Extinction blunts paraventricular thalamic contributions to heroin relapse.

Here, we use optogenetics and chemogenetics to investigate the contribution of the paraventricular thalamus (PVT) to nucleus accumbens (NAc) pathway in aversion and heroin relapse in two different heroin self-administration models in rats. In one model, rats undergo forced abstinence in the home cage prior to relapse testing, and in the other, they undergo extinction training, a procedure that is likened to cognitive behavioral therapy. We find that the PVT→NAc pathway is both sufficient and necessary to drive aversion and heroin seeking after abstinence, but not extinction. The ability of extinction to reduce this pathway's contribution to heroin relapse is accompanied by a loss of synaptic plasticity in PVT inputs onto a specific subset of NAc neurons. Thus, extinction may exert therapeutic reductions in opioid seeking by altering synaptic plasticity within the PVT→NAc pathway, resulting in reduced aversion during opioid withdrawal as well as reduced relapse propensity.

Cholinergic Transmission at Muscarinic Synapses in the Striatum Is Driven Equally by Cortical and Thalamic Inputs.

The release of acetylcholine from cholinergic interneurons (ChIs) directly modulates striatal output via muscarinic receptors on medium spiny neurons (MSNs). While thalamic inputs provide strong excitatory input to ChIs, cortical inputs primarily regulate MSN firing. Here, we found that, while thalamic inputs do drive ChI firing, a subset of ChIs responds robustly to stimulation of cortical inputs as well. To examine how input-evoked changes in ChI firing patterns drive acetylcholine release at cholinergic synapses onto MSNs, muscarinic M4-receptor-mediated synaptic events were measured in MSNs overexpressing G-protein gated potassium channels (GIRK2). Stimulation of both cortical and thalamic inputs was sufficient to equally drive muscarinic synaptic events in MSNs, resulting from the broad synaptic innervation of the stimulus-activated ChI population across many MSNs. Taken together, this indicates an underappreciated role for the extensive cholinergic network, in which small populations of ChIs can drive substantial changes in post-synaptic receptor activity across the striatum.