Drug addiction is a pervasive health problem in our society. We still lack specific therapeutic interventions to break the recurrent pattern of relapse to drug seeking that characterizes the disorder; a result of poor understanding of the neural circuits and cellular adaptations responsible for relapse. The use of illicit drugs is rising steadily in the Unites States, with the number of deaths related to drug overdose dramatically accelerating over the last 5 years. Relapse and drug craving are critically driven by neuronal activity in the interconnected nuclei of the ventral basal ganglia, which have a well described role in motivated behavior and reward learning. Within this network the ventral pallidum (VP) is a critical regulator of relapse to all known drugs of abuse. To date, much addiction research has focused on the nucleus accumbens, a primary input structure to the VP, but the VP itself has been largely disregarded as an inhibitory downstream relay of addiction-related information. However, VP neurons respond temporally quicker to rewarding emotional stimuli than upstream nucleus accumbens neurons. Furthermore, while VP neurons are generally thought to be largely GABAergic, the VP also contains a subpopulation (~30%) of glutamatergic neurons that project to the same downstream areas as inhibitory GABAergic VP neurons. These findings challenge the accepted idea that the VP is an inhibitory relay structure and suggest advanced processing of emotional information in the VP independent of nucleus accumbens inputs, with implications that transform our understanding of basal ganglia function. By using my recently developed mouse model for drug relapse, I identified an inhibitory role for glutamatergic VP neurons during relapse, demonstrating that these neurons act oppositely to GABAergic VP neurons. Based on these observations I predict that drug abuse reduces the capacity of glutamatergic VP neurons to inhibit drug seeking, and that behavioral engagement during drug seeking is carried by activity in GABAergic VP neurons. This proposal employs cutting edge technological advances in the cell type specific dissection of neural circuit function and connectivity such as optogenetics, chemogenetics, in vivo cell-type specific monitoring of calcium activity in freely behaving mice, and slice electrophysiology recordings from genetically labeled glutamatergic and GABAergic VP neurons to investigate cell type and pathway specific VP circuit adaptations following drug self administration and relapse. These studies will place the VP as a central component of basal ganglia circuits controlling addiction, and reveal the distinct functions of VP glutamatergic versus GABAergic neurons in regulating drug seeking, which could lay the groundwork for novel VP targeted strategies to treat addiction.
Addiction remains a global health threat, characterized by chronic episodes of relapse, and activity in the ventral pallidum has long been implicated in this behavioral pattern. While canonically considered an inhibitory relay in a series circuit of subcortical brain nuclei, the ventral pallidum contains a population of excitatory glutamatergic neurons. I will examine the unique anti-relapse function that these glutamatergic ventral pallidal neurons exert over drug seeking, and dissect the circuit elements that innervate glutamatergic and GABAergic ventral pallidal neurons to clarify their contributions to drug relapse.
