Despite antiretroviral therapy, approximately 50% of HIV+ patients in the USA are diagnosed with HIV-associated neurocognitive disorders (HAND). HIV alters two key regulators of cognition and psychomotor activity, the medial prefrontal cortex (mPFC) and caudate-putamen (CPu; a.k.a. dorsal striatum). Excessive Ca2+ influx (partly via NMDA receptor, NMDAR) is critical in neuronal excitotoxicity, but the mechanisms underlying HIV neuropathogenesis are not entirely clear. Our published and pilot data point to an additional mechanism in HIV-mediated neuronal hyper-excitability which involves the voltage-gated L-type Ca2+ channel, independent of NMDAR. We showed that HIV-1 transactivator of transcription (Tat) increases Ca2+ influx by upregulating L-channels in mPFC pyramidal neurons, rendering these cells more susceptible and vulnerable to hyper-excitability. Tat also potentiates the interaction between NMDAR and L-channel, and neurons showed similar over-excitation as aged or modeled using HIV-1 transgenic (Tg) rats. Together, these findings point to a unique mechanism by which HIV induces excessive neuroexcitation. Given that neither an L-channel blocker nor a NMDAR antagonist alone was able to treat HAND at late stage, understanding the intricate interplay between HIV and the L-channels may provide novel therapeutic strategies for HAND. Our central hypothesis is that HIV infection of the brain renders mPFC pyramidal neurons and CPu medium spiny neurons (MSNs) more susceptible and vulnerable to excitatory stimuli via over-activating the L-channels; and that combined treatments of an L-channel and NMDAR blocker will ameliorate the mPFC/CPu neuropathophysiology, more effectively in adolescent than in older brain. We will test this hypothesis via three aims using integrated electro- physiological, optic/fluorescence imaging and immuno/biochemical approaches.
In Aim 1 we will define the cellular/molecular mechanism(s) by which HIV mediates L-channel over-activation and consequently neuronal hyper-excitation in the mPFC/CPu of adolescent Tg rats. We expect that HIV-1 proteins released by infected cells mediate L-channel over-activation in part via engaging dopamine D1 receptor (D1R), and will reveal the domain of Tat that mediates the Tat effects on L-channels.
In Aim 2 we will evaluate the interplay between NMDAR and L-channel in mediating neuronal hyper-excitability. We hypothesize that NMDA-evoked Ca2+ signal is over-amplified and relayed by LVA-L channels to other ion channels that ultimately control firing.
In Aim 3 we will ascertain age (a significant risk factor for HAND)-associated exacerbation in L-channel over-activation and mPFC/CPu neuropathophysiology in older Tg rats. We hypothesize that mPFC/CPu neuropathophysiology will be more severe in aging Tg rats than in adolescent Tg rats (and aging non-Tg rats). Lately, we expect that combined treatments of L-channel/NMDAR blockers will diminish/ameliorate HIV-mediated neuronal hyper-excitability. Collectively, our studies will establish a novel paradigm in HIV-mediated neuropathogenesis and identify novel targets for future therapeutic intervention for HIV-mediated neuropathology.

Public Health Relevance

HIV causes excessive firing of neurons, which is a significant component of HIV-mediated neuronal dysregulation and injury. The mechanisms that drive this excessive firing are not entirely clear nor the impact of an aging brain on HIV-mediated neuronal dysregulation. HIV-infected population is aging, yet the impact of age on HIV-mediated neuronal injury is also not clear. We will use several models, including a rat model that expresses 7 of the 9 HIV proteins to understand how HIV leads to excessive neuronal excitation in young and older HIV+ rats. This understanding will pave the way for innovative approaches for therapeutic intervention. We have already identified one pathway in particular, which is the ability of HIV via one of its proteins (Tat) to induce over-activation/expression of calcium channels (L-type) on neurons. Such changes in these channels along with others (NMDA receptor) are likely to play a significant role in HIV-mediated neuronal injury through the aging process. Our proposed research will address the mechanism(s) by which this occurs and will test whether blocking both L-channels and NMDAR can prevent and/or reduce the severity of disease rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS084817-05
Application #
9296193
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2013-07-15
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Li, Ang; Zeng, Guang; Du, Congwu et al. (2018) Automated motion-artifact correction in an OCTA image using tensor voting approach. Appl Phys Lett 113:101102
Gu, Xiaochun; Chen, Wei; You, Jiang et al. (2018) Long-term optical imaging of neurovascular coupling in mouse cortex using GCaMP6f and intrinsic hemodynamic signals. Neuroimage 165:251-264
Allen, Craig P; Park, Kicheon; Li, Ang et al. (2018) Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats. Addict Biol :
Li, Ang; You, Jiang; Du, Congwu et al. (2017) Automated segmentation and quantification of OCT angiography for tracking angiogenesis progression. Biomed Opt Express 8:5604-5616
Yu, Chunjiang; Narasipura, Srinivas D; Richards, Maureen H et al. (2017) HIV and drug abuse mediate astrocyte senescence in a ?-catenin-dependent manner leading to neuronal toxicity. Aging Cell 16:956-965
You, Jiang; Li, Ang; Du, Congwu et al. (2017) Volumetric Doppler angle correction for ultrahigh-resolution optical coherence Doppler tomography. Appl Phys Lett 110:011102
Zhang, Qiujia; You, Jiang; Volkow, Nora D et al. (2016) Chronic cocaine disrupts neurovascular networks and cerebral function: optical imaging studies in rodents. J Biomed Opt 21:26006
Hu, Xiu-Ti (2016) HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions. Curr Drug Targets 17:4-14
Khodr, Christina E; Chen, Lihua; Dave, Sonya et al. (2016) Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons. Neurobiol Dis 94:85-94
Chen, Wei; You, Jiang; Gu, Xiaochun et al. (2016) High-speed swept source optical coherence Doppler tomography for deep brain microvascular imaging. Sci Rep 6:38786

Showing the most recent 10 out of 15 publications