the genetics of addiction-related traits

we are sequencing the genomes of ~100 strains rats.

that improve how behaviors are measured in rats

What we do

We study addiction-related behaviors using the rat as a model organism. We primarily study nicotine but we are also working on opioids and alcohol. We are particularly interested in the effects of genetic facotrs, social environment and sensory cue (e.g. menthol) on drug taking and seeking behavior.

Our Team

Hao Chen, Ph.D.

Associate Professor

Department of Pharmacology, Addiction Science, and Toxicology

University of Tennessee Health Science Center

Memphis, TN 38120

  • 1993, Bachelor in Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
  • 1996, Master in Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
  • 2001, Ph.D. Michigan State University, East Lansing, MI, USA

Call: +1 901 448 3720

hchen@uthsc.edu

github.com/chen42

Room 209 TSRB, 71. S. Manassas St
Memphis, TN 38103, USA

Tengfei Wang, M.D.

Instructor

Angel Garcia Martinez, B.S.

Sr. Research Assistant

Shuangying Leng, Ph.D.

Sr. Research Assistant

Jun Huang, Ph.D.

Sr. Research Assistant

Rachel Ward, B.S.

Sr. Research Assistant *

Sarah Cartwright

Research Assistant

Caroline Jones, B.S.

Research Assistant *

Hakan Gunturkun, Ph.D.

Data Analyst

Tristan de Jong, Ph.D.

Data Analyst

Paige Lemen, B.S.

Ph.D. Student

Mallory Udell, B.S.

Ph.D. Student

Gwen Johnson, B.S.

Intern

* Joint appointment with Sharp lab

Research Projects

Socially acquired nicotine i.v. self-administration in adolescent rats

Cigarette smoking is a social behavior. We established a novel rat model of socially acquired intravenous nicotine self-administration, where nicotine was delivered concurrently with a flavor cue (i.e., both taste and smell). We found that rats self-administering nicotine alone under this condition developed strong conditioned aversion to nicotine. However, when a demonstrator rat that consumed the same flavor cues was placed in the operant chamber, stable self-administration of nicotine was established.

Menthol as a conditioned reinforcer of nicotine reward

Menthol is the most common flavoring additive in tobacco and electronic cigarettes. Using licking as the operant behavior, we found that adolescent rats self-administering nicotine with contingent oral menthol obtained significantly more infusions than rats receiving a vehicle cue or rats self-administering i.v. saline with a menthol cue. Rats yoked to their menthol-nicotine masters emitted significantly fewer licks on the active spouts, indicating that contingent pairing between nicotine and menthol is required for sustained nicotine intake. These results provide a key behavioral mechanism by which menthol promotes the use of tobacco products or electronic cigarettes.

Genetic mapping of nicotine intake in rats

We are conducting two large scale genetic mapping studies on nicotine intake using adolescent rats. The first one uses heterogeneous stock rats to map socially acquired nicotine i.v. self-administration. This is part of a NIDA P50. We have already phenotyped ~1600 rats in the past five years and will continue to phenotype an additional 1,600 rats. The second genetic mapping study uses the hybrid rat diversity panel to map nicotine i.v. self-administration with or without a menthol cue. We plan to phenotype ~100 inbred strains in five years.

Oral oxycodone self-administration in rats

Pharmacokinetic factors are important contributors to the abuse liability of drugs. Oxycodone is the leading abused prescription drug, despite mostly being mostly taken orally. We are developing an oral oxycodone self-administration model in rats to study the genetic and neuronal mechanisms contributing to its addiction.

Sequencing rat genomes

Working with a team of collaborators, we are sequencing the genome of approximately 100 strains of inbred rats. We primarily use 10X Chromium high molecular weight linked reads data. We also collected data using Bionanao, Oxford Nanopore and Ion Torrent instruments. In addition to finding SNPs, we are also working on identifying structural variants and de novo assembling these genomes.

Web apps

Chilibot: mining PubMed for sentences describing gene-keyword relationships

www.chilibot.net is a web app that searches the PubMed literature database to find sentences describing the relationships between user-defined keywords. These keywords can be gene/protein names, anatomical locations, or biological concepts. Chilibot classifies these sentences into different types of relationships and present the results in a summary graph, which links these relationships to the sentences.

rats.pub: searching addiction related literature using gene symbols

http://rats.pub is a web app that searches PubMed for sentences containing query genes and a set of addiction related keywords (e.g. names of abused drugs, brain regions, etc.). Sentences are retrieved from a local copy of PubMed to improve speed. GWAS hits for addiction related traits from the EMBL-EBI GWAS catalog are also included in the results.

rn6err.opar.io: potential assembly errors in rat reference genome rn6

We sequenced several BN/NHsdMcwi rats and many other inbred rats using 10X Chromium high molecular weight libraries and found many structural variants that were consistent among all the strains. These are likely errors in the rn6 assembly. rn6err.opar.io is an R-shiny app that queries chromosomal positions or genes to view the "matrix alignment" for BN/NHsdMcwi rats to visually check if there are potential assembly errors. Code is available here: https://github.com/chen42/rn6_assembly_error_app

Other GitHub repos

Other repositories in our GitHub account include code for an R-Shiny app to visualize brain eQTL from rats , and LaTex template for writing NIH grants, code for batch retrieval of matrix view images from the Loupe browser (10X Genomics, Inc.). .

Devices for studying rat behavior

Operant licking

We created a device for conducting operant licking experiments using rats. The device uses a capacitive touch sensor to record the number of licks. A Raspberry Pi single board computer is used to drive a motor embedded in a 3D printed frame to advance a syringe once a reinforcement schedule is satisfied. The design file, source code, and assembly instruction can be found at https://github.com/chen42/openbehavior.

TailTimer: Measure tail withdrawal latency in rats

The latency of withdrawing tail from hot water is a commonly used method to measure pain sensitivity in rodents. This device uses a digital themometer to measure water temperature, a RFID scanner to record animal ID, and wire dipped into the water together to measure withdrawal latency. The design file, source code, and assembly instruction can be found at https://github.com/chen42/openbehavior/tree/master/tailTimer

Yorodent: measure social behaviors among a small group of freely moving rats

We are developing a method to extract rich social interaction data from video recordings of freely moving rats (or mice). The identity of each rodent is tracked using 3D printed colored ear tags. A convolutional neural network is used to identify five body parts per animal. Their social behaviors are then reconstructed and analyzed. The project is hosted at https://github.com/chen42/darkRodents

Publications

Genome-Wide Association Study in 3,173 Outbred Rats Identifies Multiple Loci for Body Weight, Adiposity, and Fasting Glucose.
Chitre, A. S., Polesskaya, O., Holl, K., Gao, J., Cheng, R., Bimschleger, H., Garcia Martinez, A., George, T., Gileta, A. F., Han, W., Horvath, A., Hughson, A., Ishiwari, K., King, C. P., Lamparelli, A., Versaggi, C. L., Martin, C., St. Pierre, C. L., Tripi, J. A., Wang, T., Chen, H., Flagel, S. B., Meyer, P., Richards, J., Robinson, T. E., Palmer, A. A. and Solberg Woods, L. C.
Obesity (2020).

Reduced Complexity Crosses for Complex Traits.
Bryant, C. D., Smith, D. J., Kantak, K. M., Thaddeus S. Nowak, J., Williams, R. W., Dmaj, M. I., Redei, E. E., Chen, H. and Mulligan, M. K.
Trends in Genetics (May 2020). PMC7365571

BDNF deficiency and enriched environment treatment affect neurotransmitter gene expression differently across ages.
Dong, B. E., Chen, H and Sakata, K.
J. Neurochem. (Mar. 2020). PMC7319906

Novel elvitegravir nanoformulation for drug delivery across the blood-brain barrier to achieve HIV-1 suppression in the CNS.
Gong, Y., Chowdhury, P., Nagesh, P. K., Sinha, N., Rahman, M. A., Chen, H., Yallapu, M. M. and Kumar, S.
Viruses (May 2020). PMC7290679

Reversing age: dual species measurement of epigenetic age with a single clock.
Horvath, S., Singh, K., Raj, K., Khairnar, S., Sanghavi, A., Shrivastava, A., Zoller, J. A., Li, C. Z., Herenu, C. B., Canatelli-Mallat, M., Lehmann, M., Solberg Woods, L. C., Martinez, A. G., Wang, T., Chiavellini, P., Levine, A. J., Chen, H., Goya, R. G. and Katcher, H. L.
BioRxiv (2020).

Automatic detection and counting of retina cell nuclei using deep learning
Hosseini, S. M. H., Chen, H. Jablonski, M. M.
Medical Imaging 2020: Biomedical Applications in Molecular, Structural, and Functional Imaging (SPIE, 2020), 634–646.

Classification of neurodevelopmental age in normal infants using 3D-CNN based on brain MRI.
Shabanian M, Eckstein EC, Chen H, DeVincenzo JP.
arXiv [eess.IV]. 2019.

Genetic model to study the co-morbid phenotypes of increased alcohol intake and prior stress-induced enhanced fear memory.
Lim PH, Shi G, Wang T, Jenz ST, Mulligan MK, Redei EE, Chen H.
Front Genet. 2018 Nov 27;9:566. PMC6277590

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco.
Sharp BM, Chen H.
Eur J Neurosci. 2018 Sep 26; PMID: 30256469

An open source device for operant licking in rats.
Longley M, Willis EL, Tay CX, Chen H.
PeerJ. 2017 Feb 14;5:e2981. PMC5312574

A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism.
Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Chen Y, Justicia C, Sakata K, Chen H, Planas A, Ostrom RS, Li W, Yang G, McDonald MP, Chen R, Heck DH, Liao F-F.
Mol Psychiatry. 2016 Jul 26; PMC5323357

Genotation: Actionable knowledge for the scientific reader.
Nagahawatte P, Willis E, Sakauye M, Jose R, Chen H, Davis RL.
Exp Biol Med. 2016 Jun;241(11):1202–1209. PMC4950314

Menthol facilitates the intravenous self-administration of nicotine in rats.
Wang T, Wang B, Chen H.
Front Behav Neurosci. Frontiers; 2014 Dec 16;8:437. PMC4267270

Amplified reacquisition of nicotine self-administration in rats by repeated stress during abstinence.
Yu G, Chen H, Sharp BM.
Psychopharmacology. 2014 Feb 21; PMC4892371

Protection genes in nucleus accumbens shell affect vulnerability to nicotine self-administration across isogenic strains of adolescent rat.
Chen H, Luo R, Gong S, Matta SG, Sharp BM.
PLoS One. 2014 Jan 22;9(1):e86214. PMC3899218

Evaluating statistical learning methods for cell type classification and feature selection using RNA-seq data.
Chen H.
BMC Bioinformatics. 2014;15(10):P26.

Full-gestational exposure to nicotine and ethanol augments nicotine self-administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats.
Roguski EE, Sharp BM, Chen H, Matta SG.
J Neurochem. 2013 Nov 15;128(5):701–712. PMID: 24147868

Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics.
Parker CC, Chen H, Flagel SB, Geurts AM, Richards JB, Robinson TE, Solberg Woods LC, Palmer AA.
Neuropharmacology. 2013 Jun 18;76 Pt B:250–258. PMC3823679

Fostering itself increases nicotine self-administration in young adult male rats.
Roguski EE, Chen H, Sharp BM, Matta SG.
Psychopharmacology. 2013 May 17;229(2):227–234. PMC3757107

Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cells.
Majumdar G, Adris P, Bhargava N, Chen H, Raghow R.
BMC Genomics. 2012 Dec 18;13:709. PMC3561284

Genetic factors control nicotine self-administration in isogenic adolescent rat strains.
Chen H, Hiler KA, Tolley EA, Matta SG, Sharp BM.
PLoS One. 2012 Aug 28;7(8):e44234. PMC3429443

A promoter polymorphism in the Per3 gene is associated with alcohol and stress response.
Wang X, Mozhui K, Li Z, Mulligan MK, Ingels JF, Zhou X, Hori RT, Chen H, Cook MN, Williams RW, Lu L.
Transl Psychiatry. 2012 Jan 31;2:e73. PMC3309544

Genome-Wide Gene Expression Profiling of Nucleus Accumbens Neurons Projecting to Ventral Pallidum Using both Microarray and Transcriptome Sequencing.
Chen H, Liu Z, Gong S, Wu X, Taylor WL, Williams RW, Matta SG, Sharp BM.
Front Neurosci. 2011 Aug 12;5:98. PMC3155868

Gene expression in accumbens GABA neurons from inbred rats with different drug-taking behavior.
Sharp BM, Chen H, Gong S, Wu X, Liu Z, Hiler K, Taylor WL, Matta SG.
Genes Brain Behav. 2011 Aug 1;10(7):778–788. PMC3193935

Genetic dissection of the Gpnmb network in the eye.
Lu H, Wang X, Pullen M, Guan H, Chen H, Sahu S, Zhang B, Chen H, Williams RW, Geisert EE, Lu L, Jablonski MM.
Invest Ophthalmol Vis Sci. 2011 Jun 13;52(7):4132–4142. PMC3175941

Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic-pituitary-adrenal response to stress.
Yu G, Chen H, Wu X, Matta SG, Sharp BM.
J Neurochem. 2010 Feb 25;113(4):919–929. PMC2912162

Neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration and after extinction in rats.
Wang F, Chen H, Sharp BM.
J Neurochem. 2008 May 3;106(2):943–956. PMC2587995

Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.
Yu G, Chen H, Zhao W, Matta SG, Sharp BM.
J Neurosci. 2008 Mar 12;28(11):2773–2782. PMC6670662

Chronic nicotine self-administration augments hypothalamic-pituitary-adrenal responses to mild acute stress.
Chen H, Fu Y, Sharp BM.
Neuropsychopharmacology. 2007 Jun 6;33(4):721–730. PMID: 17551542

Nicotine-induced norepinephrine release in hypothalamic paraventricular nucleus and amygdala is mediated by N-methyl-D-aspartate receptors and nitric oxide in the nucleus tractus solitarius.
Zhao R, Chen H, Sharp BM.
J Pharmacol Exp Ther. 2006 Nov 8;320(2):837–844. PMID: 17093131

Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug.
Chen H, Matta SG, Sharp BM.
Neuropsychopharmacology. 2006 Jun 14;32(3):700–709. PMID: 16794562

Combining gene expression QTL mapping and phenotypic spectrum analysis to uncover gene regulatory relationships.
Bao L, Wei L, Peirce JL, Homayouni R, Li H, Zhou M, Chen H, Lu L, Williams RW, Pfeffer LM, Goldowitz D, Cui Y.
Mamm Genome. 2006 Jun 12;17(6):575–583. PMID: 16783639

Upregulation of ionotropic glutamate receptor subunits within specific mesocorticolimbic regions during chronic nicotine self-administration.
Wang F, Chen H, Steketee JD, Sharp BM.
Neuropsychopharmacology. 2006 Feb 1;32(1):103–109. PMC2587993

Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits.
Li H, Chen H, Bao L, Manly KF, Chesler EJ, Lu L, Wang J, Zhou M, Williams RW, Cui Y.
Hum Mol Genet. 2005 Dec 21;15(3):481–492. PMID: 16371421

Gestational nicotine exposure reduces nicotinic cholinergic receptor (nAChR) expression in dopaminergic brain regions of adolescent rats.
Chen H, Parker SL, Matta SG, Sharp BM.
Eur J Neurosci. 2005 Jul;22(2):380–388. PMID: 16045491

Content-rich biological network constructed by mining PubMed abstracts.
Chen H, Sharp BM.
BMC Bioinformatics. 2004 Oct 8;5:147. PMC528731

Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats.
Chen H, Weber AJ.
Brain Res. 2004 Jun 11;1011(1):99–106. PMID: 15140649

Oliz, a suite of Perl scripts that assist in the design of microarrays using 50mer oligonucleotides from the 3’ untranslated region.
Chen H, Sharp BM.
BMC Bioinformatics. 2002 Oct 6;3:27. PMC130177

Expression of glial fibrillary acidic protein and glutamine synthetase by Müller cells after optic nerve damage and intravitreal application of brain-derived neurotrophic factor.
Chen H, Weber AJ.
Glia. 2002 Apr 15;38(2):115–125. PMID: 11948805

BDNF enhances retinal ganglion cell survival in cats with optic nerve damage.
Chen H, Weber AJ.
Invest Ophthalmol Vis Sci. 2001 Apr;42(5):966–974. PMID: 11274073

Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus.
Weber AJ, Chen H, Hubbard WC, Kaufman PL.
Invest Ophthalmol Vis Sci. 2000 May;41(6):1370–1379. PMID: 10798652

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Last update: Jan 25 2020