Intergenerational neural mediators of early-life anxious temperament

Abstract

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...

Cross-generational influences on childhood anxiety disorders: pathways and mechanisms

“…Notably, the offspring of those rats also showed significantly increased BDNF methylation, illustrating the perpetuation of the negative effects of stress across generations. Studies in primates have also clearly documented that variations in patterns of maternal rearing can lead to distinct epigenetic signatures that effect how an individual’s DNA is read in specific brain regions compared to DNA present in blood cells (Fox et al 2015; Provencal et al 2012). Given the spatial and temporal complexity of gene expression during early human brain development (Kang et al 2011), it is clear that maternal stress during pregnancy and beyond can have intergenerational consequences.…”

Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit

“…This trait-like disposition, termed anxious temperament (AT), is a prominent childhood risk factor for the later development of anxiety disorders, depression, and comorbid substance abuse (17–21). With our nonhuman primate model, we identified the altered neural circuitry that underlies the development of AT and found that it is similar to that observed in humans with anxiety disorders (3, 8, 10, 22). This neural systems level information provides the critical groundwork for directly testing regionally specific molecular hypotheses potentially important in the pathophysiology of AT.…”

“…The findings regarding the OPro/AI region may be particularly relevant as this region of the prefrontal cortex is highly connected with the amygdala (87). We recently demonstrated in a sample of 592 young rhesus monkeys that NEC-related glucose metabolism in the OPro/AI region (along with the bed nucleus of the stria terminalis (BST) and the periaqueductal gray (PAG)) correlated with AT and was heritable (10). Importantly, brain metabolism in these regions was also genetically correlated with AT, which implies the involvement of similar genes in mediating AT and altered brain function in OPro/AI, BST, and PAG.…”

“…By combining measures of threat-related behavioral inhibition (increased freezing and decreased vocalizations) and pituitary-adrenal activation (threat-induced cortisol), along with 18 fluoro-deoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we characterized a nonhuman primate developmental model of AT (6, 14). Although the AT neural circuit is distributed across prefrontal, limbic, and brain-stem regions, neuroimaging studies in monkeys and humans point to the dorsal amygdala, a region containing the central nucleus of the amygdala (Ce), as a fundamental component of the circuit (8, 10, 11) (see Figure 1). The Ce is of particular interest because it is the major outflow region of the amygdala with its downstream projections mediating the hypothalamic and brainstem contributions to the stress response (24, 25).…”

Intergenerational Neuroimaging of Human Brain Circuitry

“…Similarly, Fox et al . measured FDG-PET and behavioral responses during a well-standardized task of threat processing in a large familial sample of preadolescent rhesus monkeys [9]. The authors computed heritability of brain metabolism, heritability of a behavioral anxiety phenotype, and the bivariate heritability of both phenotypes, then conducted voxelwise bivariate genetic correlations , and found strong associations between metabolism in a prefrontal-limbic-midbrain circuit and anxious behavior.…”