Kristen A. McLaurin

Progression of temporal processing deficits in the HIV-1 transgenic rat.

The HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes, was used to investigate the effect(s) of long-term HIV-1 viral protein exposure on chronic neurocognitive deficits observed in pediatric HIV-1 (PHIV). A longitudinal experimental design was used to assess the progression of temporal processing deficits, a potential underlying dimension of neurocognitive impairment in HIV-1. Gap prepulse inhibition (gap-PPI), a translational experimental paradigm, was conducted every thirty days from postnatal day (PD) 30 to PD 180. HIV-1 Tg animals, regardless of sex, displayed profound alterations in the development of temporal processing, assessed using prepulse inhibition. A differential sensitivity to the manipulation of interstimulus interval was observed in HIV-1 Tg animals in comparison to control animals. Moreover, presence of the HIV-1 transgene was diagnosed with 90.8% accuracy using measures of prepulse inhibition and temporal sensitivity. Progression of temporal processing deficits in the HIV-1 Tg rat affords a relatively untapped opportunity to increase our mechanistic understanding of the role of long-term exposure to HIV-1 viral proteins, observed in pediatric HIV-1, in the development of chronic neurological impairment, as well as suggesting an innovative clinical diagnostic screening tool.

Temporal processsing demands in the HIV-1 transgenic rat: Amodal gating and implications for diagnostics

Despite the success of combination antiretroviral therapy (cART), approximately 50% of HIV‐1 seropositive individuals develop HIV‐1 associated neurocognitive disorders (HAND). Unfortunately, point‐of‐care screening tools for HAND lack sensitivity and specificity, especially in low‐resource countries. Temporal processing deficits have emerged as a critical underlying dimension of neurocognitive impairments observed in HIV‐1 and may provide a key target for the development of a novel point‐of‐care screening tool for HAND. Cross‐modal prepulse inhibition (PPI; i.e., auditory, visual, or tactile prepulse stimuli) and gap‐prepulse inhibition (gap‐PPI; i.e., auditory, visual or tactile prepulse stimuli), two translational experimental paradigms, were used to assess the nature of temporal processing deficits in the HIV‐1 transgenic (Tg) rat. Cross‐modal PPI revealed a relative insensitivity to the manipulation of interstimulus interval (ISI) in HIV‐1 Tg rats in comparison to controls, regardless of prestimulus modality. Gap‐PPI revealed differential sensitivity to the manipulation of ISI, independent of modality, in HIV‐1 Tg rats in comparison to control animals. Manipulation of context (i.e., concurrent visual or tactile stimulus) in auditory PPI revealed a differential sensitivity in HIV‐1 Tg animals compared to controls. The potential utility of amodal temporal processing deficits as an innovative point‐of‐care screening tool was explored using a discriminant function analysis, which diagnosed the presence of the HIV‐1 transgene with 97.4% accuracy. Thus, the presence of amodal temporal processing deficits in the HIV‐1 Tg rat supports the hypothesis of a central temporal processing deficit in HIV‐1 seropositive individuals, heralding an opportunity for the development of a point‐of‐care screening tool for HAND.

Unraveling Individual Differences In The HIV-1 Transgenic Rat: Therapeutic Efficacy Of Methylphenidate

Despite the heterogeneity of HIV-1 associated neurocognitive disorders (HAND), assignment of categorical diagnoses based on the level of impairment (e.g., Frascati criteria) obfuscates the well-acknowledged variability observed within the population of HIV-1+ individuals. The present study sought to elucidate the natural heterogeneity in adult HIV-1 transgenic (Tg) rats using three interrelated aims. First, heterogeneity of the HIV-1 transgene was examined using a pretest-posttest design to assess therapeutic efficacy of oral self-administration (OSA) of methylphenidate (MPH; 2.4 ± 0.2 mg/kg), targeting neurotransmitter alterations in HIV-1, on temporal processing. Approximately 42% of HIV-1 Tg animals displayed an improvement in temporal processing following OSA of MPH. Second, repeated OSA of MPH (22–27 days) altered dendritic spine morphology in layer II-III pyramidal neurons in the medial prefrontal cortex. HIV-1 Tg animals exhibited a population shift towards longer spines with decreased head diameter on lower order branches; a shift associated with temporal processing impairment. Third, in HIV-1 Tg animals, dendritic spine backbone length (µm) was associated with temporal processing impairment; a brain/behavior relationship not observed in control animals. Assessing the therapeutic efficacy of MPH revealed heterogeneity in the neural mechanisms underlying neurocognitive impairments, providing a key target for individualized therapeutic and diagnostic approaches for HAND.

Dose-dependent neurocognitive deficits following postnatal day 10 HIV-1 viral protein exposure: Relationship to hippocampal anatomy parameters

Despite the availability of antiretroviral prophylactic treatment, pediatric human immunodeficiency virus type 1 (HIV‐1) continues to be a significant risk factor in the post‐cART era. The time of infection (i.e., during pregnancy, delivery or breastfeeding) may play a role in the development of neurocognitive deficits in pediatric HIV‐1. HIV‐1 viral protein exposure on postnatal day (P)1, preceding the postnatal brain growth spurt in rats, had deleterious effects on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2008a,b). In the present study, rats were stereotaxically injected with HIV‐1 viral proteins, including Tat1–86 and gp120, on P10 to further examine the role of timing on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2010). The dose‐dependent virotoxin effects observed across development following P10 Tat1–86 exposure were specific to spatial learning and absent from prepulse inhibition and locomotor activity. A relationship between alterations in spatial learning and/or memory and hippocampal anatomical parameters was noted. Specifically, the estimated number of neurons and astrocytes in the hilus of the dentate gyrus explained 70% of the variance of search behavior in Morris water maze acquisition training for adolescents and 65% of the variance for adults; a brain‐behavior relationship consistent with observations following P1 viral protein exposure. Collectively, late viral protein exposure (P10) results in selective alterations in neurocognitive development without modifying measures of somatic growth, preattentive processing, or locomotor activity, as characterized by early viral protein exposure (P1). Thus, timing may be a critical factor in disease progression, with children infected with HIV earlier in life being more vulnerable to CNS disease.

Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat

Sex differences in human immunodeficiency virus type-1 (HIV-1) have been repeatedly suggested. Females, who account for 51% of HIV-1 seropositive individuals, are inadequately represented in clinical and preclinical studies, as well as in the description of HIV-1 associated neurocognitive disorders (HAND). Direct comparisons of neurocognitive decline in women and men must be made to address this underrepresentation. The effect of biological sex (i.e., the biological factors, including chromosomes and hormones, determining male or female characteristics; WHO, 2017) on sustained attention, which is commonly impaired in HIV-1 seropositive individuals, was investigated in intact HIV-1 transgenic (Tg) and control animals using a signal detection operant task. Analyses revealed a robust sex difference in the rate of task acquisition, collapsed across genotype, with female animals meeting criteria in shaping (at least 60 reinforcers for three consecutive or five non-consecutive sessions) and signal detection (70% accuracy for five consecutive or seven non-consecutive sessions) significantly more slowly than male animals. Presence of the HIV-1 transgene also had a significant effect on shaping and signal detection acquisition, with HIV-1 Tg animals displaying significant deficits in the rate of acquisition relative to control animals–deficits that were more prominent in female HIV-1 Tg animals. Once the animals’ reached asymptotic performance in the signal detection task, female animals achieved a lower percent accuracy across test sessions and exhibited a decreased response rate relative to male animals, although there was no compelling evidence for any effect of transgene. Results indicate that the factor of biological sex may be a moderator of the influence of the HIV-1 transgene on signal detection. Understanding the impact of biological sex on neurocognitive deficits in HIV-1 is crucial for the development of sex-based therapeutics and cure strategies.

Polytocus focus: Uterine position effect is dependent upon horn size

Understanding the variability caused by uterine position effects in polytocus species, such as rats, may enhance prenatal animal models for the study of drug and environmental agents. The primiparous litters of 42 intact female Sprague‐Dawley rats were studied. Uterine position, fetal body weight, and fetal brain (wet) weight were recorded on gestation day (GD) 20 (GD 0 = sperm positive). Uterine position effect for brain and body weight varied depending upon horn size. Furthermore, an inverse relationship between horn size (and, to a lesser extent, litter size) and fetal weight applied to both body and brain weight measures. There were no statistical differences in brain and body weights between the left and right uterine horns. The position of the uterine horn (left vs. right) and litter size did not influence the uterine position effect in the rat. Collectively, the present data suggest the presence of a significant uterine position effect. Prenatal differences based on uterine position provide an untapped opportunity to increase our understanding of developmental neurotoxicological and teratological studies that employ a polytocus species as an animal model.