Drug abuse and addiction remain a medical and societal burden with a relative paucity of prevention and treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory and affective information into behavioral outcomes. Changes in excitatory synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by addiction. While excitatory synaptic connections drive NAc neuronal firing, inhibitory synaptic transmission is important for coordinating and constraining neuronal excitability. Our work focuses on mechanisms of communication between NAc parvalbumin expressing fast-spiking interneurons (PV-FSIs) and specific medium spiny neuron subtypes (MSNs; D1 or D2 dopamine receptor expressing) in the NAc core. PV-FSIs, although limited in number, make vast inhibitory connections to MSNs thereby greatly influencing NAc output. Thus, PV- FSI synaptic activity is a putative mediator of NAc circuit adaptations. Changes in NAc excitatory and inhibitory circuit dynamics or the balance between excitation and inhibition, likely underlie addiction behaviors. Indeed, we find that manipulation of these PV-FSIs in the NAc modulate drug-related behaviors. Our data suggests that the strength of PV-FSI to MSN inhibitory synapses can be suppressed by endocannabinoid (eCB) signaling through cannabinoid receptor 1 (CB1R) and transient receptor potential vanillod 1 (TRPV1). We hypothesize that NAc PV-FSIs and MSNs communicate bi-directionally via the eCB system to regulate inhibitory synaptic function on MSNs underlying NAc-related behaviors and exposure to drugs of abuse leads to dysregulation of this process. In this grant, we will characterize the precise mechanisms by which PV-FSIs and eCB signaling at PV-FSI to MSN synapses mediate these actions. We will identify signaling mechanisms that alter synaptic strength at synapses onto NAc D1 or D2 MSNs using rigorous electrophysiological, optogenetic, and behavioral approaches in combinations of transgenic mouse lines. In turn, we will apply these protocols used to identify mechanisms of plasticity ex vivo to awake/behaving animals to determine behavioral responding. Furthermore, we will determine if manipulation of this signaling can regulate behavioral responding to drugs of abuse. The contribution of the proposed research is expected to be advancement in our knowledge of mechanisms by which PV-FSIs and more specifically, eCB signaling at PV-FSIs to MSN synapses, remodel NAc excitatory and inhibitory synaptic activity patterns and membrane firing properties, and the contribution this process likely plays in addiction-related disorders. These studies will identify mechanisms which can be exploited for the development of improved therapeutic tools for treating addiction.
Preclinical models suggest that drug abuse is a disease that alters the neuronal function in the brain's reward system, in particular, the nucleus accumbens. The proposed work is designed to test the hypothesis that inhibitory synaptic circuits within the nucleus accumbens are recruited by exposure to drugs of abuse and regulate motivated behavioral outcomes. By defining circuits and synaptic mechanisms recruited by drugs of abuse, the proposed research is relevant to the NIH and NIDA's mission that pertains to developing fundamental knowledge that will help reduce the burdens of addiction.