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Dr. Rosemarie M. Booze
University of South Carolina

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0 Microglia-neurons interaction
0 Cognition and Learning
0 rat behavior
0 HIV-1 associated nervous system disorders
0 Dopamine, Neurocircuitry

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Review
Published: 21 August 2021 in Cells
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Individuals living with human immunodeficiency virus type 1 (HIV-1) are often plagued by debilitating neurocognitive impairments and affective alterations;the pathophysiology underlying these deficits likely includes dopaminergic system dysfunction. The present review utilized four interrelated aims to critically examine the evidence for dopaminergic alterations following HIV-1 viral protein exposure. First, basal dopamine (DA) values are dependent upon both brain region andexperimental approach (i.e., high-performance liquid chromatography, microdialysis or fast-scan cyclic voltammetry). Second, neurochemical measurements overwhelmingly support decreased DA concentrations following chronic HIV-1 viral protein exposure. Neurocognitive impairments, including alterations in pre-attentive processes and attention, as well as apathetic behaviors, provide an additional line of evidence for dopaminergic deficits in HIV-1. Third, to date, there is no compelling evidence that combination antiretroviral therapy (cART), the primary treatment regimen for HIV-1 seropositive individuals, has any direct pharmacological action on the dopaminergic system. Fourth, the infection of microglia by HIV-1 viral proteins may mechanistically underlie the dopamine deficit observed following chronic HIV-1 viral protein exposure. An inclusive and critical evaluation of the literature, therefore, supports the fundamental conclusion that long-term HIV-1 viral protein exposure leads to a decreased dopaminergic state, which continues to persist despite the advent of cART. Thus, effective treatment of HIV-1-associated apathy/depression and neurocognitive impairments must focus on strategies for rectifying decreases in dopamine function.

ACS Style

Kristen A. McLaurin; Michael Harris; Victor Madormo; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits. Cells 2021, 10, 2158 .

AMA Style

Kristen A. McLaurin, Michael Harris, Victor Madormo, Steven B. Harrod, Charles F. Mactutus, Rosemarie M. Booze. HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits. Cells. 2021; 10 (8):2158.

Chicago/Turabian Style

Kristen A. McLaurin; Michael Harris; Victor Madormo; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. 2021. "HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits." Cells 10, no. 8: 2158.

Journal article
Published: 04 June 2021 in Scientific Reports
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Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

ACS Style

Kristen A. McLaurin; Sarah J. Bertrand; Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. S-Equol mitigates motivational deficits and dysregulation associated with HIV-1. Scientific Reports 2021, 11, 1 -17.

AMA Style

Kristen A. McLaurin, Sarah J. Bertrand, Jessica M. Illenberger, Steven B. Harrod, Charles F. Mactutus, Rosemarie M. Booze. S-Equol mitigates motivational deficits and dysregulation associated with HIV-1. Scientific Reports. 2021; 11 (1):1-17.

Chicago/Turabian Style

Kristen A. McLaurin; Sarah J. Bertrand; Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. 2021. "S-Equol mitigates motivational deficits and dysregulation associated with HIV-1." Scientific Reports 11, no. 1: 1-17.

Article
Published: 18 May 2021 in Journal of NeuroVirology
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HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.

ACS Style

Adam R. Denton; Charles F. Mactutus; Almeera U. Lateef; Steven B. Harrod; Rosemarie M. Booze. Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage. Journal of NeuroVirology 2021, 1 -19.

AMA Style

Adam R. Denton, Charles F. Mactutus, Almeera U. Lateef, Steven B. Harrod, Rosemarie M. Booze. Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage. Journal of NeuroVirology. 2021; ():1-19.

Chicago/Turabian Style

Adam R. Denton; Charles F. Mactutus; Almeera U. Lateef; Steven B. Harrod; Rosemarie M. Booze. 2021. "Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage." Journal of NeuroVirology , no. : 1-19.

Journal article
Published: 17 May 2021 in Viruses
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The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

ACS Style

Hailong Li; Kristen McLaurin; Jessica Illenberger; Charles Mactutus; Rosemarie Booze. Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders. Viruses 2021, 13, 924 .

AMA Style

Hailong Li, Kristen McLaurin, Jessica Illenberger, Charles Mactutus, Rosemarie Booze. Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders. Viruses. 2021; 13 (5):924.

Chicago/Turabian Style

Hailong Li; Kristen McLaurin; Jessica Illenberger; Charles Mactutus; Rosemarie Booze. 2021. "Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders." Viruses 13, no. 5: 924.

Video audio media
Published: 21 January 2021 in Journal of Visualized Experiments
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It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. Establishment of the EcoHIV infected rat model for studies of drug abuse and neurocognitive disorders, would be beneficial in the study of neuroHIV and HIV-1 associated neurocognitive disorders (HAND). In the present study, we demonstrate the successful creation of a rat model of active HIV infection using chimeric HIV (EcoHIV). First, the lentiviral construct of EcoHIV was packaged in cultured 293 FT cells for 48 hours. Then, the conditional medium was concentrated and titered. Next, we performed bilateral stereotaxic injections of the EcoHIV-EGFP into F344/N rat brain tissue. One week after infection, EGFP fluorescence signals were detected in the infected brain tissue, indicating that EcoHIV successfully induces an active HIV infection in rats. In addition, immunostaining for the microglial cell marker, Iba1, was performed. The results indicated that microglia were the predominant cell type harboring EcoHIV. Furthermore, EcoHIV rats exhibited alterations in temporal processing, a potential underlying neurobehavioral mechanism of HAND as well as synaptic dysfunction eight weeks after infection. Collectively, the present study extends the EcoHIV model of HIV-1 infection to the rat offering a valuable biological system to study HIV-1 viral reservoirs in the brain as well as HAND and associated comorbidities such as drug abuse.

ACS Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. A Rat Model of EcoHIV Brain Infection. Journal of Visualized Experiments 2021, e62137 .

AMA Style

Hailong Li, Kristen A. McLaurin, Charles F. Mactutus, Rosemarie M. Booze. A Rat Model of EcoHIV Brain Infection. Journal of Visualized Experiments. 2021; (167):e62137.

Chicago/Turabian Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. 2021. "A Rat Model of EcoHIV Brain Infection." Journal of Visualized Experiments , no. 167: e62137.

Preprint content
Published: 11 January 2021
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HIV-1 infection affects approximately 37 million individuals and approximately 50% of seropositive individuals will develop symptoms of clinical depression and apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1 induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.

ACS Style

Adam R. Denton; Charles F. Mactutus; Almeera U. Lateef; Steven B. Harrod; Rosemarie M. Booze. Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage. 2021, 1 .

AMA Style

Adam R. Denton, Charles F. Mactutus, Almeera U. Lateef, Steven B. Harrod, Rosemarie M. Booze. Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage. . 2021; ():1.

Chicago/Turabian Style

Adam R. Denton; Charles F. Mactutus; Almeera U. Lateef; Steven B. Harrod; Rosemarie M. Booze. 2021. "Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage." , no. : 1.

Preprint content
Published: 04 January 2021
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The persistence of motivational alterations, including apathy, in older HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

ACS Style

Kristen A. McLaurin; Sarah J. Bertrand; Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol. 2021, 1 .

AMA Style

Kristen A. McLaurin, Sarah J. Bertrand, Jessica M. Illenberger, Steven B. Harrod, Charles F. Mactutus, Rosemarie M. Booze. HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol. . 2021; ():1.

Chicago/Turabian Style

Kristen A. McLaurin; Sarah J. Bertrand; Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. 2021. "HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol." , no. : 1.

Video audio media
Published: 23 December 2020 in Journal of Visualized Experiments
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Hydrophobic tissue clearing methods are easily adjustable, fast, and low-cost procedures that allows for the study of a molecule of interest in unaltered tissue samples. Traditional immunolabeling procedures require cutting the sample into thin sections, which restricts the ability to label and examine intact structures. However, if brain tissue can remain intact during processing, structures and circuits can remain intact for the analysis. Previously established clearing methods take significant time to completely clear the tissue, and the harsh chemicals can often damage sensitive antibodies. The iDISCO method quickly and completely clears tissue, is compatible with many antibodies, and requires no special lab equipment. This technique was initially validated for the use in mice tissue, but the current protocol adapts this method to image hemispheres of control and transgenic rat brains. In addition to this, the present protocol also makes several adjustments to preexisting protocol to provide clearer images with less background staining. Antibodies for Iba-1 and tyrosine hydroxylase were validated in the HIV-1 transgenic rat and in F344/N control rats using the present hydrophobic tissue clearing method. The brain is an interwoven network, where structures work together more often than separately of one another. Analyzing the brain as a whole system as opposed to a combination of individual pieces is the greatest benefit of this whole brain clearing method.

ACS Style

Kristin N. Kirchner; Hailong Li; Adam R. Denton; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. A Hydrophobic Tissue Clearing Method for Rat Brain Tissue. Journal of Visualized Experiments 2020, e61821 .

AMA Style

Kristin N. Kirchner, Hailong Li, Adam R. Denton, Steven B. Harrod, Charles F. Mactutus, Rosemarie M. Booze. A Hydrophobic Tissue Clearing Method for Rat Brain Tissue. Journal of Visualized Experiments. 2020; (166):e61821.

Chicago/Turabian Style

Kristin N. Kirchner; Hailong Li; Adam R. Denton; Steven B. Harrod; Charles F. Mactutus; Rosemarie M. Booze. 2020. "A Hydrophobic Tissue Clearing Method for Rat Brain Tissue." Journal of Visualized Experiments , no. 166: e61821.

Preprint content
Published: 27 November 2020
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The translation of preclinical studies to human applications is associated with a high failure rate, which may be exacerbated by limited training in experimental design and statistical analysis. Nested experimental designs, which occur when data have a multilevel structure (e.g., in vitro: cells within a culture dish; in vivo: rats within a litter), often violate the independent observation assumption underlying many traditional statistical techniques. Although previous studies have empirically evaluated the analytic challenges associated with multilevel data, existing work has not focused on key parameters and design components typically observed in preclinical research. To address this knowledge gap, a Monte Carlo simulation study was conducted to systematically assess the effects of inappropriately modeling multilevel data via a fixed effects ANOVA in studies with sparse observations, no between group comparison within a single cluster, and interactive effects. Simulation results revealed a dramatic increase in the probability of type 1 error and relative bias of the standard error as the number of level-1 (e.g., cells; rats) units per cell increased in the fixed effects ANOVA; these effects were largely attenuated when the nesting was appropriately accounted for via a random effects ANOVA. Thus, failure to account for a nested experimental design may lead to reproducibility challenges and inaccurate conclusions. Appropriately accounting for multilevel data, however, may enhance statistical reliability, thereby leading to improvements in translatability. Valid analytic strategies are provided for a variety of design scenarios.

ACS Style

Kristen A. McLaurin; Amanda J. Fairchild; Dexin Shi; Rosemarie M. Booze; Charles F. Mactutus. Valid statistical approaches for clustered data: A Monte Carlo simulation study. 2020, 1 .

AMA Style

Kristen A. McLaurin, Amanda J. Fairchild, Dexin Shi, Rosemarie M. Booze, Charles F. Mactutus. Valid statistical approaches for clustered data: A Monte Carlo simulation study. . 2020; ():1.

Chicago/Turabian Style

Kristen A. McLaurin; Amanda J. Fairchild; Dexin Shi; Rosemarie M. Booze; Charles F. Mactutus. 2020. "Valid statistical approaches for clustered data: A Monte Carlo simulation study." , no. : 1.

Preprint content
Published: 03 November 2020
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The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to 1) evaluate the HIV-1 mRNA neuroanatomical distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat (i.e., under conditions of latent infection), and 2) to validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 hours of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results which are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments, synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway, and neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

ACS Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats. 2020, 1 .

AMA Style

Hailong Li, Kristen A. McLaurin, Charles F. Mactutus, Rosemarie M. Booze. HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats. . 2020; ():1.

Chicago/Turabian Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. 2020. "HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats." , no. : 1.

Correction
Published: 28 July 2020 in Journal of Neuroimmune Pharmacology
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ACS Style

Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Kristen A. McLaurin; Asha Kallianpur; Rosemarie M. Booze. Correction to: HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History. Journal of Neuroimmune Pharmacology 2020, 15, 876 -876.

AMA Style

Jessica M. Illenberger, Steven B. Harrod, Charles F. Mactutus, Kristen A. McLaurin, Asha Kallianpur, Rosemarie M. Booze. Correction to: HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History. Journal of Neuroimmune Pharmacology. 2020; 15 (4):876-876.

Chicago/Turabian Style

Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Kristen A. McLaurin; Asha Kallianpur; Rosemarie M. Booze. 2020. "Correction to: HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History." Journal of Neuroimmune Pharmacology 15, no. 4: 876-876.

Invited review
Published: 12 June 2020 in Journal of Neuroimmune Pharmacology
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The fronto-striatal circuitry, involving the nucleus accumbens, ventral tegmental area, and prefrontal cortex, mediates goal-directed behavior and is targeted by both drugs of abuse and HIV-1 infection. Acutely, both drugs and HIV-1 provoke increased dopamine activity within the circuit. However, chronic exposure to drugs or HIV-1 leads to dysregulation of the dopamine system as a result of fronto-striatal adaptations to oppose the effects of repeated instances of transiently increased dopamine. Specifically, chronic drug use leads to reduced dopaminergic tone, upregulation of dopamine transporters, and altered circuit connectivity, sending users into an allosteric state in which goal-directed behaviors are dysregulated (i.e., addiction). Similarly, chronic exposure to HIV-1, even with combination antiretroviral therapy (cART), dysregulates dopamine and dopamine transporter function and alters connectivity of the fronto-striatal circuit, contributing to apathy and clinical symptoms of HIV-1 associated neurocognitive disorders (HAND). Thus, in a drug user also exposed to HIV-1, dysregulation of the fronto-striatal dopamine circuit advances at an exacerbated rate and appears to be driven by mechanisms unique from those seen with chronic drug use or HIV-1 exposure alone. We posit that the effects of drug use and HIV-1 infection on microglia interact to drive the progression of motivational dysfunction at an accelerated rate. The current review will therefore explore how the fronto-striatal circuit adapts to drug use (using cocaine as an example), HIV-1 infection, and both together; emphasizing proper methods and providing future directions to develop treatments for pathologies disrupting goal-directed behaviors and improve clinical outcomes for affected patients. Graphical Abstract Drug use and HIV-1 in the fronto-striatal circuit. Drugs of abuse and HIV-1 infection both target the fronto-striatal circuit which mediates goal-directed behavior. Acutely, drugs and HIV-1 increase dopamine activity; in contrast chronic exposure produces circuit adaptions leading to dysregulation, addiction and/or apathy. Comorbid drug use and HIV-1 infection may interact with microglia to exacerbate motivational dysregulation.

ACS Style

Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Kristen A. McLaurin; Asha Kallianpur; Rosemarie M. Booze. HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History. Journal of Neuroimmune Pharmacology 2020, 15, 715 -728.

AMA Style

Jessica M. Illenberger, Steven B. Harrod, Charles F. Mactutus, Kristen A. McLaurin, Asha Kallianpur, Rosemarie M. Booze. HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History. Journal of Neuroimmune Pharmacology. 2020; 15 (4):715-728.

Chicago/Turabian Style

Jessica M. Illenberger; Steven B. Harrod; Charles F. Mactutus; Kristen A. McLaurin; Asha Kallianpur; Rosemarie M. Booze. 2020. "HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History." Journal of Neuroimmune Pharmacology 15, no. 4: 715-728.

Video audio media
Published: 02 April 2020 in Journal of Visualized Experiments
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It has been reported that the size and shape of dendritic spines is related to their structural plasticity. To identify the morphological structure of pyramidal neurons and dendritic spines, a ballistic labeling technique can be utilized. In the present protocol, pyramidal neurons are labeled with DilC18(3) dye and analyzed using neuronal reconstruction software to assess neuronal morphology and dendritic spines. To investigate neuronal structure, dendritic branching analysis and Sholl analysis are performed, allowing researchers to draw inferences about dendritic branching complexity and neuronal arbor complexity, respectively. The evaluation of dendritic spines is conducted using an automatic assisted classification algorithm integral to the reconstruction software, which classifies spines into four categories (i.e., thin, mushroom, stubby, filopodia). Furthermore, an additional three parameters (i.e., length, head diameter, and volume) are also chosen to assess alterations in dendritic spine morphology. To validate the potential of wide application of the ballistic labeling technique, pyramidal neurons from in vitro cell culture were successfully labeled. Overall, the ballistic labeling method is unique and useful for visualizing neurons in different brain regions in rats, which in combination with sophisticated reconstruction software, allows researchers to elucidate the possible mechanisms underlying neurocognitive dysfunction.

ACS Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. Ballistic Labeling of Pyramidal Neurons in Brain Slices and in Primary Cell Culture. Journal of Visualized Experiments 2020, e60989 .

AMA Style

Hailong Li, Kristen A. McLaurin, Charles F. Mactutus, Rosemarie M. Booze. Ballistic Labeling of Pyramidal Neurons in Brain Slices and in Primary Cell Culture. Journal of Visualized Experiments. 2020; (158):e60989.

Chicago/Turabian Style

Hailong Li; Kristen A. McLaurin; Charles F. Mactutus; Rosemarie M. Booze. 2020. "Ballistic Labeling of Pyramidal Neurons in Brain Slices and in Primary Cell Culture." Journal of Visualized Experiments , no. 158: e60989.

Review article
Published: 09 September 2019 in Brain Research
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HIV-1-associated neurocognitive disorders (HAND), characterized by alterations in the core components of cognitive function and age-related disease progression, persist in the post-cART era. However, the neurobehavioral mechanisms that mediate alterations in the core components of cognitive function and the progression of neurocognitive impairments have yet to be systematically evaluated. To address this knowledge gap, statistical mediation analysis was assessed, providing a critical opportunity to empirically evaluate putative neurobehavioral mechanisms underlying HAND. Neurocognitive assessments, conducted in HIV-1 transgenic (Tg) and control animals across the functional lifespan (i.e., Postnatal Day (PD) 30 to PD 600), tapped multiple cognitive domains including preattentive processes, learning, sustained attention, and long-term episodic memory. Three longitudinal mediation models were utilized to assess whether deficits in preattentive processes mediate alterations in learning, sustained attention and/or long-term episodic memory over time. Preattentive processes partially mediated the relationship between genotype and learning, genotype and sustained attention, and genotype and long-term episodic memory across the functional lifespan, explaining between 44% and 58% of the HIV-1 transgene effect. Understanding the neurobehavioral mechanisms mediating alterations in HAND may provide key targets for the development of a diagnostic biomarker, novel therapeutics, and cure/restoration strategies.

ACS Style

Kristen A. McLaurin; Charles F. Mactutus; Rosemarie Booze; Amanda J. Fairchild. An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders. Brain Research 2019, 1724, 146436 -146436.

AMA Style

Kristen A. McLaurin, Charles F. Mactutus, Rosemarie Booze, Amanda J. Fairchild. An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders. Brain Research. 2019; 1724 ():146436-146436.

Chicago/Turabian Style

Kristen A. McLaurin; Charles F. Mactutus; Rosemarie Booze; Amanda J. Fairchild. 2019. "An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders." Brain Research 1724, no. : 146436-146436.

Article
Published: 17 May 2019 in Journal of NeuroVirology
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Between 30 and 60% of HIV-seropositive individuals develop symptoms of clinical depression and/or apathy. Dopamine and serotonin are associated with motivational alterations; however, histamine is less well studied. In the present study, we used fast-scan cyclic voltammetry in HIV-1 transgenic (Tg) rats to simultaneously analyze the kinetics of nucleus accumbens dopamine (DA), prefrontal cortical serotonin (5-HT), and hypothalamic histamine (HA). For voltammetry, subjects were 15 HIV-1 Tg (7 male, 8 female) and 20 F344/N (11 male, 9 female) adult rats. Both serotonergic and dopaminergic release and reuptake kinetics were decreased in HIV-1 Tg animals relative to controls. In contrast, rates of histamine release and reuptake increased in HIV-1 Tg rats. Additionally, we used immunohistochemical (IHC) methods to identify histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus. For IHC, subjects were 9 HIV-1 Tg (5 male, 4 female) and 9 F344/N (5 male, 4 female) adult rats. Although the total number of TMN histaminergic cells did not differ between HIV-1 Tg rats and F344/N controls, a significant sex effect was found, with females having an increased number of histaminergic neurons, relative to males. Collectively, these findings illustrate neurochemical alterations that potentially underlie or exacerbate the pathogenesis of clinical depression and/or apathy in HIV-1.

ACS Style

Adam R. Denton; Srimal A. Samaranayake; Kristin N. Kirchner; Robert F. Roscoe; Shane N. Berger; Steven B. Harrod; Charles F. Mactutus; Parastoo Hashemi; Rosemarie M. Booze. Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure. Journal of NeuroVirology 2019, 25, 540 -550.

AMA Style

Adam R. Denton, Srimal A. Samaranayake, Kristin N. Kirchner, Robert F. Roscoe, Shane N. Berger, Steven B. Harrod, Charles F. Mactutus, Parastoo Hashemi, Rosemarie M. Booze. Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure. Journal of NeuroVirology. 2019; 25 (4):540-550.

Chicago/Turabian Style

Adam R. Denton; Srimal A. Samaranayake; Kristin N. Kirchner; Robert F. Roscoe; Shane N. Berger; Steven B. Harrod; Charles F. Mactutus; Parastoo Hashemi; Rosemarie M. Booze. 2019. "Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure." Journal of NeuroVirology 25, no. 4: 540-550.

Video audio media
Published: 19 April 2019 in Journal of Visualized Experiments
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Temporal processing deficits have been implicated as a potential elemental dimension of higher-level cognitive processes, commonly observed in neurocognitive disorders. Despite the popularization of prepulse inhibition (PPI) in recent years, many current protocols promote using a percent of control measure, thereby precluding the assessment of temporal processing. The present study used cross-modal PPI and gap prepulse inhibition (gap-PPI) to demonstrate the benefits of employing a range of interstimulus intervals (ISIs) to delineate effects of sensory modality, psychostimulant exposure, and age. Assessment of sensory modality, psychostimulant exposure, and age reveals the utility of an approach varying the interstimulus interval (ISI) to establish the shape of the ISI function, including increases (sharper curve inflections) or decreases (flattening of the response amplitude curve) in startle amplitude. Additionally, shifts in peak response inhibition, suggestive of a differential sensitivity to the manipulation of ISI, are often revealed. Thus, the systematic manipulation of ISI affords a critical opportunity to evaluate temporal processing, which may reveal the underlying neural mechanisms involved in neurocognitive disorders.

ACS Style

Kristen A McLaurin; Landhing M Moran; Hailong Li; Rosemarie M Booze; Charles F Mactutus. The Power of Interstimulus Interval for the Assessment of Temporal Processing in Rodents. Journal of Visualized Experiments 2019, e58659 .

AMA Style

Kristen A McLaurin, Landhing M Moran, Hailong Li, Rosemarie M Booze, Charles F Mactutus. The Power of Interstimulus Interval for the Assessment of Temporal Processing in Rodents. Journal of Visualized Experiments. 2019; (146):e58659.

Chicago/Turabian Style

Kristen A McLaurin; Landhing M Moran; Hailong Li; Rosemarie M Booze; Charles F Mactutus. 2019. "The Power of Interstimulus Interval for the Assessment of Temporal Processing in Rodents." Journal of Visualized Experiments , no. 146: e58659.

Research article
Published: 05 March 2019 in PLOS ONE
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Dopamine release in the nucleus accumbens from ventral tegmental area (VTA) efferent neurons is critical for orientation and response to novel stimuli in the environment. However, there are considerable differences between neuronal populations of the VTA and it is unclear which specific cell populations modulate behavioral responses to environmental novelty. A retroDREADDs (designer drugs exclusively activated by designer receptors) technique, comprising designer G protein-coupled receptors exclusively activated by designer drugs and modulated by retrograde transported Cre, was used to selectively stimulate neurons of the VTA which project to the nucleus accumbens shell (AcbSh). First, the selectivity and expression of the human M3 muscarinic receptor-based adeno-associated virus (AAV-hM3D) was confirmed in primary neuronal cell cultures. Second, AAV-CMV-GFP/Cre was infused into the AcbSh and AAV-hSyn-DIO-hM3D(Gq)-mCherry (a presynaptic enhancer in the presence of its cognate ligand clozapine-N-oxide) was infused into the VTA of ovariectomized female Fisher 344 rats to elicit hM3D(Gq)-mCherry production specifically in neurons of the VTA which synapse in the AcbSh. Finally, administration of clozapine-N-oxide significantly altered rodents’ response to novelty (e.g. absence of white background noise) by activation of hM3D(Gq) receptors, without altering gross locomotor activity or auditory processing per se. Confocal imaging confirmed production of mCherry in neurons of the posterior aspect of the VTA (pVTA) suggesting these neurons contribute to novelty responses. These results suggest the pVTA-AcbSh circuit is potentially altered in motivational disorders such as apathy, depression, and drug addiction. Targeting the pVTA-AcbSh circuit, therefore, may be an effective target for pharmacological management of such psychopathologies.

ACS Style

Hailong Li; Jessica M. Illenberger; Michael N. Cranston; Charles F. Mactutus; Kristen A. McLaurin; Steven B. Harrod; Rosemarie M. Booze. Posterior ventral tegmental area-nucleus accumbens shell circuitry modulates response to novelty. PLOS ONE 2019, 14, e0213088 .

AMA Style

Hailong Li, Jessica M. Illenberger, Michael N. Cranston, Charles F. Mactutus, Kristen A. McLaurin, Steven B. Harrod, Rosemarie M. Booze. Posterior ventral tegmental area-nucleus accumbens shell circuitry modulates response to novelty. PLOS ONE. 2019; 14 (3):e0213088.

Chicago/Turabian Style

Hailong Li; Jessica M. Illenberger; Michael N. Cranston; Charles F. Mactutus; Kristen A. McLaurin; Steven B. Harrod; Rosemarie M. Booze. 2019. "Posterior ventral tegmental area-nucleus accumbens shell circuitry modulates response to novelty." PLOS ONE 14, no. 3: e0213088.

Journal article
Published: 29 January 2019 in Scientific Reports
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The marked increase in life expectancy for HIV-1 seropositive individuals, following the great success of combination antiretroviral therapy (cART), heralds an examination of the progression of HIV-1 associated neurocognitive disorders (HAND). However, since the seminal call for animal models of HIV-1/AIDS in 1988, there has been no extant in vivo animal model system available to provide a truly longitudinal study of HAND. Here, we demonstrate that the HIV-1 transgenic (Tg) rat, resembling HIV-1 seropositive individuals on lifelong cART, exhibits age-related, progressive neurocognitive impairments (NCI), including alterations in learning, sustained attention, flexibility, and inhibition; deficits commonly observed in HIV-1 seropositive individuals. Pyramidal neurons from layers II-III of the medial prefrontal cortex (mPFC) displayed profound synaptic dysfunction in HIV-1 Tg animals relative to controls; dysfunction that was characterized by alterations in dendritic branching complexity, synaptic connectivity, and dendritic spine morphology. NCI and synaptic dysfunction in pyramidal neurons from layers II-III of the mPFC independently identified the presence of the HIV-1 transgene with at least 78.5% accuracy. Thus, even in the absence of sensory or motor system deficits and comorbidities, HAND is a neurodegenerative disease characterized by age-related disease progression; impairments which may be due, at least partly, to synaptic dysfunction in the mPFC. Further, the progression of HAND with age in the HIV-1 Tg rat and associated synaptic dysfunction affords an instrumental model system for the development of therapeutics and functional cure strategies.

ACS Style

Kristen A. McLaurin; Hailong Li; Rosemarie Booze; Charles F. Mactutus. Disruption of Timing: NeuroHIV Progression in the Post-cART Era. Scientific Reports 2019, 9, 1 -18.

AMA Style

Kristen A. McLaurin, Hailong Li, Rosemarie Booze, Charles F. Mactutus. Disruption of Timing: NeuroHIV Progression in the Post-cART Era. Scientific Reports. 2019; 9 (1):1-18.

Chicago/Turabian Style

Kristen A. McLaurin; Hailong Li; Rosemarie Booze; Charles F. Mactutus. 2019. "Disruption of Timing: NeuroHIV Progression in the Post-cART Era." Scientific Reports 9, no. 1: 1-18.

Article
Published: 03 January 2019 in Journal of NeuroVirology
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In 2007, the nosology for HIV-1-associated neurocognitive disorders (HAND) was updated to a primarily neurocognitive disorder. However, currently available diagnostic tools lack the sensitivity and specificity needed for an accurate diagnosis for HAND. Scientists and clinicians, therefore, have been on a quest for an innovative biomarker to diagnose (i.e., diagnostic biomarker) and/or predict (i.e., prognostic biomarker) the progression of HAND in the post-combination antiretroviral therapy (cART) era. The present review examined the utility and challenges of four proposed biomarkers, including neurofilament light (NFL) chain concentration, amyloid (i.e., sAPPα, sAPPβ, amyloid β) and tau proteins (i.e., total tau, phosphorylated tau), resting-state functional magnetic resonance imaging (fMRI), and prepulse inhibition (PPI). Although significant genotypic differences have been observed in NFL chain concentration, sAPPα, sAPPβ, amyloid β, total tau, phosphorylated tau, and resting-state fMRI, inconsistencies and/or assessment limitations (e.g., invasive procedures, lack of disease specificity, cost) challenge their utility as a diagnostic and/or prognostic biomarker for milder forms of neurocognitive impairment (NCI) in the post-cART era. However, critical evaluation of the literature supports the utility of PPI as a powerful diagnostic biomarker with high accuracy (i.e., 86.7–97.1%), sensitivity (i.e., 89.3–100%), and specificity (i.e., 79.5–94.1%). Additionally, the inclusion of multiple CSF and/or plasma markers, rather than a single protein, may provide a more sensitive diagnostic biomarker for HAND; however, a pressing need for additional research remains. Most notably, PPI may serve as a prognostic biomarker for milder forms of NCI, evidenced by its ability to predict later NCI in higher-order cognitive domains with regression coefficients (i.e., r) greater than 0.8. Thus, PPI heralds an opportunity for the development of a brief, noninvasive diagnostic and promising prognostic biomarker for milder forms of NCI in the post-cART era.

ACS Style

Kristen A. McLaurin; Rosemarie M. Booze; Charles F. Mactutus. Diagnostic and prognostic biomarkers for HAND. Journal of NeuroVirology 2019, 25, 686 -701.

AMA Style

Kristen A. McLaurin, Rosemarie M. Booze, Charles F. Mactutus. Diagnostic and prognostic biomarkers for HAND. Journal of NeuroVirology. 2019; 25 (5):686-701.

Chicago/Turabian Style

Kristen A. McLaurin; Rosemarie M. Booze; Charles F. Mactutus. 2019. "Diagnostic and prognostic biomarkers for HAND." Journal of NeuroVirology 25, no. 5: 686-701.

Original research article
Published: 22 November 2018 in Frontiers in Behavioral Neuroscience
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Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV-1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies.

ACS Style

Kristen A. McLaurin; Anna Cook; Hailong Li; Alexis F. League; Charles F. Mactutus; Rosemarie M. Booze. Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat. Frontiers in Behavioral Neuroscience 2018, 12, 285 .

AMA Style

Kristen A. McLaurin, Anna Cook, Hailong Li, Alexis F. League, Charles F. Mactutus, Rosemarie M. Booze. Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat. Frontiers in Behavioral Neuroscience. 2018; 12 ():285.

Chicago/Turabian Style

Kristen A. McLaurin; Anna Cook; Hailong Li; Alexis F. League; Charles F. Mactutus; Rosemarie M. Booze. 2018. "Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat." Frontiers in Behavioral Neuroscience 12, no. : 285.