Ph.D., Cell Biology, University of Bremen, Germany, 1989
Research Associate, Dept. of Pharmacology, U.C.-Irvine
Drugs can have a profound impact on the brain during development and in adults. I am interested in factors that affect neuronal survival during development and in adults, selectively targeting specific neuronal populations, and therefore, influence behavior and cognitive performance. I am also interested in how early life-long events such as drug exposure, shape behavioral characteristics for life.
My lab is currently focused on the effects of the recreational drug nicotine and its effects on the brain during development and aging. Nicotine interacts with nicotinic acetylcholine receptors (nAChR) which are ligand-gated pentameric ion channels. Different subtypes of neuronal nAChR are the result of different combinations of alpha and beta subunits expressed in the central, peripheral and enteric nervous system. Initial studies have focused on the expression of nAChR subunits in prenatal, postnatal and adult brain, using in situ hybridization and receptor autoradiography, demonstrating that nAChRs are widely expressed throughout development and in adults. There premature activation by nicotine could influence developmental processes and change gene expression pattern resulting in long-term changes in the developing brain. Activation of nAChRs is strongly neuroprotective. During development, that could interfere with developmental cell death, during aging it could delay neuronal loss and delay age-related decline.
I participate in graduate training as a member of the faculty of the Texas A&M Institute for Neuroscience.
1. Evaluating the effects of chronic nicotine treatment on brain development.
Nicotine, the major psychoactive ingredient in tobacco, is a recreational drug used by 20 % of pregnant women. It is an agonist for nAChRs, easily passes through membranes and activates nAChRs in the fetal brain. Smoking during pregnancy not only results in low birth-weight babies but can have long-term anatomical and behavioral consequences.
To investigate nicotine's effect on brain development, we developed a neonatal rat model of chronic nicotine treatment that corresponds developmentally to the third trimester in humans, a period of active brain growth and synaptogenesis (growth spurt period). In this postnatal model, pups are orally treated with nicotine mixed in infant formula. The effects of nicotine are being evaluated on a behavioral, structural (using histological staining and immunohistochemistry), and molecular level (using gene array analysis, RT-PCR, in situ hybridization), with emphasis on brain structures involved in cognitive functions, such as hippocampus and cortex.
Effects of developmental nicotine on GABAergic interneurons.
Chronic developmental nicotine interferes with developmental cell death. Neonatal nicotine exposure results in an increases survival of GABA interneurons, which could permanently alter the inhibitory tone and have major life-long consequences on hippocampal functions. Functional chances in response to chronic neonatal nicotine treatment are evaluate using electropysiological studies in collaboration with other labs in the department. Early results show permanent changes in the functional response as a result of developmental exposure to nicotine. In general, an altered balance of excitatory and inhibitory transmission as a result of developmental activation of could have major implications not only for our understanding of developmental nicotine exposure, but will also shed light on the role of the nicotinic cholinergic system on developmental disorders such as schizophrenia, bipolar and autism disorders.
Consequences of developmental nicotine on anxiety and stress.
We also study the effects of developmental nicotine exposure on the limbic system and in particular the programming of the hypothalamic-pituitary-adrenal (HPA) axis involved in the stress response. Our results show that developmental activation of nAChRs is strongly involved in the long-term programming of central and peripheral stress responses and permanently alters stress and anxiety behavior. In order to determine brain areas activated by nicotine we use the induction of immediate early genes such as cFos, as markers to determine the precise location brain activity. In rat pups, nicotine almost exclusively, activates the major areas involved in the central stress response. The stimulation of nAChRs during development could result in strengthening or establishing synaptic connections in the limbic system.
2. What is the role of nAChRs during aging?
Activation of nAChRs engages anti-apoptotic intracellular signaling pathways resulting in neuroprotection and prevention against neuronal cell death in vitro and in whole animals. In humans, smoking is negatively correlated with the development of Parkinson's and Alzheimer's disease. The mechanisms of nicotine-mediated protection against cell and neuronal death are not well understood. Accordingly, mice lacking heteromeric nAChRs exhibit accelerated aging in cortical regions, critically involved in cognitive functions. This project, carried out in collaboration with Dr. Louise Abbott (TAMU, College of Veterinary Medicine), is currently investigating a possible connection between nAChRs and regulation of neurotrophic factors such as NGF, BDNF, IFGI, and FGF2, and survival genes such as SIRT and Nampt, and Ku70, all of which have critical roles in the aging process. We generated templates to be used as probes for in situ hybridization to investigate the expression of the newly identified survival gens and their expressional regulation in aged mice, to address the question of how nicotinic receptors influence their expression and how survival pathways are regulated.
Example for the expression of the alpha7 nAChR subunit in the hippocampus of a newborn rat pup. The mRNA coding for alpha7 is detected by in situ hybridization using a subtype specific probe (left side). The receptor protein is detected by receptor autoradiography using 125I alpha-Bungarotoxin, a ligand specific for the alpha7 nAChR (right side).
Winzer-Serhan, UH, Chen, Y and Leslie, FM. (2003) "Expression of opioid peptides and receptors in striatum and substantia nigra during rat brain development". J Chemical Neuroanatomy 26:17-36.
Azam, L, Winzer-Serhan, UH and Leslie, FM. (2003) "Co-expression of alpha7 and alpha2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons". Neuroscience 119:965-977.
Winzer-Serhan, UH and Leslie, FM. (2005) "Developmental expression of alpha5 nicotinic acetylcholine receptor subunit mRNA during cortical and hippocampal development in the rat". J Comparative Neurology 48:19-30.
Huang L.Z., Hsiao S.H., Trzeciakowski J., Frye G.D. and Winzer-Serhan U.H. (2006) Chronic nicotine induces growth retardation in Neonatal Rat Pups. Life Sci.; 78:1483-93
Huang, L.Z., Winzer-Serhan U.H. (2006) Chronic neonatal nicotine up-regulates heteromeric nicotinic acetylcholine receptor expression without changes in subunit mRNA expression. Brain Research. 1113, 94-109.
Son, J.H., Winzer-Serhan UH. (2006) Developmental expression of alpha 2 nicotinic acetylcholine receptor subunit mRNA in cortex and hippocampus. J. Chemical Neuroanatomy 32, 179-190.
Huang, LZ and Winzer-Serhan, UH. (2006) "Effects of paraformaldehyde fixation on nicotinic acetylcholine receptor binding in adult and developing rat brain sections". J Neuroscience Methods 153:312-317.
Huang, LZ and Winzer-Serhan UH. (2006) "Chronic neonatal nicotine upregulates heteromeric nicotinic acetylcholine receptor expression without changes in subunit mRNA expression". Brain Research 1113:94-109./p>
Son, JH and Winzer-Serhan, UH. (2006) "Developmental expression of alpha2 nicotinic acetylcholine receptor subunit mRNA in cortex and hippocampus". J Chemical Neuroanatomy 32:179-190.
Huang L.Z., Winzer-Serhan U.H. (2007) Differential regulation of feeding-related peptides in the hypothalamus in response to chronic nicotine treatment in neonates. Developmental Neurobiol. 67, 363-377. (Formally: J. Neurobiology).
Huang L.Z., Abbott L.C., Winzer-Serhan U.H. (2007) Effects of chronic neonatal nicotine exposure on nAChR binding, cell death and morphology in hippocampus and cerebellum. Neuroscience 146(4) 1854-1868.
Huang L.Z., Liu X., Griffith W.H., Winzer-Serhan U.H.: (2007) Chronic neonatal nicotine increases anxiety but does not impair cognition in adult rats. Behavioral Neuroscience; 121(6), 1342-1352.
Huang, LZ, Liu, X, Griffith, WH and Winzer-Serhan, UH. (2007) "Chronic neonatal nicotine increases anxiety but does not impair cognition in adult rats". Behavioral Neuroscience 121:342-1352.
Moser, N, Jones, I, Mechawar, N, Gochberg-Sarver, A, Orr-Urtreger, A, Plomann, M, Roth, U, Maskos, U, Winzer-Serhan, U, Bourgeois, JP, Marubio, L, De Biasi, M, Salas, N, Molles, B, Schröder, H, Lindstrom, J, Maelicke, A, Changeux, JP and Wevers, A. (2007) "Evaluating the suitability of nicotinic acetylcholine receptor antibodies for standard immuno-detection procedures". J Neurochemistry 102:479-92.
Huang, LZ, Abbott, LC and Winzer-Serhan, UH. (2007) "Effects of chronic neonatal nicotine exposure on nAChR binding, cell death and morphology in hippocampus and cerebellum". Neuroscience 146:1854-1868.
Huang, LZ and Winzer-Serhan, UH. (2007) "Differential regulation of feeding-related peptides in the hypothalamus in response to chronic nicotine treatment in neonates". Developmental Neurobiology 67: 363-377.
Winzer-Serhan U.H.: 2008 Long-term consequences of developmental chronic nicotine exposure. Frontiers in Bioscience 13, 636-649. Review.
Son J.H., Winzer-Serhan U.H. (2008), Expression of nicotinic acetylcholine receptor subunit mRNAs in hippocampal GABAergic interneurons. J Comp. Neurol. 511(2), 286-299.
Schmitt H.F., Huang L.Z., Son J.H., Pinzon-Guzman C, Slaton G.S., Winzer-Serhan U.H: (2008) Acute nicotine activates cFos and Arc mRNA expression in limbic brain areas involved in anxiety in rat pups during a period of hypo-responsiveness to stress. Neuroscience. 157(2):349-59.
Winzer-Serhan, UH. (2008) "Long-term consequences of developmental chronic nicotine exposure".Frontiers in Bioscience 13:636-649.
Son J.H., Winzer-Serhan U.H. (2009) Chronic neonatal nicotine exposure increases expression of neurotrophic factors in the rat hippocampus. Brain Research 1278: 1-14.