Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior

Abstract

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.

Keywords: Cocaine self-administration; Cued reinstatement; Glutamate; Neuronal ensembles; Nucleus accumbens; Spines; Synaptic plasticity; Synaptic potentiation.

Figure 1

Model of the tetrapartite synapse and how it is altered after withdrawal from addictive drugs. A) Drug-naïve synaptic glutamate release probability is regulated by mGluR2/3 inhibitory autoreceptors, while the cystine-glutamate exchanger (Xc-) and glutamate transporter (GLT-1) expressed largely on astroglial cells, regulate the elimination of glutamate and determine how much glutamate spills out of the synapse. The extracellular matrix maintains synaptic structure and mediates synaptic plasticity by activating MMPs and signaling to the postsynapse via integrins. B) After drug self-administration and extinction training, presentation of the cues previously associated with the drug during acquisition of drug use induces a strong release of glutamate originating from prelimbic cortical afferents. Decreased function of mGluR2/3 and GLT-1, and withdrawal of astroglial end feet impair glutamate homeostasis and allow spillover of glutamate from the synaptic cleft. Extrasynaptic glutamate stimulates mGluR5 on nNOS interneurons (not shown), which activates matrix metalloproteases via nitrosylation. Catalytic signal transduction in the extracellular matrix by MMPs stimulates the expansion of postsynaptic spines and the insertion of AMPA receptors. AMPA-R: α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptor ECM: Extracellular Matrix GLT-1: Glutamate Transporter 1 Glu: Glutamate MMP: Matrix Metalloprotease MSN: Medium Spiny Neuron NMDA-R: N-Methyl-D-Aspartate Receptor Xc-: Cysteine/glutamate exchanger

Figure 2

Schematic of the wave of engram recruitment in the NAcore induced by a cocaine cue. We hypothesize that the cocaine/cue-associated ensemble, formed during cocaine self-administration, undergoes transient synaptic potentiation (t-SP) that spreads through the NAcore due to NO production and activation of MMPs (see figure 1). The local recruitment of a larger number of MSNs reduces the size of the ensemble activated by a sucrose cue, thereby promoting drug seeking over sucrose seeking. Cocaine-selective cells in red, sucrose-selective cells in blue, cells showing overlapping activity for cocaine and sucrose in purple, non-responding cells in grey, cells activated during reinstatement in orange. Phases A and B based on Cameron & Carelli, 2012.

Figure 3

AMPA:NMDA ratio measured in rats that underwent sucrose self-administration (sucrose) or cocaine self-administration (cocaine). In the extinction group (Ext), rats underwent an extinction session 24h before taking NAcore tissue slices and measuring A/N, in the cue group, animals were tested after 15 min of cue-induced reinstatement. Numbers on top of the data recapitulate the number of cells with ratios two standard deviations above the mean ratio over total number of cells measured, as well as the corresponding percentages. These data were originally published in (Gipson et al., 2013a).

Figure 4

DiI labeling coupled with Immunohistochemistry enhanced labeling of GFP allowed visualization of A) putative D2 neurons (D1 negative, D1−) and B) D1 positive neurons in the NAc C) Spine head diameter on D1+ and D1− neurons. After extinction from cocaine self administration (T=0, green bars), a potentiation in dh is observed in both D1+ and D1− neurons compared to saline controls (white bars). During cue-induced reinstatement (T=15, red bars), dh is elevated specifically on D1+ dendritic spines. N shown in bars is the number of neurons quantified, and the data were analyzed using a 2-way ANOVA F(1,137) = 4.613, p < 0.05 (main effect); ** D1 vs D2 p<0.01; # Between groups p< 0.001)