A thalamic input to the nucleus accumbens mediates opiate dependence

Abstract

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both rewarding effects of drug and the desire to avoid withdrawal symptoms motivate continued drug use1-3, and the nucleus accumbens (NAc) is important for orchestrating both processes4,5. While multiple inputs to the NAc regulate reward6-9, little is known about the NAc circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus (PVT) as a prominent input to the NAc mediating the expression of opiate withdrawal induced physical signs and aversive memory. Activity in the PVT to NAc pathway is necessary and sufficient to mediate behavioral 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 PVT and D2-receptor-expressing medium spiny neurons (D2-MSNs) via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at PVT→D2-MSNs synapses and robustly suppresses morphine withdrawal symptoms. These results link morphine-evoked pathway- and cell type-specific plasticity in the PVT→NAc circuit to opiate dependence, and suggest that reprogramming this circuit holds promise for treating opiate addiction.

The Other Face of the Nucleus Accumbens: Aversion

“…Optogenetic-mediated, pathway-specific stimulation reveals that the activation of inputs from the PFC, vHipp, and BLA to the NAc is rewarding and can reinforce instrumental behavior [6,7]. However, still unknown is the specific NAc circuitry that underlies negative emotional and motivational states after withdrawal.Using retrograde neuronal tracing, Zhu et al [8] showed that the NAc is densely innervated by the PVT, in addition to its well-characterized inputs from the PFC, vHipp, and BLA. Brief light stimulation of fibers that project from the PVT to the NAc evoked robust a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitatory postsynaptic currents in medium spiny neurons (MSNs), indicating that the PVT is a source of glutamatergic afferents to the NAc.…”

“…Using retrograde neuronal tracing, Zhu et al [8] showed that the NAc is densely innervated by the PVT, in addition to its well-characterized inputs from the PFC, vHipp, and BLA. Brief light stimulation of fibers that project from the PVT to the NAc evoked robust a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitatory postsynaptic currents in medium spiny neurons (MSNs), indicating that the PVT is a source of glutamatergic afferents to the NAc.…”

“…Both positive reinforcement (rewarding effects of drugs) and negative reinforcement (aversive emotional state associated with withdrawal) have been considered to play critical roles in the etiology and maintenance of drug addiction, and NAc neurons are capable of processing both reward and aversion [4,5]. Optogenetic activation of inputs from the PFC, ventral hippocampus (vHipp), and basolateral amygdala (BLA) to the NAc drives positive reinforcement and facilitates rewardseeking behavior [6,7], but a recent paper in Nature [8] has identified another face of the NAc. The pathway from the paraventricular nucleus of the thalamus (PVT) to the NAc is key to the aversive emotional state of drug withdrawal.…”

“…Zhu et al [8] used optogenetic and chemogenetic approaches to selectively silence the PVT-NAc pathway and test the effects of this manipulation on opiate withdrawal-induced somatic signs and place aversion. Robust Fos expression in PVT neurons that project to the NAc was precipitated by naloxone and induced by spontaneous withdrawal.…”

Special Topic on Mental Health and Addiction

“…Besides, the NAc is also involved in the aversive emotional state linked to drug withdrawal, which induces continued and compulsive drug use. Inputs from the prefrontal cortex, ventral hippocampus, and basolateral amygdala to the NAc have been implicated in the rewarding effects of addictive drugs, while input from the paraventricular nucleus of the thalamus to the NAc mediates the physical changes and aversive memory induced by opiate withdrawal [2,3]. In addition, Wang et al [4] showed that both intraperitoneal injection of the D1 receptor antagonist, SCH23390, and intra-NAc injection of the MEK inhibitor, U0126, attenuate the propofol self-administration and diminish the expression of phosphorylated extracellular signal-regulated kinase (ERK) in the NAc.…”