Immune-reward interactions: Contributions of the endocannabinoid system

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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.