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. Author manuscript; available in PMC: 2023 Jan 19.
Published in final edited form as: Nature. 2019 Oct 16;574(7778):372–377. doi: 10.1038/s41586-019-1653-x

Figure 4. Habenular Tcf7l2 regulates hyperglycemic response to nicotine.

Figure 4.

a, Nicotine elevated fasting blood glucose in rats (F (9, 66) = 13; ***P<0.0001; interaction effect in Two-way ANOVA; n=8). b, Self-administration of the standard dose of nicotine (0.03 mg kg−1 per infusion) did not alter blood glucose levels in rats (n=15). c, Self-administration of a higher nicotine dose (0.12 mg kg−1 per infusion) elevated blood glucose in rats (n=6). **P=0.0092, two-tailed paired t-test. d, Graphical representation of rat brain showing strategy to chemogenetically stimulate the mHb-IPn circuit. Retro-AAV-Cre was delivered into the IPn and Cre-dependent FLEX-hM3Dq (n=5) or FLEX-GFP (n=5) was delivered into the mHb. e, Clozapine-N-oxide (CNO) (3 mg kg−1) increased activity of the mHb-IPn circuit of rats expressing FLEX-hM3Dq but not in those expressing FLEX-GFP, reflected by changes in BOLD signal measured by fMRI. Experiment was performed on a single occasion. Coronal brain image adapted from the Allen Brain Reference Atlas. f, CNO injection elevated fasting blood glucose levels in rats expressing FLEX-hM3Dq (n=5 rats) compared with those expressing FLEX-GFP (n=5 rats); F (1, 8) = 85.2; ***P<0.0001; interaction effect in Two-way ANOVA. g, Intra-mHb infusion of Ex-4 (100 ng) enhanced the hyperglycemic response to self-administered nicotine in rats (n=10); F (1, 21) = 8.39; **P=0.0086; interaction effect in Two-way ANOVA. Box plot shows min-max range. h, Knockdown of Glp1r transcripts in mHb abolished the hyperglycemic response to self-administered nicotine infusions in rats (n=6 per virus); F (1, 10) = 5.15; *P=0.0466; interaction effect in Two-way ANOVA. Box plot shows min-max range. i, Tcf7l2 knockdown in mHb abolished the hyperglycemic response to self-administered nicotine in rats (n=10); F (1, 18) = 18.6; ***P<0.001; interaction effect in Two-way ANOVA. Box plot shows min-max range. j, Atenolol abolished the hyperglycemic response to self-administered nicotine in rats (n=7); F (1, 12) = 19.8; ***P<0.001; interaction effect in Two-way ANOVA. Box plot shows min-max range. k, Graphical representation of strategy to trace polysynaptic inputs from the mHb-IPn circuit to the pancreas in ChAT-tdTom reporter mice. l, Image of a pRV-GFP-labelled cholinergic cell in the ventral region of the mHb, and pRV-GFP-labelled IPn neuron in close apposition to cholinergic fibers (red) from the mHb (inserts show magnified images). Representative result from two independent experiments.