Willard Freeman, Ph.D.


  • Donald W. Reynolds Chair in Aging Research
  • Associate Professor of Physiology
  • Adjunct Associate Professor of Geriatric Medicine

  • B.A. Chemistry and English, Wake Forest University
  • Ph.D. Pharmacology, Wake Forest University School of Medicine
  • Fellowships, Vollum Institute and Yerkes National Primate Research Center

Research Summary:

Our research program is centered on systems neurobiology studies of cognitive decline with aging, diabetic retinopathy, and substance abuse.

In our cognitive decline studies we have identified the myelin associated inhibitor signaling cascade (Nogo, MAG, OMGP through NgR1) as a potential therapeutic target for preventing or reversing cognitive decline. Additionally we are investigating neuroimmune activation, specifically MHCI, with aging and their potential contribution to synaptic dysfunction. Our group also applies new sequencing technologies to assess how the epigenome changes with aging.

Our diabetic retinopathy studies are testing the hypothesis that persistent retinal cellular and molecular changes during a period of poor glycemic control persist long after establishment of good glycemic control and contribute to the pathogenesis of diabetic complications. This phenomenon, called metabolic memory, may be perpetuated by epigenetic mechanisms, both histone modifications and DNA methylation. We use and develop next generation sequencing approaches to quantify epigenetic modifications in specific retinal cell populations with diabetes. In parallel studies we are investigating the time course and mechanisms of retinal synapse loss with diabetes.

Our epigenetic studies of substance abuse are examining abstinence-persistent changes in DNA methylation resulting from stimulant and opiate abuse and their role in relapse liability.

Recent Publications:

Diabetes/Vision Research

  1. Bixler GV, VanGuilder HD, Brucklacher RM, Kimball SR, Bronson SK, Freeman WM.Chronic insulin treatment of diabetes does not fully normalize alterations in the retinal transcriptome. BMC Medical Genomics 2011; 4:40.
  2. VanGuilder HD, Bixler GV, Kutzler L, Brucklacher RM, Bronson SK, Kimball SR, Freeman WM.  Multi-modal proteomic analysis of retinal protein expression alterations in a rat model of diabetic retinopathy. PLoS ONE 2011; 6:16271.
  3. Freeman WM, Bixler GV, Brucklacher RM, Lin C-M, Patel KM, VanGuilder HD, LaNoue KM,  Barber AJ, Antonetti DA, Gardner TW, Bronson SK. A novel multi-step evaluation process of preclinical drug development biomarkers. The Pharmacogenomics Journal 2010; 10:385-395.
  4. Brucklacher RM, Patel KM, Bixler GV, VanGuilder HD, Antonetti DA, Lin C-M, LaNoue KM, Barber AJ, Gardner TW, Bronson SK, Freeman WM. Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response. BMC Medical Genomics 2008; 1:26

 Aging Research

  1. VanGuilder Starkey HD, Bixler GV, Sonntag WE, Freeman WM. Expression of NgR1-antagonizing proteins decreases with aging and cognitive decline in rat hippocampus. Cellular and Molecular Neurobiology. 2013; 33: 483-488.
  2. VanGuilder Starkey HD, Sonntag WE, Freeman WM. Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition. European J. Neuroscience. 2013; 37:1643-1658.
  3. VanGuilder Starkey HD, Van Kirk CA, Imperio C, Rountree CB, Kale V, Serfass J, Sonntag WE, Freeman WM. Induction of neuronal major histocompatibility complex class I and paired immunoglobulin-like receptor B pathway in the hippocampus with aging and cognitive decline. J. Molecular Neuroscience 2012; 48: 111-126.
  4. VanGuilder HD, Bixler GV, Sonntag WE, Freeman WM. Hippocampal expression of myelin-associated inhibitors of neuronal plasticity is induced specifically with age-related deficits of spatial learning and memory. J. Neurochemistry 2012; 121:77-98.
  5. VanGuilder HD, Bixler GV, Brucklacher RM, Farley JA, Yan H, Warrington JP, Sonntag WE, Freeman WM. Age-related induction of the hippocampal MHC2-mediated immune response and activation of astrocytes and microglia occur independently of spatial learning and memory deficits. J. Neuroinflammation 2011; 8:138.
  6. VanGuilder HD, Freeman WM. The neuroproteome and cognitive decline: past progress and future directions. Frontiers in Aging Neuroscience 2011; 3:8.
  7. VanGuilder HD, Farley JA, Yan H, Van Kirk CA, Mitschelen MC, Sonntag WE, Freeman WM. Hippocampal dyrsregulation of synaptic plasticity-associated proteins with age-related cognitive decline. Neurobiology of Disease 2011; 43:201-212.
  8. VanGuilder HD, Farley JA, Yan H, Sonntag WE, Freeman WM. Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J. Neurochemistry 2010;113:1577-1588.
  9. Freeman WM, VanGuilder HD, Bennett C, Sonntag WE. Cognitive performance and age related changes in the hippocampal proteome. Neuroscience 2009; 159:183-95.

 Substance Abuse

  1. Helms CM, Messaoudi I, Freeman WM, Vrana KE, Grant KA. A longitudinal analysis of circulating stress-related proteins and chronic ethanol self-administration in cynomolgus macaques. Alcoholism: Clinical and Experimental Research 2012; 36:995-1003.
  2. Freeman WM, VanGuilder HD, Guidone E, Krystal JH, Grant KA, Vrana KE.Plasma proteomic alterations in a non-human primate model of chronic alcohol self-administration. Int. J. Neuropsychopharmacology 2011; 14:899-911.
  3. Lebold KM, Grant KA, Freeman WM, Wiren KM, Miller GW, Kiley C, Leonard SW, Traber MG. Individual differences in hyperlipidemia and vitamin E status in response to chronic alcohol self-administration in cynomolgus monkeys. Alcoholism: Clinical and Experimental Research 2011; 35:1-10.
  4. Freeman WM, Vrana KE. Current state and future prospects for biomarkers of alcohol induced disorders. Alcoholism: Clinical and Experimental Research 2010; 34:946-954.
  5. Freeman WM, Salzberg A, Gonzales S, Grant KG, Vrana KE. Diagnostic plasma proteomic biomarkers of alcoholism. Biological Psychiatry 2010; 68:219-222.
  6. Freeman WM, Lull ME, Patel KM, Brucklacher RM, Morgan D, Roberts DCS, Vrana KE. Gene expression changes in the mesolimbic pathway following abstinence from cocaine self-administration. BMC Neuroscience 2010; 11:29.
  7. Lull ME, Erwin MS, Patel KM, Morgan D, Roberts DCS, Vrana KE, Freeman WM. Persistent proteomic alterations in mPFC with abstinence from cocaine self-administration. Proteomics: Clinical Applications; 2009 3:462-472.
  8. Freeman WM, Patel KM, Lull ME, Erwin MS, Bruchlacker RM, Morgan D, Roberts DCS, Vrana KE.   Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 2008; 33:1807-1817.

 Genomics and Proteomics

  1. Masser DR, Berg A, Freeman WM. Focused, high accuracy 5-methylcytosine quantitation with base resolution by bench-top next-generation sequencing. Epigenetics & Chromatin. 2013; 6:33.
  2. Huber-Keener KJ, Liu X, Wang Z, Wang Y, Freeman WM, Wu S, Planas-Silva MD, Ren X, Cheng Y, Zhang Y, Vrana KE, Liu C-G, Yan J-M, Wu R. Differential gene expression in tamoxifen-resistant breast cancer cells revealed by a new analytical model of RNA-Seq data. PLoS One 2012; 7: e41333.
  3. Rountree CB, Van Kirk CA, You H, Ding W, Dang H, VanGuilder HD, Freeman WM. Clinical application for the preservation of phospho-proteins through in-situ tissue stabilization. Proteome Science 2010; 8:61.

Funding Agencies:

National Institutes of Health