Trait Anxiety Mediated by Amygdala Serotonin Transporter in the Common Marmoset.

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.

Trajectories and Milestones of Cortical and Subcortical Development of the Marmoset Brain From Infancy to Adulthood.

With increasing attention on the developmental causes of neuropsychiatric disorders, appropriate animal models are crucial to identifying causes and assessing potential interventions. The common marmoset is an ideal model as it has sophisticated social/emotional behavior, reaching adulthood within 2 years of birth. Magnetic resonance imaging was used in an accelerated longitudinal cohort (n = 41; aged 3-27 months; scanned 2-7 times over 2 years). Splines were used to model nonlinear trajectories of grey matter volume development in 53 cortical areas and 16 subcortical nuclei. Generally, volumes increased before puberty, peaked, and declined into adulthood. We identified 3 milestones of grey matter development: I) age at peak volume; II) age at onset of volume decline; and III) age at maximum rate of volume decline. These milestones differentiated growth trajectories of primary sensory/motor cortical areas from those of association cortex but also revealed distinct trajectories between association cortices. Cluster analysis of trajectories showed that prefrontal cortex was the most heterogenous of association regions, comprising areas with distinct milestones and developmental trajectories. These results highlight the potential of high-field structural MRI to define the dynamics of primate brain development and importantly to identify when specific prefrontal circuits may be most vulnerable to environmental impact.