ABSTRACT Psychological symptoms are common when fighting an infection: Illness causes both physical and mental fatigue and loss of motivation. Such symptoms are harmless when they are transient during acute illnesses, such as the flu. However, chronic inflammatory disorders, including cachexia and endometriosis, produce similar but intensified behavioral disturbances, manifesting as extreme fatigue and depression. This phenomenon likely reflects an evolutionarily ancient communication channel between the immune and central nervous systems, prompting the brain to promote rest to adaptively cope with short-term insults. Yet, how this phenotypic convergence on motivational deficits arises at the level of brain regions and neural circuits controlling such behaviors remains unclear. This project aims to elucidate the function of immune-sensing neural circuits using the cutting-edge tools of neuroscience. By utilizing whole-brain cellular resolution activity mapping and cell-type-specific manipulation, coupled with a quantitative dissection of circuit dynamics, it intends to bridge the gap between sensory neuroscience and systems immunology. This will allow characterizing the cytokine codes to elucidate how neural circuits interpret and subsequently guide appropriate behavioral responses. These investigations will use a range of mouse models, spanning both acute infections and chronic inflammatory conditions, such as endometriosis, cardiac cachexia, and cancer cachexia. This research promises a paradigm shift by uncovering the principles through which neural circuits interpret cytokine codes to deduce immune states and reveal novel neuroimmune mechanisms governing mood and motivation. These insights are poised to unlock new therapeutic targets, enhancing treatment strategies to alleviate motivational symptoms for the over 50 million Americans suffering from chronic inflammatory conditions.

NARRATIVE Many non-brain disorders accompanied by acute or chronic systemic inflammation result in common behavioral symptoms like extreme fatigue and diminished motivation. The neuro-immune mechanisms and specific brain circuits mediating these convergent symptoms remain unidentified. Here, we will employ high-resolution brain-wide scans along with advanced neuroscience techniques, investigating five mouse models of systemic inflammation, aiming to pinpoint central circuits connecting inflammation to these behavioral symptoms.