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. 2024 Oct 4;10(40):eado3514. doi: 10.1126/sciadv.ado3514

Fig. 4. ANP32E—an H2A.Z-specific histone chaperone—regulates transcriptional and rewarding responses to cocaine.

Fig. 4.

(A) Mass spectrometry showed increased ANP32E in NAc chromatin with prolonged withdrawal from chronic cocaine (CS) (unpaired t test, P = 0.009, N = 6 per group). (B) Volcano plot shows dysregulated transcripts following cocaine challenge after ANP32E KD in D1 MSNs compared controls, including the plasticity-related genes Sox2, Gnas, Camk1, Nrxn2, and Kdm6a. (C) Heatmap depicts mRNA expression of gene changes in control mice (siScr) after prolonged withdrawal and their loss of transcriptional priming upon ANP32E KD. (D) GO network representing biological processes affected by 1209 transcripts (log2 fold = −0.5, false discovery rate < 0.05) with attenuated regulation postcocaine challenge in D1 MSN–specific ANP32E KD mice. (E) Model: Following repeated cocaine, increased ANP32E mediates H2A.Z eviction, heightening gene responses to cocaine. (F) D1 MSN–specific ANP32E KD suppresses cocaine self-administration. The panel shows the percent of active lever presses during fixed-ratio 2 (FR2) sessions relative to the average response rates during FR1. Control animals increase active lever presses on the FR2 schedule to maintain level of cocaine infusions, but ANP32E KD mice do not modify their lever-pressing behavior upon this contingency change [repeated measures two-way analysis of variance (ANOVA), group × session interaction: F(4,48) = 2.252, not significant; main effect of group: F(1,12) = 5.406, P = 0.0384]. (G) Timeline for cocaine-induced CPP in mice with D1 MSN– or D2 MSN–specific ANP32E KD. (H) Schematic of cocaine-induced CPP. (I) Preference scores for the cocaine-paired chamber in control mice and D1 MSN–specific ANP32E KD mice [F(1,19) = P = 0.04, confirmed by Holm-Šídák’s multiple comparisons test]. Data are mean ± SEM; P values by Wilcoxon matched-pairs signed-rank test. (J) Preference scores for the cocaine-paired chamber in control mice and mice with D2 MSN–specific KD of ANP32E in the NAc [F(19,19) = 2.804, P = 0.015]. Data are mean ± SEM; P values (*P ≤ 0.05; ****P ≤ 0.0001) by Wilcoxon matched-pairs signed-rank test.