SummaryExposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. Here, we explain this paradox by showing that both drugs induce NMDA receptor-containing, AMPA receptor (AMPAR)-silent excitatory synapses, but in distinct cell types through opposing cellular mechanisms: cocaine selectively induces silent synapses in D1-type neurons likely via a synaptogenesis process, whereas morphine induces silent synapses in D2-type neurons via internalization of AMPARs from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses become ‘unsilenced’ by recruiting AMPARs to strengthen excitatory inputs to D1-type neurons, while morphine-generated silent synapses are likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell-type specific, opposing mechanisms produce the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.

Understanding transcriptional changes engaged in stress resilience may reveal novel antidepressant targets. Here, we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical (PFC) neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB- Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in PFC neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB- Zfp189 interactions in mediating a central transcriptional network of resilience.

Cocaine-associated memories are persistent, but, upon retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, upon memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 hr later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are controlled by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1 FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1 FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1 FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1 FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1 FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc.

The development of drug addiction is associated with functional adaptations within the reward circuitry, within which the nucleus accumbens (NAc) is anatomically positioned as an interface between motivational salience and behavioral output. The functional output of NAc is profoundly altered after exposure to drugs of abuse, and some of the functional changes continue to evolve during drug abstinence, contributing to numerous emotional and motivational alterations related drug taking, seeking, and relapse. As in most brain regions, the functional output of NAc is critically dependent on the dynamic interaction between excitation and inhibition. One of the most prominent sources of inhibition within the NAc arises from fast-spiking interneurons (FSIs). Each NAc FSI innervates hundreds of principal neurons, and orchestrates population activity through its powerful and sustained feedforward inhibition. While the role of NAc FSIs in the context of drug addiction remains poorly understood, emerging evidence suggests that FSIs and FSI-mediated local circuits are key targets for drugs of abuse to tilt the functional output of NAc toward a motivational state favoring drug seeking and relapse. In this review, we discuss recent findings and our conceptualization about NAc FSI-mediated regulation of motivated and cocaine-induced behaviors. We hope that the conceptual framework proposed in this review may provide a useful guidance for ongoing and future studies to determine how FSIs influence the function of NAc and related reward circuits, ultimately leading to addictive behaviors.