| Brain is the most complex organ of the human body. It is involved in feeling, motor, learning, memory, language, emotion and other higher cognitive functions. Multiple neurotransmitters coordination control is essential to the normal brain structure function, dopamine is one of the most important neurotransmitter. Dysfunction of dopaminergic singaling can directly change the brain network, impair cognitive function and behavior that leading to a variety of mental diseases such as schizophrenia. Hence, we did imaging genetic analysis in a large sample of normal Chinese, combining multiple modal of magnetic resonance imaging data, to investigate the influence of dopamine-related genes on brain networks. The present studies revealed the effects underlying neurobiological mechanisms of the dopamine neurotransmitter system on emotional regulation and cognitive control, helped us understand the relationship between dopamine system and mental diseases.First, Brain-derived neurotrophic factor(BDNF) Val66Met(valine-to-methionine substitution at codon 66) impacts cognitive, memory, and several neurological and psychiatric disorders. Structure magnetic resonance imaging studies have shown that this genetic variant is related to the individual differences in cortical thickness and volume, but the effect of BDNF Val66 Met on the cortical surface area remains unclear. Based on multimodal magnetic resonance imaging data, we studied the effect of this polymorphism on the cortical morphology and resting-state functional connectivity in a large sample of healthy Han Chinese subjects. We calculated cortical thickness and surface area using Freesurfer, then treated morphological phenotypes and functional connectivity as the dependent variables and genotypes as the independent variables(Val/Val = 0, Val/Met = 1, Met/Met = 2). The SNP-wise general linear model analysis showed a stepwise increase in surface area of the right anterior insular cortex with the dosage of the Met allele. Moreover, we also found functional connectivity between the anterior insular and the dorsolateral prefrontal cortex was enhanced with the dosage of the Met allele. In conclusion, these data demonstrated a “dosage effect” of BDNF Val66 Met on cortical structure and function.Second, BDNF influences the dopamine release in the ventral striatum, while catechol-O-methyltransferase(COMT) impacts dopamine metabolism in the prefrontal cortex. These two brain regions act as part of the frontostriatal system, plays a critical role in emotional regulation and cognitive control. Two common single nucleotide polymorphisms in BDNF and COMT respectively are Val66 Met and Val158 Met. BDNF Val66 Met mainly affects intracellular transfer and secretion of BDNF, while COMT Val158 Met impacts dopamine level of the prefrontal cortex. Previous studies have already shown a genetic interaction of BDNF Val66 Met and COMT Val158 Met on frontostriatal-dependent memory performance, but the interaction on the dopamine-related neural circuit has not been studied. The present study did two-way analysis of variance, using functional magnetic resonance imaging, and found that BDNF and COMT epistatically interacted on the functional connectivity between the bilateral VST and the anterior cingulate cortex. Specifically, the effects of BDNF Val66 Met on the ventral striatum-perfrontal functional connectivity showed an inverted U-shaped in COMT Met carriers, while COMT Val homozygotes was a U-shaped. These data elucidated the neurobiological mechanism of the interaction between BDNF and COMT on the frontostriatal-dependent cognitive functions.Finally, the mode of gene action is not only work alone or interact with another one, more and more genome wide assosiation analysis find that most psychiatric diseases are ploygenic inheritance disease. So we further joined the dopamine system genes involved in dopamine synthesis, transport, metabolism and receptors, then used PLINK and Freesurfer to compute the dopamine polygenic risk score and the volume of putamen and caudate. Regression analysis were used to find the combined imapct of these genes related to risk of schizophrenia on the brain structural and functional network, as well as the schizophrenia-related cognitive impairments. We found that schizophrenia dopamine gene polygenic risk score was positively correlated with the volume of the left putamen. Resting-state functional connectivity analysis revealed that the higher the polygenic risk score, the stronger connection between left putamen and caudate and default mode network, while the weaker connectivity with fronto-parietal network. In addition, behavioral analysis found that working memory capabilty would decrease with rising polygenic risk score. In conclusion, the present studies helped us understand the biological mechanism of “dopamine hypothesis” of schizophrenia, and demostrated the polygenic inheritance of schizophrenia.Our studies established the relationship of the dopamine system genes, brain structure and function, and the behavior, provided evidences to find the neural mechanisms of the clinical behaviors, paved the way to prevent the happening of psychiatic diseases. |
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