Advisory Committee Chair
Lynn E Dobrunz
Advisory Committee Members
Lori L McMahon
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Dysregulation of the GABAergic system has long been implicated in anxiety disorders. Classic anxiolytic drugs, such as benzodiazepines, increase GABAergic transmission by modulating GABA¬A receptors, relieving anxiety symptoms. However, these treatments are not always effective and are often accompanied by negative side effects. Glutamate decarboxylase (GAD) is the enzyme responsible for producing GABA. Recent studies have shown that when the isoform GAD67 is reduced in specific brain regions or GABAergic subtypes, differential anxiety effects were found. These studies suggest that targeting specific GABAergic cell subtypes may provide a more effective treatment for anxiety disorders. Neuropeptide Y (NPY) is an abundant neuropeptide in the central and peripheral nervous systems. NPY is found in a subset of GABAergic interneurons and is particularly abundant in brain regions important for anxiety (e.g. amygdala, hippocampus, and prefrontal cortex). NPY has been shown to regulate several neural processes and be involved in a variety of neurodevelopmental and neuropsychiatric disorders such as epilepsy, alcoholism, depression, and anxiety disorders. NPY levels are decreased in PTSD patients. NPY has been proposed as a treatment for anxiety and post-traumatic stress disorder due to its robust anxiolytics effects when applied acutely in rodents, particularly under stress conditions. However, recent studies have found that long-term NPY increases have negative off-target effects such as cardiac dysfunction and memory deficits. The data presented here investigate the behavioral effects of chronically changing the output of NPY cells (by reducing GABA or increasing NPY) through transgenic manipulation. These data show that a reduction in GAD67, and indirectly GABA, specifically in NPY cells leads to an increase in anxiety-like behavior in adolescent mice, suggesting a direct role of GABA released from NPY interneurons in anxiety regulation. I further show that when NPY is overexpressed there is a decrease in sensitivity to NPY in the stress sensitive temporoammonic pathway. These data highlight the need for more targeted therapeutics for anxiety disorders and further study into cell-specific GABA manipulation.
Corder, Katelynn, "Neuropeptide Y Cells Regulate Anxiety Behavior" (2018). All ETDs from UAB. 1418.