PROJECT SUMMARY/ABSTRACT Despite nearly 25 years since the advent of combined antiretroviral therapy, up to 50% of people living with HIV will experience some degree of cognitive impairment in their lifetimes. These HIV-associated neurological disorders (HAND) are driven through a variety of neurotoxic effects resulting from HIV infiltration of the central nervous system (CNS). While the neuropathology of HAND has been understood for years, the specific mechanisms underpinning cognitive dysfunction in HAND individuals remain unclear. Free HIV viral proteins are known to possess independent neurotoxic effects. Of these molecules, the envelope protein gp120, is known to facilitate a wide range of cellular events which result in simplification / apoptosis of neurons in CNS regions critical for higher cognitive function. Understanding how gp120 may elicit these effects is critical for the future development of therapeutics for those living with HIV. In a mouse model of HAND which constitutively expresses gp120 in the CNS (gp120tg), our lab has established that gp120 perturbs pro-neurotrophin processing and upregulates p75NTR, a pro-apoptotic proneurotrophin receptor. Our recent work has also shown that dendritic spines are at increased risk for simplification or loss due to gp120-driven disruption of the neurotrophin-receptor environment. A central role for p75NTR in this effect is supported by partial rescue of biochemical, histological, and behavioral abnormalities in older gp120tg mice when p75NTR is removed. However, loss of a vulnerable population of cholinergic neurons in the basal forebrain (BFCNs) which highly express p75NTR and whose degeneration is observed in multiple neurodegenerative diseases may better explain cognitive impairments in HAND than broad synapse loss. Preliminary data in this direction indicates that older gp120tg mice have impaired extinction of conditioned fear, a behavior dependent on BFCN integrity. I hypothesize gp120 expression drives degeneration of these BFCNs through a mechanism involving disruption of the local neurotrophic environment. To confirm whether gp120 expression disrupts neurotrophin processing in the forebrain, I will sacrifice aged gp120 transgenic mice (and controls) and assess forebrain expression of pro nerve growth factor (proNGF) and NGF, as well as two proteases which catalyze their conversion (Aim 1a). From these groups, I will also section the forebrain and immunostain for BFCNs markers to assess cholinergic cell population and measures of BFCN complexity (Aim 1b). Synaptosomes from BFCN-targeted regions will determine if expression of markers of cholinergic innervation are decreased in gp120tg mice (Aim 1c). Finally, I will assess decrements in forebrain gray matter density and septohippocampal tract integrity (BFCN fibers) in this model through a magnetic resonance (MR) imaging approach (aim 2). I hypothesize that aged gp120tg mice will display an altered forebrain neurotrophic environment, w...