Directed by Hongxin Dong, MD, PhD, research in the traslational neurobiology laboratory focuses on the study of the interactions between genetic, epigenetic and environmental influences on neurodevelopment and neurodegeneration, and their mechanisms relevant to the pathogenesis of neuropsychiatric disorders such as schizophrenia, autism and Alzheimer’s disease. Our research strategies are multidisciplinary and collaborative, combining multiple approaches from molecular biology to animal model behavior. The ultimate goal of our research is to establish animal models for better understanding of the mechanisms of the neuropsychiatric disorders and to develop therapeutic strategies for the slowing of disease progression and the prevention of disease onset.
Aging and antipsychotic efficacy - epigenetic mechanisms
The use of psychotropic medications in the elderly population generates a number of obstacles, including decreased drug efficacy and increased side effects. It is not yet known whether the epigenetic changes that occur with aging play a role in antipsychotic efficacy. In this study, we investigate whether histone deacetylase inhibitors can improve drug efficacy and decrease extra-pyramidal side effects by regulating epigenetic alterations. This information is essential for developing an alternative treatment strategy for the aged patients with psychiatric disorders.
Transgenerational epigenetic effects on dopamine receptor development
Environmental stimuli in early life such as prenatal stress exerts a strong impact on brain development and contribute to a wide variety of neuropsychiatric diseases including anxiety, depression, schizophrenia and substance use disorders. To date, the underlying mechanisms are poorly understood, although most of these disorders have been thought to be related to dopamine system dysfunction. In this study, we investigate the mechanisms of prenatal stress induced dopamine receptor D2 (DRD2) dysfunction in the offspring due to the epigenetic transgenerational effects on Drd2 gene promoter. The results of this study will provide firm evidence of the impact of epigenetic inheritability on neuropsychiatric disorders.
CRF and its receptor regulate the progression of Alzheimer’s Disease
Increasing evidence indicates that chronic psychosocial stress and physical exercise differentially affect the development and progression of Alzheimer’s disease (AD). However, the mechanisms underlying these behavioral effects and their interactions with AD remain unclear. In this project, we use a new transgenic mouse model of AD to study the effects of corticotrophin-releasing factor, a key stress regulator, on disease neuropathogenesis and memory function, as well as ways that exercise can modulate these effects.
Effects of stress and THC on schizophrenia progression—an animal model study
Stress is believed to be an important factor in the onset of psychosis in late adolescents at elevated risk. We examine the interactions betweeen stress, PCP and THC, and the extent of induced cognitive impairment and locomotor dysfunction and how antipsychotics effect on these phenotypes. Our goal is to create a mouse model that translates well to current clinical knowledge on the ability of antipsychotic drugs to improve psychosis and the cognitive deficit in schizophrenia.
- Chen YY, Zhang W, Chen YL, Chen SJ, Dong H, Zeng YS (2008). Electro-acupunctureimproves survival and migration of transplanted neural stem cells in injured spinal cord in rats. Acupunct Electrother Res, 33(1-2):19-31. No PMID#
- Dong H, Yuede CM, Coughlan C, Lewis B, Csernansky JG (2008). Effects of memantine on neuronal structure and conditioned fear in the Tg2576 mouse model of Alzheimer's disease. Neuropsychopharmacology. 33(13): 3226-36. NIHMSID:95121
- Dong H, Yuede CM, Yoo HS, Martin MV, Deal C, Mace AG, Csernansky JG (2008). Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience. 155(1): 154-63. Corresponding author. NIHMSID: 95095
- Martin MV, Churchill JD, Dong H, Wozniak DF, Cheverud JM, Csernansky JG (2009). Genetic influences on hippocampal structure and function in recombinant inbred mice. Behav Brain Res. 196(1): 78-83. PMCID: PMC2631234
- Ding Y, Yan Q, Ruan JW, Zhang YQ, Li WJ, Zhang YJ, Li Y, Dong H, Zeng YS (2009). Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats. BMC Neurosci. Apr 20;10:35.
- Dong H, Csernansky JG (2009) Effects of stress and stress hormones on A-beta and plaque deposition (review). Journal of Alzheimer's Disease. 18(2):459-69. Review, Corresponding author
- Yuede CM, Zimmerman SD, Dong H, Kling M J, Bero AW. Timson BF, Holtzman DM, Csernansky JG (2009). The effects of voluntary and forced exercise on memory, plaque deposition and hippocampal volume in the Tg2576 mouse model of Alzheimer’s Disease. Neurobiology of Disease, 35(3):426-32.
- Dong H, Yuede CM, Coughlan CA, Murphy KM, Csernansky JG (2009). Effects of Donepezil on Amyloid-β and Synapse Density in the Tg2576 Mouse Model of Alzheimer’s disease. Brain Research. 2009 Dec 15;1303:169-78. Corresponding author
- Ding Y, Yan Q, Ruan JW, Zhang YQ, Li WJ, Zeng X, Huang SF, Zhang YJ, Wang SD, Dong H, Zeng YS(2010). Bone marrow mesenchymal stem cells and electro-acupuncture downregulate the inhibitor molecules and promote the axonal regeneration in the transected spinal cord of rats. Cell Transplant. Sep 30. [Epub ahead of print] Corresponding author
- Meng L, Lu L, Murphy KM, Yuede CM, Cheverud JM, Csernansky JG, Dong H (2011). Neuroanatomic and behavioral traits for autistic disorders in age-specific restricted index selection mice.Neuroscience. May 27. [Epub ahead of print] Corresponding author
- Dong H, Murphy KM, Meng L, Montalvo-Ortiz J, Zeng Z, Kolber BJ, Zhang S, Muglia LJ, Csernansky JG. (2012) Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer's disease.J Alzheimers Dis.28 (3): 579-92. Corresponding author
- Lin Z, Yang H, Kong Q, Li J, Lee SM, Gao B, Dong H,Wei J, Song J, Zhang DD, Fang D. (2012) USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell. May 25;46 (4):484-94.
- Zhang YJ, Zhang W, Lin CG, Ding Y, Huang SF, Wu JL, Li Y, Dong H, Zeng YS. (2012) Neurotrophin-3 gene modified mesenchymal stem cells promote remyelination and functional recovery in the demyelinated spinal cord of rats.J Neurol Sci. Feb 15;313(1-2):64-74. Epub 2011 Oct 13.
- Li F, Gong Q, Dong H, Shi J. (2012) Resveratrol, a neuroprotective supplement for Alzheimer's disease.Curr Pharm Des. 18(1): 27-33. Review
- Ding Y, Yan Q, Ruan JW, Zhang YQ, Li WJ, Zeng X, Huang SF, Zhang YJ, Wu JL, Fisher D, Dong H*, Zeng YS* (2012). Electroacupuncture promotes the differentiation of transplanted bone marrow mesenchymal stem cells overexpressing TrkC into neuron-like cells in transected spinal cord of rats. Cell Transplant. In press, Corresponding author
- Li WJ, Li SM, Ding Y, He B, Keegan J, Dong H, Ruan JW*, Zeng YS* (2012). Electro-acupuncture upregulates CGRP expression after rat spinal cord transection. Neurochem Int, Oct 13. [Epub ahead of print]
- Ding Y, Yan Q, Ruan JW, Zhang YQ, Li WJ, Zeng X, Huang SF, Zhang YJ, Wu JL, Fisher D, Dong H, Zeng YS. (2013) Electroacupuncture promotes the differentiation of transplanted bone marrow mesenchymal stem cells overexpressing TrkC into neuron-like cells in transected spinal cord of rats . Cell Transplant. 22(1):65-86.
- Dong H, Zeng ZL, Ortiz J, Chen Q, Li F, Wang S, Shi J, Rice KC, Csernansky JG. Effect of Corticotropin-Releasing Factor Antagonists on Amyloid-β Formation and Cognitive Function in Tg2576 Mice. Psychopharmacology. Under Revision. Corresponding author
- Montalvo-Ortiz J., Keegan J., Fang D., Gerst N., Tetsuka K., Csernansky J.G., Dong H. Pretreatment with Valproic Acid Diminishes Haloperidol-Induced Impairment in Memory and Motor Behavior through Modulation of Histone Acetylation. Nueropsychopharmacology. Under Revision. Corresponding author
Grants and Funding
- NIH R21 MH100919-02 Aging and Antipsychotic Efficacy—Epigenetic Mechanisms (12/26/12-11/30/14)
- NIMH 1R36MH 100912-01A1 Epigenetic modulation of antipsychotic-induced side effects in aged mice (10/01/13-09/30/2015)
- NIA 1R01AG047263-01 CRF and its receptor regulate the progression of Alzheimer’s Disease
Yong Hui Mai
Contact Hongxin Dong, MD, PhD, for more information on the Translational Neurobiology Laboratory.