Although combination antiretroviral therapy (CART) has been highly successful in reducing mother-to-child- transmission (MTCT) in the U.S., globally, MTCT is presently responsible for >1000 new HIV-1 infections each day or more than one new pediatric infection every two minutes. The dopamine (DA) system is a clinically relevant target as evidenced by recent imaging, neurocognitive, and post-mortem examinations of the HIV-1 infected patients. Using a prospective longitudinal design, in this competing renewal we will explore the hypothesis that the development and progression of neurocognitive dysfunction associated with HIV-1, is consequent of, and attributable to, pathology of the DA system, a system highly sensitive to inflammatory processes. Longitudinal studies, while challenging in non-rodent species, are critical for systematically addressing pediatric HIV-1/AIDS, and are also fundamental to our understanding of chronic HIV-1 associated neurological disorders (HAND).
The specific aims are: 1) To determine the development and progression of neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure. Developmental milestones and an array of tasks directed at the behaviors expressing the prominent components of neurocognitive dysfunction that have been clinically identified will be assessed during the rodent preweaning period, adolescence, adulthood and middle age. 2) To determine the long-term alterations in the major DA receptor subtypes and DA transporter as a candidate neurochemical mechanism for the neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV- 1 protein exposure. Quantitative autoradiography will be used to assess the expression of DA receptors (D1, D2, and D3) and DA transporters (DAT) in the nigrostriatal and mesocorticolimbic pathways of the DA system during adolescence, adulthood and middle age. 3) To determine the integrity of DAT function in the development and progression of neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure. DAT function will be studied in a transgenic rat model of chronic HIV-1 protein exposure using in vivo NNF/microdialysis. 4) To determine whether the neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure may be treated with currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction. These experiments will establish the functional role of the neurobiological changes in the DA receptors and DAT as a neurochemical mechanism contributing to, if not mediating, the neurocognitive impairments consequent to chronic expression of the HIV-1 transgene. The program goal is to advance the field with a translational model of the core components of cognition relevant to pediatric HIV-1/AIDS as well as to HAND, and more importantly, to identify (normal rats) and validate (the better characterized HIV-1 transgenic rat) novel neurotherapeutics to "tune" the cognition domains afflicted by HIV-1.

Public Health Relevance

Despite the widely acknowledged success of antiretroviral therapy in reducing mother-to-child-transmission (MTCT) in the U.S., globally, MTCT is presently responsible for >1000 new HIV-1 infections each day or more than one new pediatric infection every two minutes (UNAIDS/WHO, 2010). We are uniquely poised to advance the field with a translational model of the core components of cognition relevant to pediatric HIV-1/AIDS as well as to HIV-1-associated neurocognitive disorders (HAND). Perhaps most importantly, our preclinical studies will identify (normal rats) and validate (the better characterized HIV-1 Tg rat novel neurotherapeutics to tune the cognition domains afflicted by HIV-1.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043680-07
Application #
8705551
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Russo, Denise
Project Start
2002-12-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$292,450
Indirect Cost
$90,760
Name
University of South Carolina at Columbia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Gomez, Adrian M; Sun, Wei-Lun; Midde, Narasimha M et al. (2015) Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration. Eur J Neurosci 41:109-19
Moran, Landhing M; Fitting, Sylvia; Booze, Rosemarie M et al. (2014) Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. Int J Dev Neurosci 38:195-203
Roscoe Jr, Robert F; Mactutus, Charles F; Booze, Rosemarie M (2014) HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J Neuroimmune Pharmacol 9:642-53
Bertrand, Sarah J; Mactutus, Charles F; Aksenova, Marina V et al. (2014) Synaptodendritic recovery following HIV Tat exposure: neurorestoration by phytoestrogens. J Neurochem 128:140-51
Moran, Landhing M; Booze, Rosemarie M; Mactutus, Charles F (2014) Modeling deficits in attention, inhibition, and flexibility in HAND. J Neuroimmune Pharmacol 9:508-21
Moran, L M; Booze, R M; Webb, K M et al. (2013) Neurobehavioral alterations in HIV-1 transgenic rats: evidence for dopaminergic dysfunction. Exp Neurol 239:139-47
Moran, Landhing M; Booze, Rosemarie M; Mactutus, Charles F (2013) Time and time again: temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat. J Neuroimmune Pharmacol 8:988-97
Bertrand, Sarah J; Aksenova, Marina V; Mactutus, Charles F et al. (2013) HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury. Exp Neurol 248:228-35
Patel, Dhyanesh Arvind; Booze, Rosemarie M; Mactutus, Charles F (2012) Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain. Int J Dev Neurosci 30:1-9
Aksenov, Michael Y; Aksenova, M V; Mactutus, C F et al. (2012) D1/NMDA receptors and concurrent methamphetamine+ HIV-1 Tat neurotoxicity. J Neuroimmune Pharmacol 7:599-608

Showing the most recent 10 out of 45 publications