Endogenous barcoding to determine complex dynamics of adult neurogenesis in aging and Alzheimer's disease

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1 ABSTRACT 2 3 The population of people living with HIV gradually ages, in part due to the efficiency of antiretroviral 4 therapy (ART) which has significantly improved the life expectancy of infected individuals. This aging population 5 inevitably faces an increased risk of developing neurodegenerative disorders including Alzheimer's disease (AD). 6 These concerns are 7 These deficits may be due solely to the HIV-1 infection; 8 however, this may also indicate that long-term ART itself contributes to the impairments. The latter possibility is 9 of particular concern given that a growing number of uninfected individuals employ use antiretrovirals (ARVs) as 10 pre-exposure prophylaxis (PrEP). The mechanisms underlying ART-induced changes and their impact on brain 11 circuitry that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action 12 of ARVs in the aging and AD-afflicted brain. The mechanisms of ART-induced changes and the brain circuitry 13 that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action of 14 ARVs in the aging and AD -afflicted brain. 15 We propose to apply our recently developed array of new tools for analyzing neurogenesis and for 16 constructing, comparing, and analyzing 3D whole-brain maps of neuronal activation in the mouse brain to reveal 17 the critical neural circuitry affected by representative ARVs. Our hypothesis is that 3D patterns of neuronal 18 activation in aging and AD model animals exposed to ARVs and involved in challenging behavioral tasks can 19 both reveal the crucial circuitry defining these effects and serve as unique signatures of the treatments’ 20 effects. Furthermore, our recent results demonstrate that treatment with ARVs can affect adult hippocampal 21 neurogenesis, thus indicating another potential vulnerability of the ARV-exposed aging and AD brain. This 22 proposal is directly related to the parent R01 grant which also focuses on the aging and AD brain. 23 In specific aim 1, we will determine the effect of prolonged treatment with representative ARVs on stem 24 cells and adult-born neurons in the hippocampus of aging and AD model mice. In specific aim 2, we will 25 determine the critical shared components of neural circuitry affected by prolonged exposure to select ARVs. We 26 will generate mesoscopic global maps of neuronal activation in aging and AD model mice presented with relevant 27 cognitive challenges after exposure to ARVs. We will then subject the mapping datasets to our stepwise selection 28 pipeline to identify the critical brain regions and neural circuits altered by the treatments. Our experiments will 29 reveal the effect of ARVs on hippocampal neurogenesis and will create a circuitry map space for the action of 30 ARVs upon which other circuitry maps that describe various responses to treatments in the context of aging and 31 AD can be projected and compared. 32 further compounded by the prevalence of cognitive deficits observed in a substantial proportion of HIV-1-infected individuals undergoing ART.