No abstract

Genetic polymorphisms in the repeat upstream region of the serotonin transporter gene (SLC6A4) are associated with individual differences in stress reactivity, vulnerability to affective disorders, and response to pharmacotherapy. However, the molecular, neurodevelopmental and psychopharmacological mechanisms underlying the link between SLC6A4 polymorphisms and the emotionally vulnerable phenotype are not fully understood. Thus, using the marmoset monkey Callithrix jacchus we characterize here a new neurobiological model to help to address these questions. We first sequenced the marmoset SLC6A4 promoter and identified a double nucleotide polymorphism (−2053AC/CT) and two single-nucleotide polymorphisms (−2022C/T and −1592G/C) within the repeat upstream region. We showed their association with gene expression using in vivo quantitative PCR and with affective behavior using a primate test of anxiety (human intruder test). The low-expressing haplotype (AC/C/G) was linked with high anxiety while the high-expressing one (CT/T/C) was associated with an active coping strategy in response to threat. Pharmacological challenge with an acute dose of the selective serotonin reuptake inhibitor, citalopram, revealed a genotype-dependent behavioral response. While individuals homozygous for the high anxiety-related haplotype AC/C/G exhibited a dose-dependent, anxiogenic response, individuals homozygous for the low anxiety-related haplotype CT/T/C showed an opposing, dose-dependent anxiolytic effect. These findings provide a novel genetic and behavioral primate model to study the molecular, neurodevelopmental, and psychopharmacological mechanisms that underlie genetic variation-associated complex behaviors, with specific implications for the understanding of normal and abnormal serotonin actions and the development of personalized pharmacological treatments for psychiatric disorders.

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.

High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper-vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry.

Fear and anxiety are adaptive responses but if left unregulated, or inappropriately regulated, they become biologically and socially maladaptive. Dysregulated emotions are manifest in a wide variety of psychiatric and neurological conditions but the external expression gives little indication of the underlying causes, which are inevitably multi-determined. To go beyond the overt phenotype and begin to understand the causal mechanisms leading to conditions characterized by anxiety and disorders of mood, it is necessary to identify the base psychological processes that have become dysregulated, and map them on to their associated neural substrates. So far, attention has been focused primarily on the medial regions of prefrontal cortex (PFC) and in particular their contribution to the expression and extinction of conditioned fear. However, functional neuroimaging studies have shown that the sphere of influence within the PFC is not restricted to its medial regions, but extends into dorsal, ventrolateral (vlPFC) and orbitofrontal (OFC) regions too; although the causal role of these other areas in the regulation of fear and anxiety remains to be determined and in the case of the OFC, existing findings are conflicting. Here, we review the evidence for the contribution of these other regions in negative emotion regulation in rodents and old world and new world monkeys. We consider a variety of different contexts, including conditioned and innate fear, learned and unlearned anxiety and cost-benefit decision-making, and a range of physiological and behavioral measures of emotion. It is proposed that both the OFC and vlPFC contribute to emotion regulation via their involvement, respectively, in the prediction of future outcomes and higher-order attentional control. The fractionation of these neurocognitive and neurobehavioral systems that regulate fear and anxiety opens up new opportunities for diagnostic stratification and personalized treatment strategies.