Influence of drugs of abuse on inhibitory circuits in the striatum

University Of California Santa Barbara, Santa Barbara CA

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Abstract

PROJECT SUMMARY Reward-learning and the guidance of motivated behavior relies on the brain's ability to bind reward signals with contexts and stimuli in a long-lasting manner. The neural underpinnings of this process are thought to involve the remodeling of synaptic connections between multiple brain regions. The Nucleus Accumbens (NAc), a structure within the ventral striatum, is critical in controlling motivated behaviors and supporting reward learning, and this region is the site of numerous pathological alterations underlying addiction to drugs of abuse and compulsion disorders. Output from the NAc is mediated by medium spiny neurons (MSNs), inhibitory projection neurons which fall into two populations that project to opposing downstream targets. Local GABAergic interneurons expressing parvalbumin (PV) and somatostatin (SOM) are thought to control the output of these MSNs, but basic properties of their connectivity remain a mystery. The excitatory inputs which contact interneurons and drive their firing are unexplored, and little is known about their control over the two MSN subclasses. Given the wealth of knowledge regarding the importance of local interneuron circuits in cortical areas, it is critical to understand the GABAergic microcircuit in the NAc. Additionally, the NAc is a site of immense plasticity, allowing for both reward learning and the pathological scenario of drug addiction. This region has long been known to play a critical role in addiction-related behaviors, and recent studies have revealed synaptic plasticity mechanisms involving glutamatergic inputs to MSNs. Given their ability to regulate the activity of both types of MSNs, PV+ and SOM+ interneurons are well-suited for a potential role in both controlling the overall activity patterns of this region as well biasing the relative output of the two opposing projection pathways. Thus, these cells likely play a pivotal role in the development of both drug-related and reward-motivated behaviors. This proposal will explore inhibitory striatal circuitry in three aims. Aim 1 will identify and characterize the glutamatergic inputs that drive GABAergic interneuron populations. Aim 2 will examine the inhibitory control of different MSN subtypes by local interneurons. Aim 3 will test how this circuitry is impacted by repeated exposure to cocaine. Together, this work will provide crucial insight into NAc circuitry and how this network is modified by drugs of abuse to contribute to drug-seeking behaviors.