PROJECT 1 (P1)

Cross-Species Studies of Risk Taking in METH, HIV, and Aging

Project Director: Arpi Minassian, Ph.D.
Co-Investigators: William Perry, Ph.D.; Jared Young, Ph.D.; Mark Geyer, Ph.D.

Summary:

HIV transmission risk behaviors are common and recalcitrant among persons with METH dependence, but their underlying cognitive and neurobiological mechanisms are not well understood. During the previous funding period we learned that METH dependence may differentially impact the expression of inhibitory deficits related to risk taking in the setting of HIV infection in humans and mouse models. Building on this work, Project 1 performs parallel human and animal research to determine the individual and combined effects of METH dependence, HIV infection, and aging on risk taking. We are leveraging our expertise in implementing cross-species measures by evaluating several important components of risk taking that will be isolated paradigmatically in humans and two mouse models of HIV:

Preference for risk, reward, and/or novelty versus punishment avoidance
Motivation defined as willingness to work for a reward
Inhibition.

In the human study, we are testing our hypothesis that HIV and METH have differentiable effects on the multiple components that underlie risk taking in all 320 well-characterized subjects from the TMARC cohort, who will be stratified by METH dependence, HIV serostatus, and age. We are also examining the impact of aging on the expression of risk behaviors in HIV and METH, as well as the unique effects of risk taking and its components on real-world outcomes (e.g., adherence) in our clinical groups. Shared human subjects with TMARC Project 2 will allow us to examine the neural substrates of risky decision-making, including neuroimaging indices of functional connectivity and white matter injury. The animal studies employ two transgenic (tg) mouse models of HIV (i.e., constitutive gp120tg and conditional iTat-tg) with and without METH treatment, which are being evaluated with cognitive paradigms that map directly on to those used with our human subjects. Collaborations with the TMARC Neuroimaging (NI) and Neuroscience and Animal Models (NAM) Cores will enable us to parse out biological mechanisms of these critical cognitive functions in mouse models. The ultimate goal of this research is to propel the design of prevention efforts that target specific components of risk taking in order to reduce HIV transmission.

Relevance:

Risk taking behavior is common in persons with HIV and METH dependence. The ultimate goal of this cross-species study of humans and mice is to facilitate the design of treatment and prevention efforts that target the specific cognitive components of risk taking in HIV and METH, in order to reduce HIV transmission.