Drug addiction is fundamentally a disorder of decision making, in that addicted individuals often choose drugs over more adaptive options. Indeed, drugs of abuse persistently alter reward-related brain regions, yet the behavioral function of such circuits in basic decision making and cognition-related processes is unclear. Understanding the neural underpinnings of decision making could lead to development of targeted therapeutics to help addicted individuals tame their unrestrained bias towards drugs. Here I seek to identify a novel circuit through which the brain promotes adaptive decision making under risky circumstances?a process that may go awry in addicted individuals. The ventral pallidum (VP) lies at the nexus of reward-seeking and harm- avoidance brain circuits, and could function as a site where motivational drives influence motor output, an ideal position for a region influencing risky decision making. Recent evidence reveals a predominant role for inhibitory, GABAergic VP (VPGABA) neurons in promoting approach behavior in rodents, but VPGABA neurons target both approach (ventral tegmental area; VTA) and avoidance (lateral habenula; LHb) brain circuits, and the roles of these projections in aversion avoidance is unknown. We propose that VPGABA neurons both promote reward seeking via VTA projections, and inhibit aversion avoidance via LHb projections, when decisions about risky reward seeking are made. To model risky decision making, I employ an operant task in which rats decide between small/safe food reward and large/risky food reward that is paired with a probabilistic mild footshock. I will examine the role of VPGABA neurons and their efferent targets to VTA or LHb using cell- and pathway-specific designer receptor inhibition approaches. My preliminary data indicates that inhibiting all VPGABA neurons shifts decision making away from risky rewards, and toward safer options. Here I will replicate and extend these findings, and determine their dependence upon divergent projections to VTA and LHb. I will also determine the specific constructs influencing changes in decision making, using specific behavioral assays of motivation for reward, and sensitivity to punishment. Our findings will greatly extend our grasp of the functional roles for VPGABA circuits in risky decision making that is likely involved in addiction.
Drugs of abuse hijack decision-making brain circuits, resulting in biased choice towards drugs over healthier pursuits. The identity and function of these brain circuits, however, remains unclear, potentially hindering our ability to develop effective treatments for those suffering from drug addiction. The experiments in this proposal will examine a key, understudied node in decision-making circuits, ventral pallidum and its outputs, in risky decision making.
