The goal of this revised research proposal is to determine the pharmacologic effects of nicotine on the learning and memory deficits resulted from the presence of HIV-1 viral proteins and to define the genes and biological pathways associated with those effects by using a newly created non-infectious HIV-1 transgenic (HIV-1Tg) rat model. Although the HIV-1 genes gag and pol had been deleted, other viral genes including LTRs still kept intact and are expressed in most tissues including brain and blood of the HIV-1Tg rats. With advancing age, this HIV-1Tg rat develops clinical manifestations of human HIV disease, and, thus, mimics the infection that results from the persistent presence of HIV proteins in the host. When we examined the performance of HIV-1Tg rats in a modified Morris water maze, they showed deficits in spatial learning similar to those in patients with HIV-1 infection. Numerous epidemiological and basic research studies in both humans and rodent models reveal that nicotine can enhance cognitive abilities, indicating nicotine has neuroprotective effects. Based on these findings, we hypothesize that exposure of HIV-1Tg rats to nicotine can alter the observed learning and cognitive deficits resulted from the continuous presence of HIV-1 viral proteins in the rats. To test this hypothesis, we propose to first determine nicotine's effects in the HIV-1Tg rats at the behavioral level and then identify the genes and biological pathways that are affected by nicotine in the HIV-1Tg rats. Finally, we will characterize the specific genes and pathways that mediate nicotine's effects on HIV-1-induced learning and memory deficits. Specifically, our aims are: 1) To determine nicotine's effects on learning and memory in HIV-1Tg rats using a modified Morris water maze test with non-visual cues for navigation;2) To identify the biological pathways that are significantly affected by nicotine in HIV-1Tg rats using high-density oligonucleotide microarray;and 3) To characterize the specific genes associated those biological pathways, including those are responsible for neuroprotection and neuroinflammation, that mediate nicotine's effects on learning and memory in HIV- 1Tg rats at both RNA and protein levels using various conventional biochemistry and molecular biology techniques. To our knowledge, this represents the first study of investigating how nicotine affects on learning and cognitive deficits resulted from the HIV-1 viral proteins in a rodent model. The data generated from the proposed studies will shed light on the molecular mechanism(s) underlying nicotine's effects on learning behaviors in the presence of HIV-1 viral proteins, and can have substantial clinical significance in the understanding and treatment of neurological dysfunctions associated with HIV infection and AIDS.

Public Health Relevance

The primary goal of this proposed research is to determine the pharmacological effects of nicotine on the learning and memory deficits resulted from the presence of HIV-1 viral proteins and to define the genes and biological pathways associated with those effects by using a newly created non-infectious HIV-1 transgenic rat model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA026356-04S1
Application #
8661450
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Lynch, Minda
Project Start
2009-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$13,100
Indirect Cost
Name
Seton Hall University
Department
None
Type
Schools of Arts and Sciences
DUNS #
079324315
City
South Orange
State
NJ
Country
United States
Zip Code
07079
Dash, Bhagirathi; Li, Ming D (2014) Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) ?2 subunit influence nAChR function. Neuropharmacology 85:471-81
Dash, Bhagirathi; Li, Ming D (2014) Analysis of rare variations reveals roles of amino acid residues in the N-terminal extracellular domain of nicotinic acetylcholine receptor (nAChR) alpha6 subunit in the functional expression of human alpha6*-nAChRs. Mol Brain 7:35
Dash, Bhagirathi; Li, Ming D; Lukas, Ronald J (2014) Roles for N-terminal extracellular domains of nicotinic acetylcholine receptor (nAChR) ?3 subunits in enhanced functional expression of mouse ?6?2?3- and ?6?4?3-nAChRs. J Biol Chem 289:28338-51
Dash, Bhagirathi; Lukas, Ronald J; Li, Ming D (2014) A signal peptide missense mutation associated with nicotine dependence alters ?2*-nicotinic acetylcholine receptor function. Neuropharmacology 79:715-25
Abbondanzo, Susan J; Chang, Sulie L (2014) HIV-1 transgenic rats display alterations in immunophenotype and cellular responses associated with aging. PLoS One 9:e105256
Cao, J; Wang, J; Dwyer, J B et al. (2013) Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences. Transl Psychiatry 3:e247
Li, Ming D; Cao, Junran; Wang, Shaolin et al. (2013) Transcriptome sequencing of gene expression in the brain of the HIV-1 transgenic rat. PLoS One 8:e59582
Cao, Junran; Dwyer, Jennifer B; Gautier, Nicole M et al. (2013) Central myelin gene expression during postnatal development in rats exposed to nicotine gestationally. Neurosci Lett 553:115-20
Vigorito, Michael; Cao, Junran; Li, Ming D et al. (2013) Acquisition and long-term retention of spatial learning in the human immunodeficiency virus-1 transgenic rat: effects of repeated nicotine treatment. J Neurovirol 19:157-65
Cui, Wen-Yan; Zhao, Shufang; Polanowska-Grabowska, Renata et al. (2013) Identification and characterization of poly(I:C)-induced molecular responses attenuated by nicotine in mouse macrophages. Mol Pharmacol 83:61-72

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