Midbrain neural circuit mechanisms underlying addiction

PROJECT SUMMARY The opioid crisis has enormous consequences on the health and well-being of Veterans and their communities. Opioid addiction is propelled by opioid-induced changes in brain circuits that control behavioral responses to rewarding and aversive stimuli, and neuromodulatory therapies that reverse opioid-induced changes in these circuits are sorely needed. The mesolimbic dopamine (DA) projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is often described as the brain's reward circuit, and indeed much evidence points to a central role for this projection in processes underlying behavioral reinforcement. But what controls activity of VTA DA neurons? And where does NAc send signals that have been modulated by released DA? An answer to both those questions is: the ventral pallidum (VP). Yet much less is known about VP. For example, it has only recently become appreciated that VP contains heterogeneous populations of excitatory and inhibitory projection neurons that regulate approach and avoidance behaviors in opposite directions. Further, Mu-opioid receptors (MOR) mediate both the analgesic and addictive effects of abused opioid drugs, the VP is a MOR hotspot, and MOR activation in VP can profoundly change behavior. Thus, we know that VP can potently modulate approach and avoidance behaviors and that opioids can potently modulate VP. Yet we know remarkably little about how VP cell types are connected to NAc and VTA cell types, how VP cell types and synapses are modulated by MORs, or how opioid-induced plasticity in VP cell types and synapses modify approach and avoidance behaviors that are perturbed in opioid dependence and withdrawal. This proposal will systematically attack this knowledge gap using mouse genetics and both ex vivo and in vivo anatomical, physiological and behavioral approaches to: i) characterize the cell types and synapses in VP that express MOR, ii) define how VP cell types are connected to afferent NAc and efferent VTA cell types, iii) identify how MOR activation modulates the function of these cell types and synapses, and iv) describe how their function is perturbed in opioid dependence and withdrawal.