Sex-specific neurogenic deficits and neurocognitive disorders in middle-aged HIV-1 Tg26 transgenic mice

Abstract

Varying degrees of cognitive deficits affect over half of all HIV-1 infected patients. Because of antiretroviral treatment (ART) regimens, the HIV-1 patient population is increasing in age. Very few epidemiological studies have focused on sex-specific differences in HIV-1-associated neurocognitive disorders (HAND). The purpose of this study is to examine any possible differences between male and female mice in the progression of cognitive dementia during persistent low-level HIV-1 protein exposure, mimicking the typical clinical setting in the post-ART era. Eight to ten-month old HIV-1 Tg26(+/-) transgenic mice were utilized to assess for specific learning and memory modalities. Initial physiological screening and fear conditioning assessments revealed that Tg26 mice exhibited no significant differences in general behavioral function, contextual fear conditioning, or cued fear conditioning responses when compared to their wild-type (WT) littermates, regardless of sex. However, Barnes maze testing revealed significantly impaired short and long-term spatial memory in males, while females had impaired spatial learning abilities and short-term spatial memory. The potential cellular mechanism underlying these sex-specific neurocognitive deficits was explored with hippocampal neurogenic analysis. Compared to WT mice, both male and female Tg26(+/-) mice had fewer quiescent neural stem cells and neuroblasts in their hippocampi. Male Tg26(+/-) mice had a more robust reduction of the quiescent neural stem cell pool than female Tg26(+/-) mice. While female WT mice had a higher number of neural progenitor cells than male WT mice, only female Tg26(+/-) mice exhibited a robust reduction in the number of neural progenitor cells. Altogether, these results suggest that middle-aged male and female Tg26(+/-) mice manifest differing impairments in cognitive functioning and hippocampal neurogenesis. This study emphasizes the importance of understanding sex related differences in HAND pathology, which would aid in designing more optimized therapeutic regimens for the treatment of HAND.

Keywords: Barnes maze; Biological sex; Differentiation; Fear conditioning; HAND; HIV-1; Neural stem cells; Neurogenesis; Tg26 mouse.