Dr. Cathy W. Levenson

Research Interest

Molecular mechanisms of adult neurogenesis: stem cell proliferation, neuronal precursor survival and apoptosis, neuronal differentiation and migration.

Current Projects

The recent discovery of stem cells in the adult human brain that are capable of proliferating and becoming new neurons is a promising new development for the treatment of neurodegenerative diseases and other conditions, such as traumatic brain injury, where neurons are lost and neurogenesis is needed. While we know that these stem cells are regulated by factors such as diet, exercise, antidepressant drugs, and stress, the mechanisms that govern these cells and their role in adult neurogenesis are not well understood. The Levenson lab uses rodent models as well as cultured human neuronal precursor cells to understand the cellular and molecular mechanisms that are responsible for proliferation, survival, and differentiation of adult stem cells in the brain.

Hippocampal Neurogensis: The Molecular Roles of Zinc

Our lab has shown that the trace element zinc regulates adult stem cells in the subgranular zone of the adult dentate gyrus. Thus, we are working to identify and study the cellular and molecular mechanisms that govern the role of zinc in adult stem cell survival, neuronal precursor proliferation, and neuronal differentiation. The importance of these cells in the hippocampus is illustrated by recent observations that antidepressant drugs enhance the survival of adult stem cells in this region of the brain. This information, coupled with our recent findings that zinc deficiency induces depression-like and anxiety-like behaviors and impairs the efficacy of the commonly prescribed antidepressant drug, fluoxetine, suggests an important role for zinc not only in adult neurogenesis, but also in the behaviors that it controls. Thus, our current work is designed to examine the zinc-regulated nuclear and mitochondrial factors, such as the tumor suppressor protein p53, that are responsible for the regulation of adult stem cells and neurogenesis. Recent publications from the Levenson lab on the behavioral and molecular roles of zinc include:

Neuronal Death & Survival: The Treatment of Traumatic Brain Injury

Neuronal injury and death appears to be a trigger for stem cell proliferation and adult neurogenesis. Every year 1.5 million Americans sustain a traumatic brain injury (TBI). Among the long list of impairments that can result from TBI, including loss of both fine and gross motor skills as well as speech and language abilities, many patients also experience life-long impairment of learning, memory and cognitive function. The Levenson lab is exploring ways to promote neuronal survival after traumatic brain injury, induce neurogenesis, and improve behavioral outcomes. In collaboration with Dr. Jacob VanLandingham, of the College of Medicine, and Dr. Victor Schepkin at the National High Magnetic Field Laboratory we have been using a variety of hormonal and dietary approaches to treat traumatic brain injury including caloric restriction, vitamin D, and progesterone. Not only have we shown significant improvements in learning and memory after brain injury, we are able to track changes in cytotoxic and vasogenic edema using novel diffusion-weighted imaging at 21T. Publications from the Levenson lab on traumatic brain injury include:

Copper: Neuronal Damage and Death in Wilson's Disease

Wilson's disease is characterized by copper accumulation in the liver and brain resulting in damage to nuclear and mitochondrial DNA, hepatic fibrosis and cirrhosis, and neuronal damage. We have shown that one of the key molecular regulators of neuronal proliferation, repair and apoptotic death is the tumor suppressor protein p53. This DNA-binding transcription factor acts on downstream target genes to stop the cell cycle, initiate cellular repair, and, when there is extensive damage, induce the apoptotic cascade to eliminate the cell. Our lab uses a variety of techniques including gene expression profiling of p53 target genes, p53-responsive reporter genes, and transfection of human neurons with a dominant-negative p53 construct to determine the role of p53 in copper-mediated neuronal damage and death. We have not only identified the molecular cascade responsible for neuronal apoptosis, but have also shown that copper induces a conformational mutant form of p53 with altered transcriptional properties. Recent publications in this area include:

Publications

• Levenson CW, Somers RC. Nutritionally regulated biomarkers for breast cancer. Nutr Rev. 66(3):163-6. (2008)
• Tassabehji NM, Corniola RS, Alshingiti A, Levenson CW. Zinc deficiency induces depression-like symptoms in adult rats. Physiol Behav. 95(3):365-9. (2008)
• Corniola RS, Tassabehji NM, Hare J, Sharma G, Levenson CW. Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Res. 1237:52-61. (2008)
• Levenson CW, Figueiroa SM. Gestational vitamin D deficiency: long-term effects on the brain. Nutr Rev. 66(12):726-9. (2008)
• Levenson CW, Rich NJ. Eat less, live longer? New insights into the role of caloric restriction in the brain. Nutr Rev. 65(9):412-5. (2007)
• Hooshmand S, Soung do Y, Lucas EA, Madihally SV, Levenson CW, Arjmandi BH. Genistein reduces the production of proinflammatory molecules in human chondrocytes. J Nutr Biochem. 18(9):609-14. (2007)
• Blakemore LJ, Levenson CW, Trombley PQ. Neuropeptide Y modulates excitatory synaptic transmission in the olfactory bulb. Neuroscience. 138(2):663-74. (2006)
• Levenson CW. Zinc: the new antidepressant?. Nutr Rev. 64(1):39-42. (2006)
• Levenson CW. Regulation of the NMDA receptor: implications for neuropsychological development. Nutr Rev. 64(9):428-32. (2006)
• Levenson CW, Axelrad DM. Too much of a good thing? Update on fish consumption and mercury exposure. Nutr Rev. 64(3):139-45. (2006)
• Levenson CW. Zinc supplementation: neuroprotective or neurotoxic?. Nutr Rev. 63(4):122-5. (2005)
• Levenson CW. Trace metal regulation of neuronal apoptosis: from genes to behavior. Physiol Behav. 86(3):399-406. (2005)
• Tassabehji NM, VanLandingham JW, Levenson CW. Copper alters the conformation and transcriptional activity of the tumor suppressor protein p53 in human Hep G2 cells. Exp Biol Med (Maywood). 230(10):699-708. (2005)
• Vanlandingham JW, Tassabehji NM, Somers RC, Levenson CW. Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. Neuromolecular Med. 7(4):311-24. (2005)
• Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP. Role of dietary iron restriction in a mouse model of Parkinson's disease. Exp Neurol. 190(2):506-14. (2004)
• Levenson CW, Tassabehji NM. Iron and ageing: an introduction to iron regulatory mechanisms. Ageing Res Rev. 3(3):251-63. (2004)
• Evans SA, Overton JM, Alshingiti A, Levenson CW. Regulation of metabolic rate and substrate utilization by zinc deficiency. Metabolism. 53(6):727-32. (2004)
• Evans SA, Overton JM, Alshingiti A, Levenson CW. Regulation of metabolic rate and substrate utilization by zinc deficiency. Metabolism. 53(6):727-32. (2004)