Pilot: The Honeybee as a Model for Brain Inflammatory and Metabolic Effects of Systemic Inflammation

Program Director/Principal Investigator (Last, First, Middle): Rittschof, Clare C. PROJECT SUMMARY (See instructions): Systemic inflammation caused by stress, infection, and chronic disease can lead to cognitive decline and increased incidence of Alzheimer’s disease. Neuroinflammation and associated changes in brain metabolic homeostasis underlie these effects; however, these mechanisms are complex, involving a variety of neuronal and glial sub-types, interconnected metabolic pathways, and the energetic and oxidative stress contributions of mitochondria. Our goal is to develop the honey bee (Apis mellifera) as a simple model to study the connections between systemic inflammation, brain metabolic homeostasis, and cognition. The honey bee is a well- established model for learning and memory studies. The building blocks of brain metabolism in honey bees are nearly identical to mammals: interventions that modulate brain mitochondrial respiration in mammals behave similarly, and brain metabolic homeostasis covaries with aggression, a behavioral phenotype often associated with cognitive decline. Our preliminary data show that systemic infection in honey bees alters aggression and decreases associative learning abilities, suggesting impacts on brain metabolism, but no study has assessed the accompanying inflammatory and metabolic responses. We propose a series of experiments to characterize the brain cellular and metabolic response to systemic infection, with the eventual goal of determining how changes in metabolic homeostasis give rise to infection-related declines in cognition. In Aim 1, we use mitochondrial functional assays to assess whether infection modulates brain mitochondrial respiration in learning centers of the brain. In Aim 2, we use metabolomics approaches to assess how infection alters central and fatty acid metabolism in the brain. Aim 3, we use single-nucleus RNAseq in the brain to determine the nervous system processes and cell types associated with infection, and whether these are localized to sensory integration and learning centers. Evaluating the neuroinflammatory and metabolic effects of systemic infection is critical to mitigating cognitive impacts of common, chronic diseases. Our proposed work develops a novel, tractable animal model in which it is possible to study the effects of acute inflammation in healthy animals, as well as longer-term, chronic effects on nervous system function and cognition. RELEVANCE (See instructions): Systemic inflammation caused by stress, infection, and chronic disease can lead to cognitive decline and increased incidence of Alzheimer’s disease. Neuroinflammation and associated changes in brain metabolic homeostasis underlie these effects; however, these mechanisms are complex, involving a variety of neuronal and glial sub-types, interconnected metabolic pathways, and the energetic and oxidative stress contributions of mitochondria. Simple animal models can be used to dissect the brain molecular and metabolic effects of systemic inflammation, and to link these components to short- and long-term cognitive outcomes. Our goal is to develop the honey bee (Apis mellifera) as a simple model to study the connections between systemic inflammation, brain metabolic homeostasis, and cognition. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: University of Kentucky Research Foundation DUNS: H1HYA8Z1NTM5 Street 1: 500 South Limestone Street 2: 109 Kinkaid Hall City: Lexington County: Fayette State: KY Province: Country: USA Zip/Postal Code: 40526-0001 Project/Performance Site Congressional Districts: KY-006 Additional Project/Performance Site Location Organizational Name: DUNS: Street 1: Street 2: City: County: State: Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: Page 2 OMB No. 0925-0001 PHS 398 (Rev. 03/2020 Approved Through 02/28/2023) Form Page 2