? PROJECT 3 Sensory and molecular signals from the environment influence brain activity and help shape psychological or physical responses. The gastrointestinal (GI) tract represents our largest portal to the molecular world around us, and sends signals that travel to all organs of the body that impact their function, including the brain. Conduits used for gut-to-brain communication include, among others, metabolites produced in the gut that may activate the enteric nervous system (ENS) and signal via the vagus nerve, or molecules may even reach the brain through systemic circulation. However, there is remarkably little known about the cellular and molecular mechanisms that connect the gut to the brain. Further, if indeed the flow of complex signals from the gut modulates brain activity, perhaps changes due to altered environments may result in deviations from brain health. Humans share an intimate and life-long association with multitudes of resident microbial species, known as the microbiome, which represents a potentially strong environmental factor in may diseases. Gut bacteria regulate nutrition and metabolism, and orchestrate the development and function of the immune system. Intriguingly, the community structure and composition of the gut microbiome is altered in neurologic conditions such as anxiety, depression, autism spectrum disorder (ASD), schizophrenia, Parkinson?s disease (PD) and Alzheimer?s disease (AD). Whether these changes are a consequence of disease or a contributor remain entirely unknown. Studies that distinguish correlation from causation are both challenging and unjustified in humans. Thus, we propose to study the functional contributions of the human microbiome in novel mouse models of AD to test the hypothesis that microbial signals that travel from the gut to the brain promote neuroimmune activation, pathology, and symptoms of neurodegeneration. While basic and clinical research is rapidly defining the pathophysiology of AD, the cause(s) of most cases remain unknown. Thus, even the best medicines, which are relatively ineffective or have severe side effects, only address symptoms and are not disease-modifying. We provide seminal evidence that the gut microbiome is a key contributor to the pathology of AD using mouse models, offering entirely novel perspectives into disease etiology. Unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially revolutionary diagnostics and treatments for Alzheimer?s disease.