CORE--FUNCTIONAL ASSESSMENT

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NeuroAIDS is a significant aspect of HIV infection in which the pathological and toxic changes induced by the virus affect central nervous system structure and function. HIV-Associated Cognitive and Motor Complex may affect up to 30% of patients in the early stages of immune suppression and up to 50% of symptomatic patients, while about 10-20% of those with AIDS develop frank dementia. With recent treatment-induced increases in survival time for AIDS patients, the large and growing numbers of surviving AIDS patients likely to experience NeuroAIDS obliges us to understand and treat the bases of this complex. Animal models of NeuroAIDS have been developed which mimic the overall pathogenesis of immunodeficiency infection (FIV,SIV) or focus on selected potential candidates for virus- derived or host-derived factors involved in HIV neuropathogenesis (transgenic mice). The utility of the animal models is augmented by demonstration that the neurologic disease evident in these models is sufficient to produce CNS functional changes reminiscent of those associated with HIV infection in humans. The goal of the Functional Assessment Core is to document alterations of CNS functions that develop in the various mouse, cat and monkey models of NeuroAIDS, and to determine if such functional alterations can be reversed or arrested by therapeutic means. This Core is divided into 2 aspects: electrophysiological and behavioral assessment. Electrophysiological assessment will directly measure neuronal function as electrical excitability and responsivity to synaptic input or neurotransmitters, before and after viral infection or cytokine expression, using four in vivo and in vitro assays: 1) Extracellularly recorded evoked field potentials and single unit activity (in vivo and in vitro; a regional assay of circuit functionality); 2) Intracellularly recorded membrane properties of single neurons in vitro (i.e., a cellular assay of neuronal function); 3) Intracellularly- or path-clamp-recorded responses to synaptic input, transmitters, cytokines and viral fragments (i.e., a receptor/molecular assay); 4) Infrared videomicroscopic evaluation of global changes in neuronal excitability in large brain regions (in vitro); Neurobehavioral assessment will be conducted from birth through adulthood, in order to study the consequences of transgene protein production on neurobehavioral maturation and behavior in adults. Targeted behaviors include those known to be impaired in patients with NeuroAIDS and behaviors associated with brain regions, affected in AIDS patients and recapitulated in the mouse models. In adult mice, the neurobehavioral sequelae of transgenic expression will be probed in tasks related to motor ability, reactivity to stressors and novelty/exploration, and cognition. Thus, the Functional Assessment Core will help to integrate the overall purpose of the Center by correlating disruptions in brain function, measured by electrophysiological and behavioral means, with virological, morphological, and immunopathological findings.