Immune-reward interactions: Contributions of the endocannabinoid system

我们的研究计划旨在回答一个简单的问题：当你生病时，你为什么会感到不快乐？当我们研究奖励刺激，如食物或药物，如何产生强迫性反应时，我们偶然发现了这个问题。经过特定生物操作的大鼠会生病，免疫功能受损，并表现出类似于人类抑郁症的行为。最终，我们意识到，我们忽视了一整篇关于免疫激活与奖赏缺陷的文献，这一现象有助于解释压力对心理健康的有害影响。通过研究这种联系的机制基础，我们提出了一个新的假说，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形床核(OvBNST)神经元可塑性的改变来调节应激对奖赏加工的影响。我们将从五个不同的角度来检验这一假设，每个角度都与特定的方法论方法相关联。这些学科包括行为药理学、分子生物学、电生理学、计算模型和人类神经成像。我已经建立了国家和国际合作，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，并为他们提供机会，在培训的不同点在大型跨学科团队中工作。我们研究计划的一个主要优势是临床实用性：我们在啮齿类动物和人类身上使用相同的奖励行为衡量标准，这些测试基于国家卫生研究院研究领域标准指定的核心功能领域。因此，我们的工作有可能影响药物的发现和治疗干预措施的开发，以治疗与奖赏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回报效应，将这项工作从近距离(因果)解释扩展到最终(功能)解释。研究奖励的行为神经学家通常关注自然主义行为，如进食、繁殖或母爱。但包括人类在内的许多动物都花了大量的时间进行梳理，这有助于将寄生虫降至最低，减少感染。我现在正在与行为生态学家合作，研究奖励机制是如何在不同的物种中维持梳理的。一种耐人寻味的可能性是，在自然环境中从事有益的行为可以“挽救”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。它可以解释压力易感性的个体差异，因为对压力的行为和生物反应可能是性别相关的。

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.