Abstract
The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.
Highlights
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Within the MedLHb, morphine withdrawal (MORwd) i. reduced microglial markers including Iba[1] and CD68 and ii. diminished microglial cell volume (Fig. 2a–d)
AAVCre-TNF-R1fl/fl mice failed to show MORwd-driven AMPAR:NMDAR ratio reduction compared to AAVControl-infused mice (Fig. 3d)
Summary
In the absence of a copyright statement, users should assume that standard copyright protection applies, unless the article contains an explicit statement to the contrary. Spontaneous MORwd decreased AMPAR:NMDAR ratios in the MedLHb up to 30 days after the last MOR injection MORwd diminished AMPAR:NMDAR ratios solely in retrobeadslabeled Raphe– but not VTA–projecting LHb neurons (LHbRaphe and LHbVTA) TNFα-dependent AMPAR internalization, partly underlying drug-mediated behavioral adaptations[8].
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