PROJECT SUMMARY/ABSTRACT Tremor is the most common neurological movement disorder in the world, affecting over 10 million people in the U.S. alone. Characterized by involuntary, uncontrollable oscillating movements of body parts, tremor is debilitating to patients and can emerge at any age, in both genders, from genetic or idiopathic origins. Tremor pathology is thought to involve motor brain centers such as the cerebellum, but the identities of specific cellular activity patterns and molecular mechanisms underlying tremor remain a mystery. To study these unknowns, I developed a method of studying tremor using the prescription drug propranolol as a mechanistic tool to uncover cerebellar pathways and circuit activity patterns that drive tremor, with hopes of revealing potential therapeutic targets. Propranolol is a β-adrenergic receptor blocker (or beta-blocker) that has been continuously prescribed to patients as a first-line treatment for tremor since 1965. Though its neural mechanisms for tremor reduction are not yet understood, propranolol’s high rate of efficacy in tremor patients makes it an ideal and unique tool for the study of tremor pathology. Motivated by the increasingly extensive literature implicating that cerebellar circuit activity abnormalities may contribute to tremor, I administered propranolol to mice that exhibit a robust genetic form of tremor, and found that not only was propranolol highly effective in eliminating the tremor phenotype, but that cerebellar activity was significantly altered during propranolol’s active tremor reduction. In mice with genetic tremor, Purkinje cells are known to fire more irregularly and at a much higher firing rate. Using in vivo electro- physiology, I found that propranolol dramatically reduces Purkinje cell firing rate in mice with genetic tremor. Moreover, the duration of this reduced firing rate correlated with the duration of decreased tremor severity; once enough time had passed that propranolol was eliminated from the system, Purkinje rates returned to tremorgenic levels, and the tremor phenotype returned as well. My data raise the intriguing hypothesis that abnormal firing patterns of key cells in the cerebellar circuit, such as Purkinje cells whose activity patterns are readily altered by propranolol, are at the heart of tremor pathology in the brain. To test this hypothesis, I generated two aims to further uncover the cerebellar functions underlying tremor, using propranolol as a mechanistic tool to test the molecular genetic properties of the cerebellum in tremor (Aim 1), and to dissect the role of Purkinje cell activity in generating and reducing tremor (Aim 2). For both aims, I will use genetic crosses to create mice with targeted manipulations of genes in the cerebellar circuit and in vivo electrophysiology recordings of cerebellar neurons in behaving animals. The completion of these aims will call for a reevaluation of the unsolved and debated theories that attempt to explain how ...