Summary: The VMAT1 gene underwent adaptive changes during human evolution. Individuals carrying the isoleucine (Ile) variant at position 136 of VMAT1 tend to show lower susceptibility to anxiety and depression.
Source: Tohoku University
Monoamine neurotransmitters such as serotonin and dopamine are central to cognitive and emotional processing. These signaling systems originated early in animal evolution, and while many related genes are highly conserved, genetic variation both within and between species can substantially influence behaviors including sociality, aggression, anxiety, and depression.
A research team led by Dr. Daiki Sato and Professor Masakado Kawata previously reported that the vesicular monoamine transporter 1 (VMAT1) gene, which packages neurotransmitters into secretory vesicles in neurons and endocrine cells, shows evidence of adaptive evolution in the human lineage. In particular, the amino acid at position 136 changed from asparagine (Asn) to threonine (Thr) during human evolution, and a subsequent variant — isoleucine (Ile) at the same position — emerged and rose in frequency across human populations.
Prior human genetic association studies suggested that individuals carrying the Ile variant are less prone to symptoms of anxiety and depression compared with those carrying Thr. However, the biological mechanisms linking this human-specific amino acid substitution to brain function and to behavioral differences had been unclear.
To investigate causality and mechanism, Sato, Kawata, Yukiko U. Inoue (National Center of Neurology and Psychiatry), and colleagues created genetically modified mice in which the mouse Vmat1 gene was edited so that the 136th amino acid matched the human variants (Thr or Ile). Using genome editing to introduce humanized substitutions allowed the team to compare effects of the different VMAT1 variants on gene expression, neural activity, and behavior in a controlled animal model.
Behavioral testing revealed that mice carrying the Ile-type humanized Vmat1 exhibited reduced anxiety-like behaviors compared with mice carrying the Thr-type variant, a result that aligns with earlier human epidemiological findings. At the molecular and neural circuit levels, the genotype influenced post-synaptic gene expression profiles and altered neural activity in the amygdala, a brain region central to processing emotions and fear-related responses.
These findings indicate that a single, human-specific amino acid substitution in VMAT1 can shape amygdala-dependent neural circuits and associated behaviors. While the precise cellular mechanisms remain to be fully delineated, the study supports the concept that evolutionary changes in genes involved in monoamine neurotransmitter regulation can modulate emotional traits such as anxiety and vulnerability to depression.
Importantly, this work illustrates the power of genome editing in experimental evolution and behavioral neuroscience: by introducing human-specific substitutions into an animal model, researchers can directly test how particular genetic changes affect brain function and behavior. Such experiments are relatively rare for amino acid substitutions inferred to have been targets of natural selection during human evolution.
Overall, the study highlights the functional significance of VMAT1 variation in the regulatory network of monoamine signaling and its potential relevance to neuropsychiatric conditions. These results contribute to a better understanding of the genetic and neurobiological underpinnings of anxiety and depression and may guide future research into mechanisms and therapeutic targets.
About this genetics, evolution and psychology research news
Author: Press Office
Source: Tohoku University
Contact: Press Office – Tohoku University
Image: The image is in the public domain
Original Research: Open access.
“Humanized substitutions of Vmat1 in mice alter amygdala-dependent behaviors associated with the evolution of anxiety” by Daiki X. Sato et al. iScience