a, Schematic of the Rattus norvegicus Tcf7l2 gene. Exons are spliced to generate Tcf7l2 mRNA (NCBI reference sequence: NM_001191052.1). Primers for genotyping and Sanger sequencing are indicated by arrows flanking exon 5. b, Sequencing chromatograph of the Tcf7l2 mutant allele. The site of the 169-bp deletion from exon 5 and the following intron is labelled. c, Illustration of TCF7L2 wild-type protein, containing an N-terminal β-catenin binding domain (blue) and C-terminal DNA binding domain (red). Predicted open reading frames and truncated proteins generated from the Tcf7l2 mutant mRNA. Green regions on predicted truncated proteins denote ectopic amino acid sequences not found in wild-type TCF7L2 protein. d, Genotyping of wild-type and mutant Tcf7l2 rats: wild-type animal (+/+) with single band at 304 bp; heterozygous animal (+/−) with bands at 304 and 144 bp; and mutant animal (−/−) with a single band at 144 bp. Image is representative of genotyping results obtained for wild-type and mutant Tcf7l2 rats used each experiment. e, Graphical representation of mHb in coronal slice of rat brain. Image adapted from the Allen Brain Reference Atlas. f, Nissl staining showed similar mHb volumes in wild-type and mutant Tc7l2 rats. Image is representative of results obtained in three biologically independent animals from each genotype. g, Diffusion tensor imaging tractography of the fasciculus retroflexus in wild-type (n = 3) and mutant (n = 5) Tcf7l2 rats. h, Fractional anisotropy showed similar integrity (left and right sides) of the fasciculus retroflexus in wild-type (n = 3) and mutant (n = 5) Tcf7l2 rats (‘genotype’: F 1, 6 = 0.000003; P = 0.99; ‘brain side’: F 1, 6 = 2.562, P = 0.16; ‘genotype × brain side’: F 1, 6 = 0.0007, P = 0.98). i, The frequency at different steps of positive current used to calculate the slope of the input–output curve from dorsal mHb neurons. Example traces showing typical current steps at −20, 0 and 40 pA in dorsal mHb neurons from wild-type and mutant Tcf7l2 rats. j, Input–output curve in dorsal mHb neurons from wild-type and mutant Tcf7l2 (n = 16 cells from 5 rats) rats. k, The frequency at different steps of positive current used to calculate the slope of the input-output curve from ventral mHb neurons. l, Input–output curve in ventral mHb neurons from wild-type and mutant Tcf7l2 (n = 16 cells, 5 rats) rats. m, Input resistance from mHb neurons from wild-type (13 cells, 4 rats) and mutant (16 cells, 5 rats) Tcf7l2 rats (P = 0.1036, unpaired two-tailed t-test). n, Afterhyperpolarization in mHb neurons from wild-type (13 cells, 4 rats) and mutant (16 cells, 5 rats) Tcf7l2 rats; P = 0.3043, unpaired two-tailed t-test. o, Sag current in mHb neurons wild-type (13 cells, 4 rats) and mutant (17 cells, 5 rats) Tcf7l2 rats (P = 0.1386, unpaired two-tailed t-test). p, Total distance travelled by drug-naive wild-type (n = 6) and mutant (n = 5) Tcf7l2 rats during a 60 min session. q, Total distance travelled by wild-type (n = 6) and mutant (n = 5) Tcf7l2 rats after daily injections of saline or nicotine (0.4 mg kg−1) (15 min pre-treatment time). r, Responses to the training dose of nicotine (0.03 mg kg−1 per infusion) were assessed in a group of wild-type (n = 9) and mutant (n = 11) Tcf7l2 rats on days 1 and 35 of access. Nicotine responses were similar between the wild-type and mutant Tcf7l2 rats on day 1 of access, but mutant Tcf7l2 rats escalated their intake such that their responses were higher on day 35 compared with wild-type Tcf7l2 rats, and compared with their own intake on day 1 (F 1, 18 = 30.8, ****P < 0.0001, interaction effect between ‘genotype’ and ‘session’ in two-way ANOVA). Box plots show minimum–maximum range. Data are mean ± s.e.m. Source data