I am interested in studying how gene environmental interactions shape the brain during development. Drugs have a profound impact on the brain. During critical prenatal and postnatal periods, drugs can alter neuronal migration, differentiation, survival, and synapse formation, thereby influencing brain circuitry, behavior and cognitive performance. In particular, I am interested in how early life exposure to psychoactive drugs, like nicotine and alcohol, permanently shape the brain which could result in long-term cognitive impairments, anxiety, and anti-social behavior.
My lab is currently focused on the effects of nicotine. Nicotine interacts with nicotinic acetylcholine receptors (nAChR) which are ligand-gated, pentameric cation channels. Different subtypes of neuronal nAChR are expressed in the central, peripheral and enteric nervous system. We studied the expression of nAChR in prenatal, postnatal and adult brain, using in situ hybridization, immunohistochemistry and receptor autoradiography, demonstrating widespread expression of nAChRs in developing and adult brains. Premature activation of nAChRs by nicotine, has a profound short term and long-term effects, and may cause epigenetic modifications and altered synaptogenesis. Activation of nAChRs is strongly neuroprotective and anti-inflammatory, properties which could interfere with cell death, which could be beneficial during aging and reduce neuronal loss and delay age-related cognitive decline.
1. Effects of chronic nicotine treatment on the developing brain.
Neonatal nicotine exposure increases inhibitory GABA neurons, and excitatory synapse formation. In general, an altered balance of excitatory and inhibitory transmission 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. We currently study the mechanisms by which nAChR activation influences excitatory synaptogenesis in vitro and in vivo models.
2. What is the role of nAChRs during aging?
In humans, smoking is negatively correlated with the development of Parkinson's and Alzheimer's disease. Activation of nAChRs engages anti-apoptotic and anti-inflammatory intracellular signaling pathways resulting in protection against neuronal cell death. 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. This project, investigates a possible connection between nAChRs and regulation of neurotrophic factors and survival genes such as SIRT and Nampt, and Ku70, which are critical in the aging process.
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).
Publications (past five years)
- Garza A., Huang L.Z, Son J.H., Winzer-Serhan U.H. (2009) Expression of nicotinic acetylcholine receptors and mRNA subunits in the enteric nervous system. Neuroscience; 158(4):1521-1529.
- Son, J.H. Winzer-Serhan U.H. (2009) Signal intensities of radiolabeled cRNA probes used alone or in combination with nonisotopic in situ hybridization histochemistry. Journal of Neuroscience Methods 179, 159–165.
- 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.
- Huang, PS. Son JH., Abbott LC., Winzer-Serhan U.H. (2011) Expression and regulation of brain SIRT1 and its target genes by aging and neuronal heteromeric nicotinic cholinergic receptors. Neuroscience 196:189-202.
- Mitchell MR, Mendez IA, Vokes CM, Damborsky JC, Winzer-Serhan UH, Setlow B. (2012) Effects of developmental nicotine exposure on decision-making in adulthood. Behav Pharmacol. Feb;23(1):34-42.
- Damborsky, JC, Griffith, WH, Winzer-Serhan, UH. (2012). Chronic neonatal nicotine exposure increases excitation in the young adult rat hippocampus in a sex-dependent manner. Brain Res.; 1430:8-17.
- Abbott, LC, Winzer-Serhan UH (2012). Smoking during pregnancy: Lessons learned from epidemiological studies and experimental studies using animal models. Review. Critical Reviews in Toxicology, 42(4):279-303.
- Balaraman S., Winzer-Serhan UH, Miranda RC. (2012). Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells. Alcoholism: Clinical and Experimental Research Alcohol Clin Exp Res. 36(10:1669-77.
- Andersson RH, Johnston A, Herman PA, Winzer-Serhan UH, Karavanova I, Vullhorst D, Fisahn A, Buonanno A. (2012). Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors. Proc Natl Acad Sci U S A.; 109(32):13118-23.
- Damborsky, JC, Winzer-Serhan UH. (2012). Effects of sex and chronic neonatal nicotine treatment on NKCC1, KCC2, BDNF, NR2A and NR2B mRNA expression in the postnatal rat hippocampus. Neuroscience; 225:105-17.
- Mendez IA., Damborsky JC., Winzer-Serhan UH., Bizon JL., Setlow B. (2013) Nicotinic Acetylcholine Receptor Binding Predicts Choice Preference in Two Cost Benefit Decision Making Tasks. Neuroscience; 230:121-31.
- DuBois, DW, Fincher, AS, Damborsky, JC, Frye, GD, Winzer-Serhan, UH (2013). Varenicline and Nicotine Enhance GABAergic Synaptic Transmission in Rat CA1Hippocampal and Medial Septum / Diagonal Band Neurons. Life Sciences; 92(6-7): 337-44. PMID: 23352971.
Former Graduate Students: Luping Z Huang, Jong-Hyun Son, Pei-San Huang, Joanne C. Damborsky
- Damborsky* JC, Griffith WH, Winzer-Serhan UH. Neonatal nicotine exposure increases excitatory synaptic transmission and attenuates nicotine-stimulated GABA release in the adult rat hippocampus. Neuropharmacology. 2014 Jun 17.
- Damborsky* JC, Winzer-Serhan UH. Effects of sex and chronic neonatal nicotine treatment on Na²⁺/K⁺/Cl⁻ co-transporter 1, K⁺/Cl⁻ co-transporter 2, brain-derived neurotrophic factor, NMDA receptor subunit 2A and NMDA receptor subunit 2B mRNA expression in the postnatal rat hippocampus. Neuroscience. 2012 Dec 6;225:105-17.
- Damborsky* JC, Griffith WH, Winzer-Serhan UH. Chronic neonatal nicotine exposure increases excitation in the young adult rat hippocampus in a sex-dependent manner. Brain Res. 2012 Jan 9;1430:8-17.
- DuBois DW, Damborsky* JC, Fincher AS, Frye GD, Winzer-Serhan UH. Varenicline and nicotine enhance GABAergic synaptic transmission in rat CA1 hippocampal and medial septum/diagonal band neurons. Life Sci. 2013 Mar 14;92(6-7):337-44.
- Mitchell MR, Mendez IA, Vokes CM, Damborsky* JC, Winzer-Serhan UH, Setlow B. Effects of developmental nicotine exposure in rats on decision-making in adulthood. Behav Pharmacol. 2012 Feb;23(1):34-42.
- Balaraman S, Winzer-Serhan UH, Miranda RC. Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells. Alcohol Clin Exp Res. 2012 Oct;36(10):1669-77.
- Winzer-Serhan, UH. (2008) "Long-term consequences of developmental chronic nicotine exposure". Frontiers in Bioscience 13:636-649. Review.
- Abbott LC, Winzer-Serhan UH. Smoking during pregnancy: lessons learned from epidemiological studies and experimental studies using animal models. Crit Rev Toxicol. 2012 Apr;42(4):279-303. Review.
- 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.
- 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.
- 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.
- 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* 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.
- 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.
- 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.