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Scientific Understanding of Consciousness |
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Thalamic Input to the Nucleus Accumbens mediates Opiate Dependence
Nature 530, 219–222 (11 February 2016) A thalamic input to the nucleus accumbens mediates opiate dependence Yingjie Zhu,Et.Al. Department of Biology, Stanford University, Stanford, California 94305, USA [paraphrase] 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 use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, 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. To systematically map brain regions that directly innervate the nucleus accumbens (NAc), we stereotaxically injected a rabies virus in which the viral glycoprotein was replaced by red fluorescent protein mCherry (RV-mCherry) into the medial shell of the NAc. Besides well-characterized inputs to the NAc, such as the prefrontal cortex, ventral hippocampus and basolateral amygdala (BLA), we also detected mCherry-expressing neurons in the paraventricular nucleus of the thalamus (PVT). This result was particularly interesting because although previous studies have suggested a potentially important role for the PVT in drug-seeking behaviour, its underlying circuitry mechanism remains unknown. Activation of inputs from the prefrontal cortex, ventral hippocampus and BLA to the NAc is rewarding and drives self-stimulation behaviour. To directly assess the behavioural consequences of PVT→NAc circuit activity, we optogenetically activated this pathway in freely moving mice and examined their motivational valence using a real-time place preference assay. Chronic opiate use causes profound neuroadaptive changes in the NAc. The NAc comprises two major subtypes of MSN, defined by the expression of either D1 or D2 dopamine receptors (D1- or D2-MSNs). D1- and D2-MSNs are proposed to play opposing roles in mediating behavioural motivation and reward learning, and synaptic plasticity of these MSNs appears to be causally involved in behavioural adaptations to drug addiction and chronic pain states. Complementary to previous studies that highlight the contribution of the prefrontal cortex, BLA, and ventral hippocampus inputs to the NAc in mediating drug reward and their plasticity onto D1-MSNs after chronic drug exposure, here we show that the PVT input transmits negative valence and its plasticity at PVT→D2-MSN synapses is necessary for the expression of aversive states associate with opiate withdrawal. We further demonstrate that optogenetic restoration of normal synaptic transmission at these synapses effectively relieves withdrawal symptoms. Our optogenetic LTD protocol may inspire the development of novel treatments for opiate addiction involving deep brain stimulation to induce plasticity at relevant synapses. [end of paraphrase]
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