摘要：SummaryThe human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmissions, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouseVmat1via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological, and molecular levels. Behavioral tests revealed reduced anxiety-related traits ofVmat1Ilemice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified changes in gene expressions in the amygdala involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.Graphical abstractDisplay OmittedHighlights•VMAT1harbors human-unique substitutions under natural selection•Those mutations are known to be associated with psychopathological traits•EstablishedVmat1-humanized mice show behavioral changes in anxiety•Altered gene expression and neuronal activity in the amygdala may cause the changesBehavior genetics; Molecular Genetics; Molecular mechanism of behavior; Evolutionary biology
