Biology subjects

McLaurin, K. A.

Publications and source records attributed to McLaurin, K. A..

12 recordsLinked to original sources

bioRxiv2026

EcoHIV Treated Primary Microglia Exhibit a Highly Specialized and Sex-Dependent Transcriptional State

The pathogenesis of HIV-1-associated neurocognitive disorders (HAND) is partly driven by microglial dysregulation. Indeed, HIV-1-induced microglial dyshomeostasis is characterized by a sustained pro-inflammatory state and exacerbated microglia proliferation. Herein, in vitro studies were conducted in primary microglia to elucidate the transcriptomic alterations underlying EcoHIV induced microglia hyperproliferation. Consistent with, and expanding upon, prior studies, treatment with EcoHIV exacerbated microglia proliferation evidenced by the upregulation of Pcna and Mki67. With regards to microglial receptors and adapter proteins, the transcriptomic expression of Trem2 and Dap12 was suppressed and increased, respectively, in microglia treated with EcoHIV. Crucially, dysregulation of the Trem2/Dap12 signaling complex explained 51.4% of the variance in microglial proliferation in EcoHIV treated microglia. A preliminary investigation of the Trem2-mediated microglial survival and immunoregulation pathway affords additional support for a unique EcoHIV-induced transcriptomic profile. Specifically, independent of biological sex, EcoHIV treatment upregulated Syk and downregulated Ctnnb1 mRNA expression. Notably, biological sex regulates precisely how EcoHIV treated microglia respond to the suppression of Trem2 and compensatory hyperproliferative state. Collectively, primary microglia treated with EcoHIV exhibit a highly specialized and sex-dependent transcriptional state. Enhancing our understanding of how HIV-1 alters microglial homeostasis is crucial for the identification of novel therapeutic targets for HAND.

neuroscience↗

bioRxiv2026

A HISTORY OF ADOLESCENT OXYCODONE SELF-ADMINISTRATION: NEURAL MECHANISMS UNDERLYING NEUROCOGNITIVE IMPAIRMENTS

Maturation of the prefrontal cortex and higher-order cognitive processes is ongoing through adolescence and young adulthood; developmental periods associated with the nonmedical use of prescription opioids. Initiation of oxycodone (OXY) self-administration during adolescence induces long-term dose-dependent impairments in neurobehavioral and neurocognitive development. To date, however, the neural mechanisms underlying neurocognitive impairments induced by adolescent prescription opioid use disorder (APOUD) have not been systematically evaluated. A DiOlistic labeling technique, in concert with sophisticated neuronal reconstruction software, revealed a prominent sex- and dose-dependent population shift in the morphological parameters of dendritic spines in pyramidal neurons in the anterior cingulate cortex (ACC) of rodents with a history of adolescent OXY self-administration relative to their control counterparts. Similarly, the biochemical mechanisms underlying dendritic spine dysmorphology, which were investigated using quantitative polymerase chain reaction, were dependent upon biological sex. In male rodents, a dose-dependent decrease in mRNA expression of GRIN1, a N-methyl-D-aspartate receptor, was observed in animals with a history of adolescent OXY self-administration relative to controls. In contrast, female rats with a history of adolescent OXY self-administration exhibited increased mRNA expression of cdk5, a protein kinase involved in the regulation of pre- and post-synaptic function; a transcriptional alteration that may result from excessive glutamate accumulation. Fundamentally, transcriptional dysregulation and dendritic spine dysmorphology mechanistically underlie, at least partly, APOUD-induced neurocognitive impairments. Collectively, results support that sex-dependent glutamatergic dysregulation may underlie dendritic spine dysmorphology in the ACC resulting in APOUD-induced neurocognitive impairments. Glutamatergic dysregulation, therefore, may afford a key target for the development of novel therapeutics. SIGNIFICANCE STATEMENTIndividuals with a history of adolescent prescription opioid use disorder (APOUD) are afflicted with profound neurocognitive impairments. Herein, sex-dependent glutamatergic dysregulation may underlie dendritic spine dysmorphology in the ACC resulting in APOUD-induced neurocognitive impairments, thereby affording a key target for the development of novel therapeutics.

neuroscience↗

bioRxiv2025

S-Equol: A Novel Therapeutic For HIV-1-Associated Gastrointestinal Dysbiosis

HIV-1 infection affects approximately 38.4 million people around the world. The advent of combination anti-retroviral therapy (cART) has greatly improved the quality of life of infected individuals; however, roughly 50% of these individuals will still experience HIV-1-associated neurocognitive disorders (HAND). Additionally, the gastrointestinal microbiome has been reported to be dysbiotic in HIV-1 infected individuals, regardless of adherence to cART. Current research has pointed to the gut-brain-microbiota axis as a potential target to treat both cognitive deficits and microbial changes. The present study investigated S-Equol (SE) as a potential therapeutic for HAND by modulating the gastrointestinal microbiome. The study included 21 HIV-1 Tg rats and 21 F344 control animals to test the effect 0.2mg SE has on cocaine-maintained responding on a PR schedule of reinforcement. Gastrointestinal microbiome alterations between genotypes were found at the phylum and genus level, regardless of treatment group, and SE treatment had both main effects and interactions with genotype. Prevotella_UCG_001 was significantly associated with lever presses for drug, suggesting an effect on motivation for cocaine. Alloprevotella was found to significantly differentiate between genotype by treatment effects, indicating that SE differently affects genotypes.

neuroscience↗

bioRxiv2025

SEX-DEPENDENT MODULATION OF BEHAVIORAL ALLOCATION VIA VENTRAL TEGMENTAL AREA-NUCLEUS ACCUMBENS SHELL CIRCUITRY

Diagnostic criteria for substance use disorder, cocaine type (i.e., cocaine use disorder), outlined in the 5th edition of the Diagnostic and Statistical Manual, imply that the disorder arises, at least in part, from the maladaptive allocation of behavior to drug use. To date, however, the neural circuits involved in the allocation of behavior have not been systematically evaluated. Herein, a chemogenetics approach (i.e., designer receptors exclusively activated by designer drugs (DREADDs)) was utilized in combination with a concurrent choice self-administration experimental paradigm to evaluate the role of the mesolimbic neurocircuit in the allocation of behavior. Pharmacological activation of hM3D(Gq) DREADDs in neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (AcbSh) induced a sex-dependent shift in the allocation of behavior in rodents transduced with DREADDs. Specifically, male DREADDs animals exhibited a robust increase in responding for a natural (i.e., sucrose) reward following pharmacological activation of the VTA-AcbSh circuit; female DREADDs rodents, in sharp contrast, displayed a prominent decrease in drug-reinforced (i.e., cocaine) responding. The sequential activation of hM3D(Gq) and KORD DREADDs within the same neuronal population validated the role of the VTA-AcbSh circuit in reinforced responding for concurrently available natural and drug rewards. Collectively, the VTA-AcbSh circuit is fundamentally involved in behavioral allocation affording a key target for the development of novel pharmacotherapies.

neuroscience↗

bioRxiv2023

SARS-CoV-2 RNA Persists in the Central Nervous System of Non-Human Primates Despite Clinical Recovery

Adverse neurological and psychiatric outcomes, collectively termed the post-acute sequelae of SARS-CoV-2 infection (PASC), persist in adults clinically recovered from COVID-19. Effective therapeutic interventions are fundamental to reducing the burden of PASC, necessitating an investigation of the pathophysiology underlying the debilitating neurological symptoms associated with the condition. Herein, eight non-human primates (Wild-Caught African Green Monkeys, n=4; Indian Rhesus Macaques, n=4) were inoculated with the SARS-CoV-2 isolate USA-WA1/2020 by either small particle aerosol or via multiple routes. At necropsy, tissue from the olfactory epithelium and pyriform cortex/amygdala of SARS-CoV-2 infected non-human primates were collected for ribonucleic acid in situ hybridization (i.e., RNAscope). First, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) mRNA are downregulated in the pyriform cortex/amygdala of non-human primates clinically recovered from SARS-CoV-2 inoculation relative to wildtype controls. Second, abundant SARS-CoV-2 mRNA was detected in clinically recovered non-human primates; mRNA which is predominantly harbored in pericytes. Collectively, examination of post-mortem pyriform cortex/amygdala brain tissue of non-human primates clinically recovered from SARS-CoV-2 infection revealed two early pathophysiological mechanisms potentially underlying PASC. Indeed, therapeutic interventions targeting the downregulation of ACE2, decreased expression of TMPRSS2, and/or persistent infection of pericytes in the central nervous system may effectively mitigate the debilitating symptoms of PASC.

neuroscience↗

bioRxiv2023

Microglia Proliferation Underlies Synaptic Dysfunction in the Prefrontal Cortex: Implications for the Pathogenesis of HIV-1-Associated Neurocognitive and Affective Alterations

Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the predominant cell type expressing HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of a combined RNAscope multiplex fluorescent and immunostaining assay revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal damage were evaluated in chimeric HIV (EcoHIV) rats. Eight weeks after EcoHIV innoculation, enhanced microglial proliferation was observed in the medial prefrontal cortex (mPFC) of EcoHIV rats, evidenced by an increased number of cells co-localized with both Iba1+ and Ki67+ relative to control animals. Neuronal damage in EcoHIV infected rats was evidenced by pronounced decreases in both synaptophysin and post synaptic density protein 95 (PSD-95), markers of pre-synaptic and post-synaptic damage, respectively. Third, regression analyses were conducted to evaluate whether microglia proliferation mechanistically underlies neuronal damage in EcoHIV and control animals. Indeed, microglia proliferation accounts for 42-68.6% of the variance in synaptic dysfunction. Collectively, microglia proliferation induced by chronic HIV-1 viral protein exposure may underlie the profound synaptodendritic alterations in HIV-1. Understanding how microglia are involved in the pathogenesis of HAND and HIV-1-associated affective disorders affords a key target for the development of novel therapeutics.

neuroscience↗

bioRxiv2022

Disrupted Decision-Making: EcoHIV Inoculation Following a History of Cocaine Use

Independently, chronic cocaine use and HIV-1 viral protein exposure induce neuroadaptations in the frontal-striatal circuit; how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use, however, has remained elusive. After establishing a history of both sucrose and cocaine self-administration, a pretest-posttest experimental design was utilized to evaluate preference judgment, a simple form of decision-making dependent upon the integrity of frontal- striatal circuit function. During the pretest assessment, male rats exhibited a clear preference for cocaine, whereas female animals preferred sucrose. Two posttest evaluations (3 Days and 6 Weeks Post Inoculation) revealed that, independent of biological sex, inoculation with chimeric HIV (EcoHIV), but not saline, disrupted decision-making. Prominent structural alterations in frontal-striatal circuit dysfunction were evidenced by synaptodendritic alterations in pyramidal neurons in the medial prefrontal cortex. Thus, the EcoHIV rat affords a biological system to model how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use.

neuroscience↗

bioRxiv2021

SYNAPTIC DYSFUNCTION UNDERLIES ALTERATIONS IN THE INITIATION OF GOAL-DIRECTED BEHAVIORS: IMPLICATIONS FOR HIV-1 ASSOCIATED APATHY

Individuals living with human immunodeficiency virus type 1 (HIV-1) exhibit an increased prevalence of neuropsychiatric comorbities (e.g., apathy) relative to their seronegative counterparts. Given the profound functional consequences associated with apathy, conceptualizing the multidimensional neuropsychiatric syndrome, and associated neural mechanisms, following chronic HIV-1 viral protein exposure remains a critical need. HIV-1 associated apathy was examined by quantifying goal-directed behaviors, indexed using voluntary wheel running, during the diurnal and nocturnal cycle. Apathetic behaviors in the HIV-1 Tg rat were characterized by a profound decrease in the number of running bouts during both the diurnal and nocturnal cycle, supporting a prominent deficit in the self-initiation of spontaneous behaviors. Additionally, HIV-1 Tg animals exhibited a decreased reinforcing efficacy of voluntary wheel running during the nocturnal cycle. Following the completion of voluntary wheel running, synaptic dysfunction in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) was examined as a potential neural mechanism underlying HIV-1 associated apathy. HIV-1 Tg animals displayed prominent synaptic dysfunction in MSNs of the NAc, characterized by decreased synaptic connectivity and a population shift towards an immature dendritic spine phenotype relative to control animals. Synaptic dysfunction accounted for 42.0% to 68.5% of the variance in the number of running bouts affording a key neural mechanism underlying the self-initiation of spontaneous behaviors. The establishment of a fundamental neural mechanism underlying apathy affords a key target for the development of novel therapeutics and cure strategies for affective alterations associated with HIV-1.

neuroscience↗

bioRxiv2021

Neurodevelopmental processes in the prefrontal cortex derailed by chronic HIV-1 viral protein exposure

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remains understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC). Three putative neuroinflammatory markers (i.e., IL-1{beta}, IL-6, and TNF-) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. Specifically, HIV-1 transgenic rats exhibited prominent deficits in dendritic and synaptic pruning, a developmental decrease in synaptic connectivity, and an age-related decline in synaptic efficacy. Examination of dendritic spine morphology revealed an age-related population shift towards a more immature dendritic spine phenotype in HIV-1 transgenic animals. There was no compelling evidence for neuroinflammation in the mPFC during early development. Understanding the neural mechanisms underlying chronic neurocognitive impairments in pALHIV may afford a key target for innovative therapeutics and cure strategies; an urgent need given the growing population of pALHIV.

neuroscience↗

bioRxiv2021

HIV-1-induced apathy: Mitigation by the gut metabolite, S-equol

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 {beta} 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.

neuroscience↗

bioRxiv2020

Valid statistical approaches for clustered data: A Monte Carlo simulation study

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.

scientific communication and education↗

bioRxiv2020

HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats

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.

neuroscience↗