Immune-reward interactions: Contributions of the endocannabinoid system

我们的研究项目旨在回答一个简单的问题：当你生病时，为什么会感到不开心？我们在研究食物或药物等有益刺激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会生病，免疫功能低下，并表现出模仿人类抑郁的行为。最终，我们认识到，我们忽略了整个有关免疫激活与奖励缺陷的文献，这种现象有助于解释压力对心理健康的有害影响。通过研究这种关联的机制基础，我们提出了一种新的假设，即神经炎症通过与内源性大麻素系统（ECS）的相互作用和终纹椭圆床核（ovBNST）神经元可塑性的改变，介导应激对奖励处理的影响。我们将从五个不同的角度来检验这一假设，每个角度都有一个特定的方法方法。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。我建立了国内和国际合作，提供这些最先进的技术，确保我的学生接受该领域专家的技术培训，并在培训的不同阶段为他们提供在大型跨学科团队中工作的机会。我们研究项目的一个主要优势是临床效用：我们在啮齿动物和人类身上使用相同的奖励行为测量方法，这些测试基于美国国立卫生研究院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干预措施的发展，以治疗与奖励功能障碍相关的疾病，如抑郁症或药物滥用。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，将这项工作从近因（因果）扩展到最终（功能）解释。研究奖励的行为神经学家通常关注自然行为，如喂养、繁殖或照顾母亲。但包括人类在内的许多动物都会花大量时间梳理毛发，以减少寄生虫和感染。我现在正在与行为生态学家合作，研究不同物种的奖励机制是如何维持毛发梳理的。一种有趣的可能性是，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-奖励相互作用的系统研究将提供应激诱导的神经炎症如何在行为中表现出来的概述。它可以解释个体对压力敏感性的差异，因为对压力的行为和生物反应可能是性别依赖的。

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.