Orr Laboratory

Memory loss, or forgetting, is prevalent in the elderly and is a key symptom of Alzheimer’s disease, the most common neurodegenerative illness. The causes of memory loss are not known and no effective treatments are available. This NIH-funded project aims to address how memory loss is influenced by astrocytes and could be alleviated by targeting astrocytic proteins. Advanced methods are being used to manipulate receptor signaling in astrocytes and enable functional and biochemical analyses of multiple neural cell types in parallel. The specific goal of this award is to elucidate how astrocytic Gs-coupled receptor signaling influences neuronal plasticity, cognitive function and behavior. This work promises to generate important advances in how we understand the brain and treat cognitive and behavioral deficits in diverse neurological disorders.

Astrocytes are abundant in the brain and astrocytic-neuronal interactions are crucial for brain function. However, the nature and roles of these interactions in health and disease are not clear. We recently discovered that receptor-mediated astrocytic-neuronal interactions regulate memory loss, possibly by affecting memory-linked gene transcription. In this project, we are investigating the causes of these effects by using spatially resolved astrocytic-neuronal transcriptomic profiling in combination with a novel protein marker linked to memory loss and disease. The ultimate goal of this project is to determine how gene expression is altered in hippocampal astrocytes and neurons in the context of neurodegeneration.

Despite a growing understanding of the various pathogenic mechanisms contributing to neurodegeneration, there are currently no disease-modifying treatments available for Alzheimer’s disease, frontotemporal dementia, and other related neurological disorders. New treatment strategies based on novel targets are essential for realizing this critical need. We hypothesize that progressive changes in cellular redox status and reactive oxygen species produced by the mitochondria are primary drivers of neuronal dysfunction and neuroinflammation in neurodegenerative disorders. In this project, we are testing candidate agents to reduce mitochondrial dysfunction in experimental models of neurodegenerative disease.

Astrocytes are critical for various neural functions, including synaptic development, neuronal communication, and responses to injury and disease. However, the roles of astrocytes in cognitive function are poorly understood. The main goal of this project is to elucidate how astrocytic receptor activation influences glial-neuronal interactions and behavior. Insights gained from these studies will shed light on novel neurobiological mechanisms that affect behavioral and cognitive processes, and may facilitate the development of effective therapies for diverse neurological disorders that involve aberrant changes in astrocytic receptor signaling and glial-neuronal interactions.

Astrocytes express a variety of Gprotein-coupled receptors that likely affect intracellular signaling, cell health and function, and animal behavior. This study is taking advantage of new advances in genome editing and engineered G protein-coupled receptors to selectively manipulate astrocytic receptor expression and activity in vivo. Using these techniques, we aim to determine how astrocytic receptor activation affects behavior and other neural processes.

Aging and neurodegenerative disease are associated with the accumulation of free radicals (also called oxidative stress) in the brain and other organs. Oxidative stress can damage cells and organs, promote inflammation and disease, and impair brain function. We previously discovered small molecules that can block specific sources of oxidative stress in the mitochondria without disturbing normal functions such as metabolism. In the current project, we are testing if these highly selective small molecules have therapeutic benefits in experimental models of neurodegenerative disease. Our goal is to determine whether blocking specific origins of oxidative stress is a promising therapeutic approach for dementia. We are using uniquely selective blockers of free radicals that we predict will have multipronged benefits on neuronal and glial functions in experimental models of disease. If successful, these translational studies would provide the first evidence that this approach is effective in reducing brain damage and neuroinflammation, and might be effective for treating a variety of neurodegenerative disorders that involve oxidative stress and mitochondrial impairments.