Here, we present the first evidence for brain adaptation in pigs tolerant to the human presence, as a behavioral trait favoring domestication. The study was carried out on minipiglets from population bred in the Institute of Cytology and Genetics (Novosibirsk, Russia). We compared the behavior, metabolism of monoaminergic neurotransmitter systems and functional activity of the hypothalamic-pituitary-adrenal system, as well as neurotrophic markers in the brain of minipigs differing by tolerance to human presence (HT and LT - High and Low Tolerance). The piglets did not differ in the levels of activity in the open field test. However, the concentration of cortisol plasma was significantly higher in minipigs with a low tolerance to the presence of humans. Moreover, LT minipigs demonstrated the decreased level of serotonin in the hypothalamus and augmented levels of serotonin and its metabolite 5-HIAA in the substantia nigra as compared to HT animals. In addition, LT minipigs showed increased content of dopamine and its metabolite DOPAC in the substantia nigra and decreased dopamine level in the striatum as well as reduced content of noradrenaline in the hippocampus. Increased mRNA levels of two markers of the serotonin system - TPH2 and HTR7 genes in the raphe nuclei and in the prefrontal cortex, respectively, were associated in minipigs with a low tolerance to the human presence. However, the expression of genes regulating a dopaminergic system (COMT, DRD1 and DRD2) in HT and LT animal groups varied depending on brain structure. Also, a decrease in the expression of genes encoding BDNF (Brain-derived neurotrophic factor) and GDNF (Glial cell line-derived neurotrophic factor) was revealed in LT minipigs. The results may contribute to our understanding of the initial stage of domestication in pig.