Dissecting circuit- and stage-specific neural adaptations in an animal model of drug addiction

Drug addiction is a major global health problem, persisting due to a lack of effective treatments. This is largely due to insufficient understanding of the pathophysiology and neural circuitry underlying the progression of a healthy individual into drug addiction. Rodent models of cocaine addiction implicate the activity of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) in the progression to addiction. MSNs of the NAc can be classified as dopamine receptor D1 or D2 expressing neurons, and cocaine exposure has previously been shown to induce many changes in these two cells types, including differential modifications of dendritic spine densities. While the neural substrates driving these changes remains unknown, these changes are likely due to synaptic changes driven by the neural adaptation in the regions upstream of the NAc in response to cocaine administration. Therefore, we seek to determine whether major excitatory projections to the NAc MSNs exhibit changes during the progression to addiction. In particular, previous work has shown the basolateral amygdala (BLA), prefrontal cortex (PFC), and the ventral hippocampus (VH) projections to the NAc as facilitating behavioral aspects of addiction. We utilized a method of monosynaptic retrograde tracing using an EnvA pseudotyped rabies virus that would allow us to label neurons in these areas that directly project to MSNs. The effect of cocaine on spine density was measured in multiple stages: initial use (5 days of cocaine exposure), withdrawal (5 days of cocaine followed by 2 week withdrawal period without cocaine), and relapse (5 days of cocaine followed by a single cocaine reinstatement shot at the end of 2 week withdrawal). Here, we characterize the distinct effects of cocaine exposure on dendritic modifications in a projection-, cell type-, and stage-specific manner. Our findings suggest cocaine differentially alters spine densities on neurons in brain areas that send excitatory projections to NAc MSNs. These neuroanatomical results establish a framework to further understand the circuit-basis of progression to drug addiction