Circadian (ca. 24 hr) rhythms are disrupted in mood disorders, and some treatments for mood disorders have specific effects on circadian clocks, pointing to a fundamental connection between cellular mechanisms of circadian clock function and mood regulation. However, because of the complexities of circadian and mood disorder phenotypes in humans, and the difficulty of assessing circadian function in psychiatric patients, previous studies have been limited to indirect or incomplete measures of circadian and mood phenotypes, and to small numbers of subjects. Mice bearing a mutation of the core clock gene Clock have recently shown promise as an animal model of mania, but circadian function has not been examined in relevant brain areas in such animal models. Objectives: Our long-term goal is to define the precise relationship between genetically determined cellular circadian clock function and human mood dysregulation. In this proposed project, we plan to determine the nature of cellular circadian dysfunction in mood disorders, whether this dysfunction extends to neurons from brain regions implicated in reward control in animal models, and whether there is a causal relationship between circadian clock dysfunction in such neurons and vulnerability to depression-like behavior. Research Design:
Our specific aims are to: (1) test for circadian dysfunction in human fibroblasts from mood disorders patients and healthy controls, (2) test for circadian dysfunction in neuronal cells from mouse models of mood disorders, and (3) test whether genetically manipulating neuronal circadian clocks affects depression- like behavior in a mouse model of depression. Methodology: We will obtain human cells from Dr. John Kelsoe at VASDHS, Dr. Richard Shelton at Vanderbilt University, and Dr. Bruce Cohen at McLean Hospital. We will assess circadian function in these cells by introducing a firefly luciferase reporter of Per2 clock gene expression, so that the cells glow with a circadian rhythm. Using a luminometer to measure the cells' bioluminescence, we will then be able to monitor cellular circadian function longitudinally in real time in these human cells, including quantitative measures of period, phase, amplitude, precision, and phase shifting response. We will use similar methods to assess circadian function in neurons from Clock-d19 mutant mice, a model of bipolar disorder, and mice in which we have induced learned helplessness, a model of depression. We will also quantify learned helplessness behavior in mice in which neuronal circadian clocks are genetically altered, either generally throughout the entire brain and body, or specifically in brai regions regulating mood, such as the lateral habenula, the ventral tegmental area, or the hippocampus. Clinical Relationships: This project's goal is an improved understanding of the relationship between cellular circadian clock mechanisms and mood disorders, particularly bipolar disorder. The project may ultimately lead to improved diagnostic and therapeutic approaches to mood disorders, which are major afflictions and sources of disability in veterans.
Of veterans returning from Iraq and Afghanistan seeking health care at V.A. facilities between 2001 and 2007, 35% received a mental health diagnosis (Cohen BE, J Gen Intern Med 25:18, 2010). Mood disorders are among the most common of these diagnoses, and leading causes of death and disability. Furthermore, the V.A. spends billions of dollars per year on healthcare for veterans with depression or bipolar disorder. The biological basis of these disorders is poorly understood, however, and novel approaches are needed. Dysfunction of the circadian (ca. 24 hr) timing system has been suspected for many years to play a role in mood disorders. With recent developments in circadian biology, it is now possible to test the function of the circadian clock rigorously in skin cells cultured from human patients, as well as in animal models of mood disorders. The studies proposed here, by delineating how the circadian clock is disrupted in mood disorders, could lead to improved therapeutic approaches to these common disorders that afflict our nation's veterans.
