A brain mechanism underlying the evolution of anxiety

New research using genome editing technology has allowed scientists to create a model and to evaluate a genetic mutation associated with neuropsychiatric difficulties in humans. The study revealed how the mutation works in the brain and affects anxiety and sociality.

Monoamine neurotransmitters such as serotonin and dopamine play an important role in our cognitive and emotional functions. Their evolutionary origins can be traced back to metazoans, and although the function of related genes is highly conserved through evolution, genetic variation within and between species has been reported to have a significant influence on the mental characteristics of animals such as as sociality, aggression, anxiety, and depression.

A research group led by Dr. Daiki Sato and Professor Masakado Kawata previously reported that the vesicular monoamine transporter 1 (VMAT1) gene, which transports neurotransmitters to the secretory vesicles of neurons and secretory cells, evolved by natural selection during human evolution. In particular, the 136th amino acid locus of this gene evolved in the human line of asparagine (Asn) to threonine (Thr), and moreover, a new allele (isoleucine, Ile) has emerged and increased its frequencies worldwide. Previous reports suggested that people with the Ile genotype were less prone to depression and anxiety than those with the Thr genotype, but it was unclear how these human-specific mutations work in the brain and lead to changes in neuropsychiatric behavior.

In this study, Sato, Kawata (Tohoku University), Yukiko U. Inoue (National Center for Neurology and Psychiatry) and their colleagues prepared Vmat1 gene-modified mice in which the th amino acid locus a was replaced with the human genotype (Thr or Ile) through genome editing technology, and compared gene expression, neuronal activity and behavior between genotypes. The Ile spell mice showed decreased levels of anxious behaviors, consistent with human studies. Additionally, genotype affected post-synaptic gene expression and neuronal activity in the amygdala, a brain region involved in emotional regulation. The functional role of the VMAT1 gene in the central nervous system remains unclear, and this study may provide a stepping stone towards elucidating its molecular mechanisms. Additionally, there are few studies in which the effects of single amino acid substitutions under natural selection during human evolution have been verified using genome editing technology. This study demonstrates the functional importance of human-specific variants in neurotransmitter regulatory circuits involved in cognitive and emotional functions and should shed light on the pathogenic mechanisms of neuropsychiatric conditions such as anxiety and depression.

AnxietyBrainGeneGenomeGenotypeMutationNeuropsychiatryThreonine

2022 2022

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