A Gap in Time: Extending our Knowledge of Temporal Processing Deficits in the HIV-1 Transgenic Rat

Intl J of Devlp Neuroscience

2016

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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 an insensitivity 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.

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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

Intl J of Devlp Neuroscience

2016

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“…Temporal processing deficits, which have been implicated as a potential elemental dimension of HAND, may underlie sustained attention deficits observed in the present study. Significant alterations in temporal processing, assessed using prepulse inhibition (PPI), have been well-defined and appear highly replicable in the HIV-1 Tg rat (e.g., Moran et al, 2013a ; McLaurin et al, 2016 , 2017a , b , d ). Ovariectomized female HIV-1 Tg animals displayed alterations in the development of perceptual sharpening, assessed using auditory and visual PPI in a time-limited repeated measures assessment (Moran et al, 2013a ).…”

Section: Discussionmentioning

confidence: 99%

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

Front. Behav. Neurosci.

et al. 2017

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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.

“…Analyses of gap-PPI in HIV-1 Tg rat at an advanced age (i.e., 9, 10 months of age) revealed a differential sensitivity to the manipulation of ISI. Specifically, control animals exhibited maximal inhibition at the 50 msec ISI, while HIV-1 Tg animals displayed a rightward shift, to maximal inhibition at the 100 msec ISI23. Additionally, gap-PPI has been used as an innovative paradigm for studies of tinnitus in animals, including guinea pigs33, mice32 and rats343536, providing proof-of-concept for the utility of gap-PPI as a translational diagnostic tool for tinnitus in humans.…”

mentioning

confidence: 99%

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

2016

Sci Rep

Self Cite

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.