Lei Yu
Professor II

Molecular genetics of alcoholism. compulsive behavior. drug abuse. pain. stress

Our laboratory is interested in the molecular and genetic bases of complex brain disorders. including genetic predisposition for alcoholism and drug abuse. and molecular mechanisms underlie such neuro-sensory processes as stress. neuropathic pain. and pain-relief analgesia.

Regarding genetic predisposition for alcoholism and drug abuse. we have carried out human genetic studies with a focus on genetic variations in human populations. especially those with potential impact on physiological function and behavior. This is based on the belief that human genetics is for the most part about small. subtle functional polymorphisms that underlie individual differences in physiology and disease vulnerability. One example is a prevalent genetic variation in the mu opioid receptor that we have studied. This small genetic polymorphism only changes one base pair in the gene. thus is a SNP (single nucleotide polymorphism). giving rise to the subtle variation of a single amino acid. Recent studies from several groups have shown that this SNP is associated with functional consequences in humans. including predisposition to opioid dependence. differential stress hormone response to opioid antagonist challenge. and potential impact on treatment outcome for alcoholism. nicotine dependence. and Parkinson disease pharmacotherapy.

A related direction we are undertaking is to investigate genetic mediators of complex brain disorders. utilizing SNP's as informative markers. to track gene-behavior correlations. As an example. we are conducting a SNP genotyping project using a well-characterized sample set that has been collected and subjects followed over twenty years. to determine potential association between relevant genetic factors and cellular functions on one hand. and alcohol usage and risk behaviors on the other. By systematically examining the genetic pathways that subserve the neurobiological mechanisms. we hope to advance our knowledge in the genetic factors contributing to disease process. so as to provide useful information for developing effective therapeutic interventions.

Chronic pain from nerve injury is rather common. and represents a major public health problem. For people who suffer neuropathic pain. current treatment options are woefully inadequate. To develop more effective therapeutic approaches. it is important to understand the mechanistic basis for neuropathic pain. so that molecular targets can be identified for exploring medication development and/or other types of interventions. Using a molecular genetic strategy. we have identified a number of genes that participate in neuropathic pain. When we inhibited the activity of these genes. the pain from nerve damage is alleviated. We also discovered that it is possible to completely block the chronic pain from developing in the rodent models by inhibiting nerve transduction during a specific time window. We are conducting further research to advance our knowledge on how genes are involved in chronic pain. as well as the mechanisms of analgesia from drugs such as opioids.

Selected Publications

Qi, C., Zou, H., Zhang, R., Zhao, G., Jin, M., and Yu, L. (2008) Age-related differential sensitivity to MK-801-induced locomotion and stereotypy in C57BL/6 mice. Eur. J. Pharmacol. 580:161-168.

Yates, J.W., Meij, T.A.J., Sullivan, J.R, Richtand, N.M, and Yu, L. (2007) Bimodal effect of amphetamine on motor behaviors in C57BL/6 mice. Neurosci. Lett. 427: 66-70.

Tang. Y.. Zou. H.. Strong. J.A.. Cui. Y.. Xie. Q.. Zhao. G.. Jin. M.. and Yu. L. (2006) Paradoxical effects of very low dose MK-801. Eur. J. Pharmacol. 537:77-84.

Ulrich-Lai. Y.M.. Xie. W.. Meij. J.T.A.. Dolgas. C.M.. Yu. L.. and Herman. J.P. (2006) Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiology and Behavior 88:67-76.

Strong. J.A.. Dalvi. A.. Revilla. F.J.. Sahay. A.. Samaha. F.J.. Welge. J.A.. Gong. J.. Gartner. M.. Yue. X.. and Yu. L. (2006) Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease. Movement Disorders 21:654-659.

Balfour. M.E.. Brown. J.L.. Yu. L.. and Coolen. L.M. (2006) Potential contributions of efferents from medial prefrontal cortex to neural activation following sexual behavior in the male rat. Neuroscience 137:1259-1276.

Wang. X.M.. Gao. X.. Zhang. X.H.. Tu. Y.Y.. Jin. M.L.. Zhao. G.P.. Yu. L.. Jing. N.H.. and Li. B.M. (2006) The negative cell cycle regulator. Tob (transducer of ErbB-2). is involved in motor skill learning. Biochem. Biophys. Res. Commun. 340:1023-1027.

Wang. X.. Zhang. Y.. Kong. L.. Xie. Z.. Lin. Z.. Guo. N.. Strong. J.A.. Meij. J.T.. Zhao. Z.. Jing. N.. and Yu. L. (2005) RSEP1 is a novel gene with functional involvement in neuropathic pain behavior. Eur. J. Neurosci. 22:1090-1096.

Zhang. X.-H.. Zhang. H.. Tu. Y.. Gao. X.. Zhou. C.. Jin. M.. Zhao. G.. Jing. N.. Li. B.-M.. and Yu. L. (2005) Identification of a novel protein for memory regulation in the hippocampus. Biochem. Biophys. Res. Commun. 334:418-424.

Xie. W.. Strong. J.A.. Meij. J.T.. Zhang. J.M.. and Yu. L. (2005) Neuropathic pain: Early spontaneous afferent activity is the trigger. Pain 116:243-56.

Jin. M.. Wang. X.. Tu. Y.. Zhang. X.. Gao. X.. Guo. N.. Xie. Z.. Zhao. G.. Jing. N.. Li. B.. and Yu. L. (2005) The negative cell cycle regulator. Tob (Transducer of ErbB-2). is a multifunctional protein involved in hippocampus-dependent learning and memory. Neuroscience 131:647-659.

Moalem. G.. Xu. K.. and Yu. L. (2004) T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 129:767-777.

Hou. Q.. Gao. X.. Zhang. X.. Kong. L.. Wang. X.. Bian. W.. Tu. Y.. Jin. M.. Zhao. G.. Li. B.. Jing. N.. and Yu. L. (2004) SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur. J. Neurosci. 20:1593-1603.

Meij. J.T.A.. Haselton. C.L.. Hillman. K.L.. Muralikrishnan. D.. Ebadi. M.. and Yu. L. (2004) Differential mechanisms of nitric oxide- and peroxynitrite-induced cell death. Mol. Pharmacol. 66:1043-1053.

You. H.. Qi. X.. Grabowski. G.A.. and Yu. L. (2003) Phospholipid membrane interactions of saposin C: in situ atomic force microscopic study. Biophys. J. 84: 2043-2057.