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Background: Children exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit., Methods: Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT's molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n = 3) and tract-tracing (n = 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts., Results: We found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis., Conclusions: These findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region., Methods: Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions., Results: Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity., Conclusions: This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Hunger enhances sensitivity to reward, yet individuals with anorexia nervosa (AN) are not motivated to eat when starved. This study investigated brain response to rewards during hunger and satiated states to examine whether diminished response to reward could underlie food restriction in AN., Methods: Using a delay discounting monetary decision task known to discriminate brain regions contributing to processing of immediate rewards and cognitive control important for decision making regarding future rewards, we compared 23 women remitted from AN (RAN group; to reduce the confounding effects of starvation) with 17 healthy comparison women (CW group). Monetary rewards were used because the rewarding value of food may be confounded by anxiety in AN., Results: Interactions of Group (RAN, CW) × Visit (hunger, satiety) revealed that, for the CW group, hunger significantly increased activation in reward salience circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during processing of immediate reward, whereas satiety increased activation in cognitive control circuitry (ventrolateral prefrontal cortex, insula) during decision making. In contrast, brain response in reward and cognitive neurocircuitry did not differ during hunger and satiety in the RAN group. A main effect of group revealed elevated response in the middle frontal gyrus for the RAN group compared with the CW group., Conclusions: Women remitted from AN failed to increase activation of reward valuation circuitry when hungry and showed elevated response in cognitive control circuitry independent of metabolic state. Decreased sensitivity to the motivational drive of hunger may explain the ability of individuals with AN to restrict food when emaciated. Difficulties in valuating emotional salience may contribute to inabilities to appreciate the risks inherent in this disorder., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The serotonin transporter 5-HTT mediates responses to serotonin reuptake inhibitors (SSRIs), a mainstay treatment in mood disorders. The amygdala, a key emotional processing center, has functional abnormalities in mood disorders, which resolve following successful SSRI treatment. To better understand the effects of SSRIs in mood disorders, we examined the distribution of 5-HTT labeled fibers relative to specific nuclear groups in the amygdala., Methods: Immunocytochemical techniques were used to chart 5-HTT labeled fibers in the amygdala in coronal sections through the brain of six adult Macaques. Nissl staining was used to define nuclear groups in the amygdala., Results: The serotonin transporter 5-HTT is distributed heterogeneously in the primate amygdala, with the lateral subdivision of the central nucleus, intercalated cell islands, amygdalohippocampal area, and the paralaminar nucleus showing the heaviest concentrations., Conclusions: 5HTT-labeled fibers are very densely concentrated in output regions of the amygdala. High concentrations of 5-HTT-positive fibers in the central nucleus indicate that tight regulation of serotonin is critical in modulating fear responses mediated by this nucleus. High concentrations of 5-HTT-labeled fibers in the intercalated islands and parvicellular basal nucleus/paralaminar nucleus, which contain immature -appearing neurons, suggest a potential trophic role for serotonin in these subregions.