Time and time again: Temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat

摘要

HIV-1-associated neurocognitive disorders (HAND) afflict up to 50 % of HIV-1+ individuals, despite the effectiveness of combination antiretroviral therapy (CART) in reducing the prevalence of more severe neurocognitive impairment. Alterations in brainstem auditory evoked potentials (BAEP), a measure of temporal processing, are one of the earliest neurological abnormalities of HIV-1-positive individuals. Prepulse inhibition (PPI) of the auditory startle response (ASR), a measure of sensorimotor gating, was studied in HIV-1 transgenic (Tg) rats, which express 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and control rats (ns = 41-42) were tested for PPI at three test periods, with at least 2 months separating each test period, using auditory and visual prepulses, an auditory startle stimulus, and interstimulus intervals (ISI) ranging from 0 to 4000 msec. Auditory and visual prepulse trial blocks were presented in counterbalanced order. For both auditory and visual prepulses, HIV-1 Tg animals exhibited a flatter ISI function, which did not sharpen with age, as it did in controls. Over time, auditory prepulses precipitated a temporal shift in peak inhibition in HIV-1 Tg animals relative to controls, whereas with visual prepulses, both groups displayed peak inhibition at the 40 msec ISI. A lack of perceptual sharpening with age and a relative insensitivity to the temporal dimension of sensorimotor gating are evident in the HIV-1 Tg rat prior to clinical signs of wasting. Deficits in sensorimotor gating may not only provide an early subtle diagnostic marker of HAND, but may also afford a key target for development of potential therapeutics.