Animal Models: Behavior and Pathology: Preclinical Assessment of the Putative Cognitive Deficits in HAND

Abstract

Despite the reduced prevalence of HIV-1-associated dementia in the era of combination antiretroviral therapy (CART), nearly half of all HIV-1-positive individuals on CART are afflicted with mild to severe HIV-1-associated neurocognitive disorders (HAND). A greater understanding of the progression of HAND and the development of potential therapeutics require preclinical studies that utilize an integrative profile of cognitive function, from which valid inferences can be drawn about underlying processes. We propose a set of preclinical behavioral tasks that tap various components of executive function, the cognitive domain which shows the greatest decline in the progression of HAND. Fronto-striatal circuitry and dopaminergic systems are integral to executive function and are also particularly vulnerable to injury by HIV-1 infection. The tasks described in this chapter provide measures that are both sensitive to alterations in the function of these systems and relevant to typical cognitive deficits observed in HAND. Further, each of the tasks presently described has a very clear human analogue. Prepulse inhibition of the auditory startle response is a measure of preattentive processing and sensory gating. The multi-choice serial reaction time task assesses different types of attentional processes, including sustained attention, selective attention, and set-shifting. The Morris water maze provides a profile of reference and working memory. Within each behavioral measure, there are a number of variables, which can be manipulated to provide information on several components of executive function, affording the opportunity to model the specific cognitive deficits of HAND.