Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety

•Nicotine injection activates or inhibits distinct VTA dopaminergic subpopulations•NAc-projecting neurons are excited by nicotine, and their activation is reinforcing•Amygdala-projecting inhibited silencing anxiogenic•Nicotine-mediated anxiety prevented activating VTA-amygdala DA Nicotine stimulates dopamine (DA) of the ventral tegmental area (VTA) to establish maintain reinforcement. also induces through an as yet unknown circuitry. We found that nicotine drives opposite functional responses two populations with anatomically segregated projections: it project nucleus accumbens (NAc), whereas amygdala nuclei (Amg). further show mediates anxiety-like behavior acting on ?2-subunit-containing nicotinic acetylcholine receptors VTA. Finally, using optogenetics, we bidirectionally manipulate VTA-NAc VTA-Amg pathways dissociate contributions behavior. inhibition behavior, while prevents anxiogenic effects nicotine. 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In addition, nicotine-induced changes and, importantly, maintained polarity decrease) all tested 1E). rule out confounding anesthesia putative 16) mice (Figures S2A–S2B), injected tail vein ?g/kg i.v.; STAR Methods). observed 8) (Nic?; 1F), replicating results (comparisons saline-induced Student’s t test Bonferroni correction, 0.02 0.001 neurons). nature inhibition) constitutes marker allows robust segregation populations. sought determine spontaneous these basal characterized percentage spikes burst (%SWB) Bursts classically discrete events consisting sequence (1) onset consecutive interval <80 ms (2) end inter-spike >160 (Grace Bunney, 1984aGrace Bunney B.S. nigral neurons: firing.J. 1984; 4: 2877-2890Crossref nicotine-activated nicotine-inhibited rates (? 0.26 Hz, 0.0506) bursting activities 3.5%, 0.064) S2C). An analysis intervals highlighted profiles depending length Other parameters describing (e.g., coefficient frequency) analyzed, none them revealed difference neurons. logistic regression predict probability type (inhibited/activated) predictor variables (the frequency, variation, %SWB, frequency). Only statistically outcome (p 0.007), classification prediction very low 36%). Overall, differences could detected, predicted sole activity. next asked segregated. NB-filled bodies each responding 243) positioned mouse atlas plates (Paxinos Franklin, 2004Paxinos Franklin K.B.J. Mouse Stereotaxic Coordinates. Gulf Professional Publishing, 2004Google S3) study anatomical location. As illustrated single plate schematic (bregma ? 3.3 mm), coordinates located medially independently anteroposterior dorsoventral positions 1G). increasingly about terms functionally sub-networks (Watabe-Uchida 2012Watabe-Uchida Zhu Ogawa S.K. 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(Pearson’s chi-square 0.001). carried NAcMSh NAcLSh examine this effect driven sub-nucleus. Analysis NAcMSh-projecting 14 RB+, TH+; 8 RB?, NAcLSh-projecting 6 leads conclusion regardless sub-nucleus they S5). second series experiments, (Amg), targeting basolateral (BLA) (CeA) S4C). once again triple-labeling (TH+, NB+, RB+/?; 2D; S4D). 26 Amg (BLA CeA) 2E 2F), 22 Amg-projecting 86% (19 22) inhibited, 14% (3 activated. without mainly (77% [23 30]), 23% (7 2F). distributions (Kolmogorov-Smirnov 0.001) modes positive negative variations; 2G). indicate (core shell), (comparison percentages Pearson’s Notably, triple-labeled sections S4E). 0.8), tended 0.28), S4F; probed translate Amg. Using fiber photometry encoded sensor (GRABDA2m; Sun 2018Sun Zeng Jing Zhou Feng Owen S.F. Li Wang Yamaguchi T. al.A fluorescent enables rapid detection flies, fish, mice.Cell. 174: 481-496.e19Abstract (308) 2020Sun Dai Qian X. 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