Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Abstract

Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine selfadministration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1 d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short-and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.

Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers

“…When Hamlin and colleagues (Hamlin et al 2009) demonstrated a role for the PVT in context-induced reinstatement, they also showed that this renewal of drug-seeking behavior engaged the PVT-NAc shell pathway, which included the entire rostrocaudal extent of the PVT. Additionally, the PVT-NAc pathway is involved in the acquisition of cocaine self-administration (Neumann et al 2016), as well as mediating symptoms during drug withdrawal (Zhu et al 2016). Recently, however, it was shown that pharmacological inactivation of the anterior, but not the posterior, PVT increases sucrose-seeking behavior upon reward omission, and that this behavior is specifically mediated by aPVT projections to the NAc shell (Do-Monte et al 2017).…”

“…In the current study, however, we targeted a specific nucleus that had been identified as a key player in these Pavlovian learning processes (Flagel et al 2011a, Haight and Flagel 2014, Haight et al 2015, Yager et al 2015, Haight et al 2017), to determine whether the same nucleus acts to encode the incentive value of a cue that was previously paired with operant drug delivery. While it is known that the neural circuitry mediating Pavlovian conditioning can differ from that mediating instrumental behavior (Ostlund et al 2007, Yin et al 2008, Wassum et al 2011), the paraventricular nucleus of the thalamus appears to be involved in both (Hamlin et al 2009, James et al 2010, Browning et al 2014, Haight et al 2015, Matzeu et al 2015, Neumann et al 2016, Do-Monte et al 2017, Matzeu et al 2017, Otis et al 2017). The current findings support a role for this nucleus in the attribution of incentive value to reward cues and suggest that, in a subset of individuals, the PVT acts to suppress the learned incentive value of such cues.…”

“…In recent years, the PVT has been increasingly acknowledged for its role in addiction-related behaviors (Deutch et al 1995, Deutch et al 1998, Young et al 1998, Stephenson et al 1999, James et al 2013, Browning et al 2014, Haight and Flagel 2014, Yeoh et al 2014, Neumann et al 2016, Zhu et al 2016, Matzeu et al 2017), with a particular emphasis on reinstatement of drug-seeking behavior (Hamlin et al 2009, James et al 2010, Matzeu et al 2015, Matzeu et al 2016). However, these prior studies were not designed to examine individual differences in the role of the PVT in cue-motivated behaviors (Flagel et al 2011a, Haight and Flagel 2014, Yager et al 2015, Haight et al 2017).…”

A synthetic likelihood solution to the silent synapse estimation problem

“…It has been long understood that the plasticity potential of a network is in part determined by the fraction of synapses which exist in a silent state, and the proportion of silent synapses is regulated both throughout development (4-5) and in response to diseases or drugs (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Despite a growing appreciation of the overall importance of silent synapses in mature neural networks, a systematic analysis of quantification methods for this parameter, to our knowledge, is lacking.…”

“…distribution falls below zero, which are biologically irrelevant estimates. Since negative values are expected, yet have not been reported from FRA (8)(9)(10)(11)(16)(17)(18)(19)(20)(21), it is possible that these negative values returned from the equation are systematically set to a biologically relevant value of 0% silent (i.e., systematically 'zeroed'). This procedure would artificially inflate the mean silent synapse estimate (see Supplemental Information for more details).…”