫奖赏相互作用：内源性大麻素系统的贡献

• 批准号: RGPIN-2020-04118
• 负责人: Olmstead, Mary
• 金额: $ 4.01万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764101
• 关键词: Immune; reward; interactions; Contributions; endocannabinoid

Our research program is directed towards answering a simple question: When you are sick, why do you feel unhappy? We stumbled across this problem as we were examining how rewarding stimuli, such as food or drugs, produce compulsive responding. Rats that underwent a specific biological manipulation became ill, were immunocompromised, and displayed behaviours mimicking depression in humans. Eventually, we recognized that we had overlooked an entire literature relating immune activation to reward deficits, a phenomenon that helps to explain the detrimental effects of stress on mental health. Examining the mechanistic underpinnings of this association led us to develop a novel hypothesis that neuroinflammation mediates the impact of stress on reward processing via an interaction with the endocannabinoid system (ECS) and altered neuronal plasticity in the oval bed nucleus of the stria terminalis (ovBNST). We will examine this hypothesis from five different perspectives, each associated with a specific methodological approach. These include behavioural pharmacology, molecular biology, electrophysiology, computational modelling, and human neuroimaging. I have established national and international collaborations that provide access to these state-of-the-art techniques, ensuring that my students receive technical training from experts in the field and providing them with the opportunity to work in large, interdisciplinary teams at various points in their training. A primary strength of our research program is clinical utility: we use the same behavioural measures of reward in rodents and humans, tests that are based on core domains of functioning as specified by the National Institutes of Health Research Domain Criteria. Our work, therefore, has the potential to impact drug discovery and the development of therapeutic interventions for treating conditions associated with reward dysfunction, such as depression or substance abuse. In the long-term, I propose to extend this work from proximate (causal) to ultimate (functional) explanations by analyzing the rewarding effect of behaviours that promote immune function. Behavioural neuroscientists studying reward often focus on naturalistic behaviours such as feeding, reproduction, or maternal care. But many animals, including humans, devote an enormous amount of time to grooming, which functions to minimize parasites and reduce infection. I am now establishing collaborations with behavioural ecologists to investigate how reward mechanisms maintain grooming in different species. One intriguing possibility is that engaging in rewarding behaviour in the natural environment `rescues' deficits induced by stress or neuroinflammation. Our systematic study of immune-reward interactions will provide an overview of how stress-induced neuroinflammation is manifested in behaviour. It could explain individual differences in stress susceptibility in that behavioural and biological responses to stress may be sex-dependent.

我们的研究项目旨在回答一个简单的问题：当你生病时，为什么你感到不快乐？我们在研究奖励性刺激（如食物或药物）如何产生强迫性反应时偶然发现了这个问题。接受特定生物操作的大鼠生病，免疫功能低下，并表现出模仿人类抑郁症的行为。最终，我们认识到，我们忽略了一整篇将免疫激活与奖励缺陷联系起来的文献，这一现象有助于解释压力对心理健康的有害影响。研究这种关联的机制基础使我们提出了一个新的假设，即神经炎症通过与内源性大麻素系统（ECS）的相互作用和终纹卵圆床核（ovBNST）中神经元可塑性的改变来介导压力对奖励处理的影响。我们将从五个不同的角度来检验这一假设，每个角度都与一种特定的方法论方法相关联。这些包括行为药理学、分子生物学、电生理学、计算建模和人类神经成像。我已经建立了国家和国际合作，提供访问这些国家的最先进的技术，确保我的学生接受该领域专家的技术培训，并为他们提供机会，在大型，跨学科的团队工作在不同的点在他们的培训。我们研究项目的主要优势是临床实用性：我们在啮齿动物和人类中使用相同的奖励行为措施，这些测试基于美国国立卫生研究院研究领域标准规定的核心功能领域。因此，我们的工作有可能影响药物发现和治疗与奖励功能障碍相关的疾病（如抑郁症或药物滥用）的治疗干预措施的开发。从长远来看，我建议通过分析促进免疫功能的行为的奖励效应，将这项工作从近似（因果）扩展到最终（功能）解释。研究奖赏的行为神经科学家通常关注自然行为，如喂养、生殖或母亲护理。但是，包括人类在内的许多动物都花了大量的时间来梳理，这有助于减少寄生虫和减少感染。我现在正在与行为生态学家建立合作关系，研究奖励机制如何维持不同物种的梳理。一个有趣的可能性是，在自然环境中参与奖励行为可以“拯救”由压力或神经炎症引起的缺陷。 我们对免疫-奖赏相互作用的系统研究将提供一个关于压力诱导的神经炎症如何在行为中表现的概述。它可以解释压力敏感性的个体差异，因为对压力的行为和生物反应可能是性别依赖的。