Oral Presentations Brain Iron Relation to Dopamine and Glutamate in Restless Legs Syndrome

The restless legs syndrome (RLS) (AKA Willis Ekbom Disease) is a common and to some a disabling neurological disorder significantly disrupting lives of 2-3 % of adults in North America and Europe. It occurs with marked sleep loss, decreased work productivity, impaired quality of life and increased risk of cardiovascular disease. It has a well-documented brain iron deficiency affecting mostly the substantia nigra and striatum. Medications treating RLS indicate possible underlying biological dopaminergic and glutamatergic abnormalities. The medical and neuroscience question: How brain iron deficiency produces the neurobiological abnormalities of RLS. Cellular and animal models of brain iron deficiency reveal somewhat unexpected processes altering the dopaminergic and glutamatergic systems. These processes reveal pathways to the disease that include hypoxic pathway activation and changes in gene expression. Clinical and autopsy studies confirm and indicate clinical utility of these findings for guiding treatment development. This presentation after a brief video introduction to RLS will review evidence for hyper-dopaminergic state in RLS (pre-synaptic and extra-cellular dopamine increase) with post-synaptic adjustments. Iron deficiency and hypoxic pathway involvement relate to genetic findings and contribute to an expanded clinical presentation of RLS. Next will be consideration of possible alternate aspect of brain iron deficiency and RLS with glutamate involvement and hyperarousal. These combine to provide a more complete view of RLS and effects of brain iron deficiency. Finally iron treatment effects on brain iron and RLS will be noted in relation to issues of brain iron regulation and possible RLS treatment development. Leptin regulates energy balance. However, knowledge of the critical intracellular transducers of leptin signaling remains incomplete. Here we report that Rho-kinase 1 (ROCK1) regulates leptin action on body weight homeostasis by activating JAK2, an initial trigger of leptin receptor signaling. Leptin promotes the physical interaction of JAK2 and ROCK1, thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1. Mice lacking ROCK1 in either POMC or AgRP neurons, mediators of leptin action, display obesity and impaired leptin sensitivity. In addition, deletion of ROCK1 in the arcuate nucleus markedly enhances food intake, resulting in severe obesity. Of note, ROCK1 is a specific mediator of leptin, but not insulin, regulation of POMC neuronal activity. Our data identify ROCK1 as a key regulator of leptin action on energy homeostasis. In the context of developing novel non-invasive diagnostic and prognostic tools for mild traumatic brain injury (mTBI), this study aims to develop circulating microRNAs (miRNAs) as …