A thalamic input to the nucleus accumbens mediates opiate dependence

The paraventricular nucleus of the thalamus to the nucleus accumbens pathway mediates physical signs and aversive memory of opiate withdrawal. The desire to avoid withdrawal symptoms is a major driver of continued drug use in opiate addicts, but the neural circuitry that mediates withdrawal symptoms is not well understood. Xiaoke Chen and colleagues show that a pathway from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) mediates behavioural aversion, including opiate withdrawal symptoms, through potentiation of synaptic transmission between PVT neurons and dopamine 2 (D2)-receptor-expressing medium spiny neurons. Optogenetic silencing of this pathway abolishes opiate withdrawal symptoms and suppresses behavioural aversion in response to stressful stimuli, pointing to a generic role in controlling the response to negative experiences. Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use1,2,3, and the nucleus accumbens is important for orchestrating both processes4,5. While multiple inputs to the nucleus accumbens regulate reward6,7,8,9, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.