Abstract
The serotonin-1A (5-HT1A) receptor is strongly implicated in major depression and other affective disorders due to its negative regulation of serotonin neurone firing rates. Behavioural and clinical studies have repeatedly reported that the −1019G allele carries a high susceptibility for affective disorders. However, the underlying pathophysiology remains unknown. Here, we employed a genetic neuroimaging strategy in 99 healthy human subjects to explore the effect of serotonin-1A receptor polymorphism on brain resting-state functional connectivity (FC). We used functional magnetic resonance imaging, along with a seed-based approach, to identify three main brain networks: the default mode network (DMN), the salience network (SN) and the central executive network. We observed a significant decrease in the FC of the DMN within the dorsolateral and ventromedial prefrontal cortices in G-carriers. Furthermore, compared with the C-homozygote group, we observed decreased FC of the SN within the ventromedial prefrontal cortex and subgenual anterior cingulate cortex in the G-carrier group. Our results indicate that 5-HT1A receptor genetic polymorphism modulates the activity of resting-state FC within brain networks including the DMN and SN. These genotype-related alterations in brain networks and FC may provide novel insights into the neural mechanism underlying the predisposition for affective disorders in G allele carriers.
Highlights
5-Hydroxytryptamine (5-HT), more commonly known as serotonin, is the most widely distributed neurotransmitter in the brain, and dysfunctions of the serotonergic system are thought to be important factors for major depressive disorder and other forms of affective disorders[1,2,3]
We examined three main large-scale networks known to underlie a broad range of human emotional-cognitive operations: the default mode network (DMN), which is a network important in self-referential activities[24]; the salience network (SN), which is critical for emotional awareness; and the central executive network (CEN), a network associated with emotional regulation and top-down cognitive control of attention[24,25]
There were no significant differences in age, gender and neuropsychological scores between G-carrier and C-homozygote groups (Table 1)
Summary
5-Hydroxytryptamine (5-HT), more commonly known as serotonin, is the most widely distributed neurotransmitter in the brain, and dysfunctions of the serotonergic system are thought to be important factors for major depressive disorder and other forms of affective disorders[1,2,3]. Human positron emission tomography (PET) studies have demonstrated that the expression of autoreceptors is modulated by a 5-HT1A receptor gene C(−1019)G polymorphism, and, that the binding potential is increased with increasing frequency of the G allele[5,6] This is associated with increased negative feedback and, decreased serotonin signalling. An increase of FC in the cortex, hippocampus, amygdala and dorsomedial thalamus was observed after giving 5-HT1A receptor agonist, 8-OH-DPAT14 These brain areas are known to express high levels of the 5-HT1A receptor[15,16] and are involved in the frontal cortex-basal ganglia circuits that play critical roles in affective disorders[17]. We examined three main large-scale networks known to underlie a broad range of human emotional-cognitive operations: the DMN, which is a network important in self-referential activities[24]; the SN, which is critical for emotional awareness; and the CEN, a network associated with emotional regulation and top-down cognitive control of attention[24,25]
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