"This finding is very important as it focuses our thinking about treatment on promoting recovery after stress rather than suppressing the normal adaptive reaction to threatening situations. Fear, at times, is the best possible reaction to life events. However, persistent fear can be destructive. This new finding points us in the direction of new treatments that aim to promote resilience rather than blunting one's life experiences," said Dr. John Krystal, Editor of Biological Psychiatry. The authors agree, with first author Dr. Patrick Roseboom noting that "extreme anxiety in children is a prominent predictor of the later development of anxiety disorders and other illnesses such as depression and substance abuse. Using young rhesus monkeys in our model of anxious temperament is critical as brain structure and function in non-human primates closely resembles that of humans."

Background: Anxious temperament (AT) is identifiable early in life and predicts the later development of anxiety disorders and depression. Neuropeptide Y (NPY) is a putative endogenous anxiolytic neurotransmitter that adaptively regulates responses to stress and might confer resilience to stress-related psychopathology. With a well-validated nonhuman primate model of AT, we examined expression of the NPY system in the central nucleus (Ce) of the amygdala, a critical neural substrate for extreme anxiety.Methods: In 24 young rhesus monkeys, we measured Ce messenger RNA (mRNA) levels of all members of the NPY system that are detectable in the Ce with quantitative real time polymerase chain reaction. We then examined the relationship between these mRNA levels and both AT expression and brain metabolism.Results: Lower mRNA levels of neuropeptide Y receptor 1 (NPY1R) and NPY5R but not NPY or NPY2R in the Ce predicted elevated AT; mRNA levels for NPY1R and NPY5R in the motor cortex were not related to AT. In situ hybridization analysis provided for the first time a detailed description of NPY1R and NPY5R mRNA distribution in the rhesus amygdala and associated regions. Lastly, mRNA levels for these two receptors in the Ce predicted metabolic activity in several regions that have the capacity to regulate the Ce.Conclusions: Decreased NPY signaling in the Ce might contribute to the altered metabolic activity that is a component of the neural substrate underlying AT. This suggests that enhancement of NPY signaling might reduce the risk to develop psychopathology.

Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, children who display extreme BI as a stable trait are at risk for development of anxiety disorders and depression. The present study validates a rodent model of BI based on an ethologically relevant predator exposure paradigm. We show that individual differences in rat BI are stable and trait‐like from adolescence into adulthood. Using in situ hybridization to quantify expression of the immediate early genes homer1a and fos as measures of neuronal activation, we show that individual differences in BI are correlated with the activation of various stress‐responsive brain regions that include the paraventricular nucleus of the hypothalamus and CA3 region of the hippocampus. Further supporting the concept that threat‐induced BI in rodents reflects levels of anxiety, we also show that BI is decreased by administration of the anxiolytic, diazepam. Finally, we developed criteria for identifying extreme BI animals that are stable in their expression of high levels of BI and also show that high BI (HBI) individuals exhibit maladaptive appetitive responses following stress exposure. These findings support the use of predator threat as a stimulus and HBI rats as a model to study mechanisms underlying extreme and stable BI in humans.

Behavioral inhibition (BI) is an adaptive defensive response to threat that has been evolutionarily conserved. Extreme BI in childhood is a temperamental disposition for the development of psychopathology. Our goal was to develop a rodent model of BI that is elicited by predator exposure. The ferret exposure test consists of placing a rat in a housing cage in the ferret colony room for 15 min and rating behavior for BI. We show that predator‐induced BI is stable across development when measured in rats (n = 37) in adolescence and again in adulthood (r = 0.475, p < 0.01). BI is reduced by the anxiolytic diazepam (1 mg/kg, 30 min pretreatment; n = 8/group; p < 0.05), and BI is associated with heightened paraventricular nucleus of the hypothalamus (PVN) and CA3 activity as measured by expression of the immediate early gene homer1a (r = 0.379, p < 0.05; r = 0.309, p < 0.05 respectively). Finally, we show that rats with high levels of BI display disruptions in appetitive behavior as a consequence of prior threat exposure compared to rats with low levels of BI (p < 0.001, n = 7 and 8). Taken together, these findings show that rodent BI is a stable, trait‐like characteristic that is associated with maladaptive responding. This model can be useful in identifying the molecular underpinnings for the childhood risk to develop psychiatric illness. This work was supported by NIH grant MH43454, Meriter Hospital and UW HealthEmotions Research Institute.

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, extreme BI is associated with anxiety-related psychopathology. When rats are exposed to a natural predator they display stress- and anxiety-related behavioral alterations and physiological activation. To develop a preclinical rodent model to study mechanisms underlying human BI and anxiety, we examined the extent to which ferret exposure elicits anxiety-related BI and HPA and amygdala activation of the CRF system. In the first experiment, BI and other behaviors were assessed in the presence or absence of a ferret. In the second experiment, ferret-induced corticosterone release and changes in brain c-fos expression were assessed. In the final experiment, gene chip and quantitative real time-PCR analyses were performed on amygdala tissue from control and ferret-exposed rats. Ferret exposure increased BI and submissive posturing, as well as plasma corticosterone and the number of Fos-positive cells in several brain regions including the amygdala. Gene expression analysis revealed increased amygdalar mRNA for CRF-binding protein, but not the CRF1 receptor, CRF2 receptor or CRF. In rodents, ferret exposure can be used to elicit anxiety-related BI, which is associated with HPA and amygdala activation. Since the amygdala and the CRF system have been implicated in adaptive and maladaptive anxiety responses in humans, these data support use of our rodent model to further investigate mechanisms underlying anxiety-related psychopathology in humans.