Abstract
Inflammation profoundly changes behavior, producing sickness behaviors such as fever, anorexia, fatigue, and reduced motivation. Rather than passive symptoms of illness, these behaviors are coordinated host defense mechanisms organized by the brain. However, how the brain interprets diverse peripheral immune signals, and how these adaptive mechanisms become maladaptive during chronic disease, remains incompletely understood. We investigate sickness behavior across three scales: circulating cytokine codes, acute behavioral function, and chronic neuroimmune circuit dysfunction. First, we profiled plasma cytokines and behavior across bacterial and viral pathogen mimics in mice to understand how cytokine conveys inflammation to the brain. Distinct immune challenges generate unique multi-cytokine patterns that predict both pathogen type and behavioral outcomes, including reduced movement and motivation. These findings suggest that the innate immune response conveys structured peripheral information to the brain through a combinatorial cytokine code. Second, we examine how infection-responsive brainstem circuits contribute to host defense during acute bacterial infection. Using an Escherichia coli infection model, we identify an ArP/NTS-PBN circuit that is engaged during illness and contributes to key physiological components of the host response. Silencing this pathway blunts fever, prolongs fat-based fuel utilization, and increases bacterial burden in the liver, suggesting impaired antibacterial defense. Although locomotor activity was altered by this manipulation, baseline activity differences limited direct interpretation of its role in sickness-induced fatigue. These findings identify the ArP/NTS-PBN circuit as a caudal brainstem circuit associated with thermoregulation, metabolic adaptation, and bacterial control during acute infection, while leaving its direct role in fatigue unresolved. Third, we identify how this adaptive neuroimmune mechanism becomes maladaptive in chronic inflammation using a mouse model of cancer cachexia. In this model, cancer cachexia increases effort sensitivity leading to apathy. We identify a brainstem-to-basal-ganglia circuit through which tumor-derived IL-6 suppresses mesolimbic dopamine and induce motivational deficits. Targeting this pathway with anti-IL-6 antibodies, ablating brainstem cytokine-receptor, or boosting mesolimbic dopamine reverses these behavioral symptoms, revealing a potential framework for treating inflammation-induced motivational deficits. Together, this work defines sickness behavior as an active brain-body process that can support host defense during acute infection but contribute to motivational dysfunction during chronic inflammation. By linking peripheral cytokine codes to infection-responsive brainstem circuits and chronic inflammation-induced motivational deficits, this dissertation reframes motivation and effort allocation as central features of the brain’s response to inflammation.
Committee Chair
Adam Kepecs
Committee Members
Alexxai Kravitz; Kodi Ravichandran; Meaghan Creed; Timothy Holy
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Neurosciences)
Document Type
Dissertation
Date of Award
8-11-2026
Language
English (en)
DOI
https://doi.org/10.7936/d1dz-n030
Recommended Citation
Zhu, Xiaoyue, "Circuit and Cytokine Regulation of Effort Allocation in Acute and Chronic Sickness States" (2026). Arts & Sciences Graduate Student Theses and Dissertations. 3857.
The definitive version is available at https://doi.org/10.7936/d1dz-n030