Previous work demonstrates that early life stress (ELS) and HPA-axis function predict later psychopathology. Animal work and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortical (vmPFC) circuitry implicated in emotion regulation. The current study prospectively investigated the roles of ELS and childhood basal cortisol in the development of adolescent resting-state functional connectivity (fcMRI) in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which, in turn, predicted decreased amygdala-vmPFC fcMRI 14 years later. Further, for females, amygdala-vmPFC fcMRI was inversely correlated with concurrent anxious symptoms, but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli 1–4. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression, and comorbid substance abuse 5. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we performed a study in a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution 18F-deoxyglucose positron emission tomography (FDG-PET) was selected as the imaging modality since it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited to assess temperament-associated sustained brain responses. Results demonstrated that the central nucleus region of amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. Quantitative genetic analysis demonstrated significant heritability of the AT phenotype. Additionally, a voxelwise analysis revealed significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT was not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differed from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk to develop anxiety and depression.

The central extended amygdala is an evolutionarily conserved set of interconnected brain regions that play an important role in threat processing to promote survival. Two core components of the central extended amygdala, the central nucleus of the amygdala (Ce) and the lateral bed nucleus of the stria terminalis (BST) are highly similar regions that serve complimentary roles by integrating fear- and anxiety-relevant information. Survival depends on the central extended amygdala's ability to rapidly integrate and respond to threats that vary in their immediacy, proximity, and characteristics. Future studies will benefit from understanding alterations in central extended amygdala function in relation to stress-related psychopathology.

Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism-not brain structure-that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.anxiety | primate | heritability | positron emission tomography | brain volume P arents with anxiety and depressive disorders are considerably more likely to have children with an extremely anxious temperament (AT) (1-3). Extreme-AT children have heightened behavioral and physiological reactivity to potential threat and have a markedly increased risk to develop anxiety and depressive disorders (4, 5). These disorders emerge as inborn tendencies and environmental factors converge to disrupt the neural systems that mediate adaptive anxiety; as many as 50% of children with extreme-AT develop a psychiatric disorder (6). In addition to environmental influences that facilitate the cross-generational transfer of psychopathology (e.g., parent-child interactions), genetic variance accounts for ∼35% of the likelihood that a child will develop an anxiety disorder (7, 8) The neural substrates of AT are distributed throughout the brain and range from primitive brainstem structures to primate-specific cortical subfields. Multiple brain regions causally contribute to AT, and damage to any one of these regions is sufficient to decrease, although not abolish, anxiety (9-14). Thus, the inherited risk to develop stressrelated psychopathology likely manifests via its effects on multiple components of the neural circuit underlying AT. Here we use a genetic correlation approach to identify brain regions where function and structure contribute to the intergenerational transmission of AT. Genetic correlation analyses are crucial for identifying regions that are likely to mediate the genetic contributions to AT, and to distinguish them from regions that, although heritable, rely on an independent set of genetic variations.The recent evolutionary divergence of humans and rhesus monkeys is reflected in their shared capacity for higher-order cognition, complex social behavior, and homologous neural circuits, which make the young rhesus monkey an ideal mode...

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression, and substance abuse. These disorders are highly prevalent, debilitating, and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central nucleus (Ce) of the amygdala is an important substrate. While it is widely believed that the flow of information across the structural network connecting the Ce to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily-conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex (dlPFC), a region thought to play a central role in the control of cognition and emotion, and the Ce was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provided evidence that elevated Ce metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.