IMPAIRED BRIDGING OF TEMPORAL DISCONTINUITIES IN OLDER ADULT HIV-1 TG RATS

The advent and widespread uptake of combination antiretroviral therapy dramatically changed the epidemiological features of human immunodeficiency virus type 1 (HIV-1), whereby older individuals (>50 years of age) account for approximately 50% of HIV-1 seropositive individuals in the United States. Nevertheless, to date, there is no extant in vivo biological system to model the unique age-related neurocognitive impairments observed in HIV-1 seropositive individuals. Herein, the utility of the HIV-1 transgenic (Tg) rat as a biological system to model age-related neurocognitive impairments and neuroanatomical alterations was evaluated. Older adult HIV-1 Tg rodents (i.e., >12 months of age upon testing initiation), relative to their control counterparts, exhibited profound neurocognitive alterations characterized by impairments in stimulus-reinforcement learning, sustained attention, and selective attention; neurocognitive deficits which support a fundamental distortion of temporal processing. Neuronal dysfunction in older adult HIV-1 Tg animals was characterized by structural alterations in pyramidal neurons, and their associated dendritic spines, in the medial prefrontal cortex and abnormal accumulation of amyloid beta (Aβ). Interestingly, the abnormal accumulation of Aβ mechanistically underlies, at least in part, the profound dendritic spine dysmorphology in male, but not female, HIV-1 Tg rats. More critically, however, neuronal dysfunction mechanistically underlies neurocognitive impairments in both male and female HIV-1 Tg rodents, whereby neuronal dysfunction accounts for 65.4% and 60.8% of the variance in neurocognitive function, respectively. Establishing the utility of the HIV-1 Tg rat for age-related neurocognitive impairments is fundamental to disentangling the role of HIV-1 viral proteins and comorbidities in neurocognitive function.