David R. Riddle, PhD
University of Michigan, 1990
Current research in the Riddle lab focuses on brain aging, brain injury, and the neurobiological mechanisms underlying cognitive dysfunction. The research program includes basic science studies of the mechanisms of normal brain aging and aging-related cognitive decline, as well as translational studies of the effects of aging on the ability of the brain to resist and repair injury.
For several years we have been investigating the effects of the aging-related decline in the activity of the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis, one of the most consistent and striking aging-related endocrine changes, on the hippocampus and cerebral cortex and on learning and memory. In addition, we are studying the effects of aging on the mechanisms and extent of radiation-induced brain injury, with the goal of developing new therapies to reduce or prevent the radiation-induced cognitive dysfunction that is experienced by many cancer survivors that receive therapeutic brain irradiation.
Major goals of the studies of normal brain aging and the investigations of radiation-induced brain injury are 1) understanding the dynamic regulation and turnover of neuronal, macroglial, and microglial populations in the brain and 2) clarifying the role of oxidative stress and neuroinflammatory responses in contributing to normal aging and injury responses.
The laboratory uses both in vivo and in vitro approaches in normal and genetically modified rodent models and applies a variety of anatomical and cell-biological methods, including confocal microscopy, quantitative morphometric analyses, immunocytochemistry, behavioral testing, and biochemical and molecular assays. Collaborations with colleagues in several departments and institutions provide a diverse training environment for students and postdoctoral fellows. The laboratory is supported by grants from the National Institute on Aging and the National Cancer Institute.
Regulation of neuronal and glial turnover by aging and the GH/IGF-I axis. Recognition that new neurons are added in some neural regions and that glial cells turnover throughout the brain throughout life raises questions about the role of cell turnover in normal neural function and in mechanisms of and recovery from neural injury. We currently are investigating neurogenesis and oligodendrocyte turnover in normal aging, in models of GH/IGF-I deficiency, and following neural injury in order to better understand the regulation of these dynamic processes, how they contribute to neural deficits and plasticity, and how the processes might be modulated to promote better recovery following neural damage.
Neurobiological mechanisms and treatment of radiation-induced brain injury and cognitive dysfunction. More than 1.4 million patients will be diagnosed with cancer this year. Almost 22,000 will have primary brain tumors and 20-40% of the rest will develop brain metastases. Annually, up to 300,000 patients are treated with large field partial or whole brain irradiation (WBI). WBI has proven efficacy in eliminating neoplasms, but the dose that can be administered is limited by damage to the surrounding normal tissues. Up to 100,000 long-term survivors per year develop radiation-induced cognitive deficits that affect their daily life and there currently are neither preventative measures nor proven and effective treatments for late delayed effects of radiation-induced brain injury. We are working to better understand the neurobiological mechanisms of normal tissue injury and evaluating new therapeutic approaches that target radiation-induced neuroinflammation
In-field and out-of-field effects of stereotactic radiosurgery. Stereotactic radiosurgery (SRS) is used increasingly in the treatment of brain tumors and other intracranial pathologies. Clinical evidence indicates that normal brain injury and cognitive side effects are reduced with SRS (compared to whole-brain irradiation) but that neurobiological effects still may extend beyond the target tissue and affect neural function. With collaborators in the Department of Radiation Oncology we are using the Leksell Gamma Knife® to accomplish focal, unilateral irradiation of the rat brain in novel studies of in- and out-of-field effects and of dose-responses of radiation-induced neurobiological changes.
Current Laboratory Personnel:
- Liz Forbes – Research Assistant and laboratory manager
- Dr. Kun Hua – Research Associate
- Kelly Conner – Individual NRSA predoctoral fellow, Interdisciplinary Program in Neuroscience
- Dr. Gabriel Gutierrez Ospina – Fulbright Scholar and Visiting Professor, Universidad Nacional Autónoma de México
- Dr. Alma Fuentes Farias - Visiting Professor, Universidad Nacional Autónoma de México
- Dr. Hong Qu Shan – Postdoctoral fellow WFSM Dept. Neurobiology and Anatomy
- Dr. Matthew Schindler – 4th year Medical Student, WFSM (MD/PhD Interdisciplinary Program in Neuroscience
- Dr. Joshua Grill – Director of Recruitment and Education, Alzheimer's Disease Research Center, UCLA
- Dr. Robin Lichtenwalner Stromberg – Science Writer, JK Associates, Inc.
- Dr. Mary Melissa Niblock – Assistant Professor of Biology, Dickinson College
- Friedrich Hahn - Research Scientist, BD Technologies
Major Collaborators and Related Interests:
- Dr. Judy Brunso-Bechtold (WFSM – Neurobiology) – Regulation of GH/IGF-I axis by aging and caloric restriction; influence of GH/IGF-I on neural structure and function
- Dr. Mike Robbins (WFSM – Cancer Biology) – Radiation-induced normal tissue injury
- Dr. Michelle Nicolle (WFSM – Gerontology) – Analysis and mechanisms of cognitive decline
- Dr. J. Daniel Bourland (WFSM Radiation Oncology) – Neurobiological effects of stereotaxic radiosurgery using the Leksell Gamma Knife®
- Dr. William Sonntag (University of Oklahoma Health Sciences Center) – Regulation of cerebrovascular structure and function; molecular genetic models for studies of brain aging
- Dr. Gabriel Gutierrez Ospina (National Autonomous University of Mexico) and Dr. Barry Stein (WFSM Neurobiology) – Neural plasticity and neuronal substrates of multisensory integration
Hua K, Forbes ME, Lichtenwalner LJ, Sonntag WE, Riddle DR (2009) Adult-onset deficiency in growth hormone and insulin-like growth factor-I alters oligodendrocyte turnover in the corpus callosum. Glia 2008 Dec. 29 (Epub ahead of print).
Adams MM, Elizabeth Forbes M, Constance Linville M, Riddle DR, Sonntag WE, Brunso-Bechtold JK (2009) Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I. Growth Factors Apr 2:1. [Epub ahead of print]
Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK (2008) Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol 211(1):141-9.
Schindler MK, Forbes ME, Robbins ME, Riddle DR (2008) Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys 70(3):826-34.
Ingraham JP, Forbes ME, Riddle DR, Sonntag WE (2008) Aging reduces hypoxia-induced microvascular growth in the rodent hippocampus. J Gerontol A Biol Sci Med Sci 63(1):12-20.
Riddle DR, Schindler MK (2007) Brain aging research. Rev Clin Gerontol 17:229-235.
Newton IG, Forbes ME, Linville MC, Pang H, Tucker EW, Riddle DR, Brunso-Bechtold JK (2007) Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits. Neurobiol Aging 29(9): 1308-1318.
Shi L, Adams MM, Linville MC, Newton IG, Forbes ME, Long AB, Riddle DR, Brunso-Bechtold JK (2007) Caloric restriction eliminates the aging-related decline in NMDA and AMPA receptor subunits in the rat hippocampus and induces homeostasis. Exp Neurol 206(1):70-79.
Sonntag WE, Bennett C, Ingram R, Donahue A, Ingraham J, Chen H, Moore T, Brunso-Bechtold JK, Riddle DR (2006) Growth hormone and IGF-1 modulate local cerebral glucose utilization and adenosine triphosphate levels in a model of adult-onset growth hormone deficiency. Am J Physiol Endocrinol Metab 291(3):E604-10.
Lichtenwalner RJ, Forbes ME, Sonntag WE, Riddle DR (2006) Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: Insights into the regulation of adult hippocampal neurogenesis. Journal of Neuroscience Research 83(2): 199-210.
Grill JD, Sonntag WE, Riddle DR (2005) Dendritic stability in a model of adult-onset IGF-I deficiency. Growth Hormone and IGF Research 15(5):337-48.
Riddle DR, Forbes ME (2005) Regulation of cytochrome oxidase activity in the rat forebrain throughout adulthood. Neurobiology of Aging 26(7): 1035-1050.
Newton IG, Forbes ME, Legault C, Johnson JE, Brunso-Bechtold JK, and Riddle DR (2005) Caloric restriction does not affect aging-related changes in hippocampal BDNF protein levels. Neurobiology of Aging 26(5): 683-688.
Books and Recent Chapters
Riddle, DR (2007) Brain Aging: Models, Methods and Mechanisms. (DR Riddle, ed.), CRC Press, 384 pp.
Sonntag WE, Eckman D, Riddle DR (2007) Age-related changes in the microcirculation. In: Handbook of Physiology: Section 2: The Cardiovascular System: Microcirculation (R.F. Tuma, W.N. Duran, K. Ley, ed.) Oxford University Press.
Riddle DR, Lichtenwalner RJ (2007) Neurogenesis in the adult and aging brain. In: Brain Aging: Models, Methods and Mechanisms. (DR Riddle, ed.), CRC Press, pp. 127-157.
Sonntag WE, Eckmann DM, Ingraham J, Riddle DR (2007) Regulation of cerebrovascular aging. In: Brain Aging: Models, Methods and Mechanisms. (DR Riddle, ed.), CRC Press, pp. 279-304.