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. 2020 Mar 11;26(6):1860–1879. doi: 10.1038/s41380-020-0686-8

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 8 — a Experimental timeline. b Mice were injected with unilateral AAV₁-CaMKII-ChR2-eYFP into the VH. Contralateral disconnection and ipsilateral control group mice were injected with AAV₁-EF1α-DIO-KIR_2.1-2A-tdtomato into the contralateral or ipsilateral NAc, respectively. c Freezing on day 4 was not significantly different between control and footshock stress mice (n = 11–12 per group; two-way ANOVA; treatment main effect; F_(1,21) = 0.01, p = 0.91; time main effect; F_(14,294) = 8.83, p < 0.001; treatment × time interaction; F_{(14, 294)} = 0.94, p = 0.52). d Contralateral disconnection of increased VH synaptic strength in the NAc and increased excitability of NAc D1-MSNs restores sucrose preference (n = 12; t-test; t₍₂₂₎ = 3.36, p = 0.003) and mobility in the forced swim test (n = 11–12; t-test; t₍₂₁₎ = 6.42, p < 0.0001). e CTB-594 was injected into the LH of WT mice. LH-projecting D1-MSNs were recorded. f Input–output curves and rheobase of action potential firing in LH-projecting NAc D1-MSNs. Input–output curves (n = 12–13 per group; two-way ANOVA; treatment × current interaction; F_{(10, 230)} = 8.92, p < 0.0001). Rheobase (t-test; t₍₂₃₎ = 3.77, p = 0.001). g Decreased IRK currents in LH-projecting D1-MSNs from stressed mice (t-test; t₍₂₄₎ = 2.84, p = 0.0091). h AAV₁-CaMKII-ChR2-eYFP and CTB-594 were injected into the VH and LH, respectively, of mice. LH-projecting NAc D1-MSNs were recorded. Increased input–output transformations in the VH-NAc D1-MSN-LH pathway in naïve and footshock stress mice (two-way ANOVA; treatment main effect; F_{(1, 13)} = 29.84, p = 0.0001; stimulation intensity main effect; F_{(2, 26)} = 16.11, p < 0.0001; treatment × stimulation intensity interaction; F_{(2, 26)} = 1.53, p = 0.236). i AAV₂-retro-CMV-iRFP-2A-Cre was injected into the LH, while AAV₉-EF1a-DIO-KIR2.1-2A-tdtomato or AAV₉-EF1a-DIO-eYFP was injected into the NAc of WT mice. j Freezing on day 4 in mice expressing control fluorophore or KIR2.1-tdtomato in LH-projecting D1-MSNs. k Overexpression of KIR2.1 in LH-projecting D1-MSNs rescues footshock stress-induced decreases in sucrose preference (n = 9–10; t-test; t₍₁₇₎ = 2.80, p = 0.012) and increases in immobility in the forced swim test (n = 9–10; t-test; t₍₁₇₎ = 2.417, p = 0.027). l Model depicting that increased information flow in a VH to NAc to LH circuit drives passive coping and anhedonia. This is mediated by increased synaptic strength of VH inputs to D1-MSNs, via increased AMPAR function and or number, and increased excitability, via decreased IRK function and/or number, in LH.