S on other brain regions and anxious temperament. FDG was injected into lesioned and control animals both before and after the lesions, and differences in brain activity during the NEC condition were compared. Consistent with previous lesion studies, OFC lesions produced significant decreases in freezing. OFC lesions also resulted in less activation in the bed nucleus of the stria teminalis (BNST), part of the “extended amygdala” that plays a critical role in anxiety (Davis et al., 1997; Walker and Davis, 2008). Importantly, BNST activation was also correlated with freezing during the NEC condition, providing a link between brain activity and behavior. OFC lesions also produced increased activation in other brain regions–including the parietal cortex, midcingulate cortex, and motor cortex– suggesting that these regions may be part of a more complex HMPL-013MedChemExpress Fruquintinib circuit underlying behavior during the NEC condition. This study provides the first evidence for the BNST involvement in anxious temperament and suggests that a broader neural circuit, including the OFC and BNST, may mediate anxious temperament. Based on neuroimaging studies in large samples of non-human primates, anxious temperament broadly is associated with activity in the amygdala, hippocampus, BNST, and brainstem. Cortisol reactivity may be mediated by activity in the anterior Lixisenatide web hippocampus and freezing behavior may be mediated by the amygdala, BNST, and motor cortex. There are some inconsistencies in findings between lesion studies and neuroimaging studies in nonhuman primates, such as the role of the hippocampus in cortisol reactivity. These inconsistencies may be because neuroimaging studies are more specific and can pinpoint activity in a particular subregion of a brain region, whereas lesion studies typically encompass the entire region, which may have mixed effects. Additionally, anxious temperament is a complex phenotype based on three individual components–freezing, cortisol, and cooing–which is likely mediated by a network of brain regions, rather than a single brain region. 2.8. Rodent Models of Inhibited Temperament Several rodent models of inhibited temperament have been developed and have been used to replicate behavioral and physiological findings in humans (for a review on the Wistar Kyoto rat model of inhibited temperament, see: Jiao et al., 2011a, pp. 95?10). Individual differences in rodent inhibited temperament can be elicited by exposing rats to a novel environment (Cavigelli and McClintock, 2003) or to a natural predator (i.e., ferret; Qi et al., 2010). Inhibited temperament in rodent models is stable over time and has been associated with increased anxiety-like behavior throughout development and increased corticosterone response to novelty (Cavigelli and McClintock, 2003; Clinton et al., 2011; Jiao et al., 2011b; Qi et al., 2010). Similar to findings in humans with anxiety disorders, inhibited rats exhibit alterations in avoidance learning. During avoidance learning, more inhibited rats had less activation of the medial prefrontal cortex, but no differences in amygdala activation (Perrotti et al., 2013). Inhibited behaviors in rats can be reduced by diazepam administration, a common treatment for anxiety in humans, (Qi et al., 2010). In rats, inhibited temperament was associated with increased immediate early gene expression in the hippocampus and hypothalamus in response to a predator threat, but not in the amygdala (Qi et al., 2010). Additionally, inhibited tem.S on other brain regions and anxious temperament. FDG was injected into lesioned and control animals both before and after the lesions, and differences in brain activity during the NEC condition were compared. Consistent with previous lesion studies, OFC lesions produced significant decreases in freezing. OFC lesions also resulted in less activation in the bed nucleus of the stria teminalis (BNST), part of the “extended amygdala” that plays a critical role in anxiety (Davis et al., 1997; Walker and Davis, 2008). Importantly, BNST activation was also correlated with freezing during the NEC condition, providing a link between brain activity and behavior. OFC lesions also produced increased activation in other brain regions–including the parietal cortex, midcingulate cortex, and motor cortex– suggesting that these regions may be part of a more complex circuit underlying behavior during the NEC condition. This study provides the first evidence for the BNST involvement in anxious temperament and suggests that a broader neural circuit, including the OFC and BNST, may mediate anxious temperament. Based on neuroimaging studies in large samples of non-human primates, anxious temperament broadly is associated with activity in the amygdala, hippocampus, BNST, and brainstem. Cortisol reactivity may be mediated by activity in the anterior hippocampus and freezing behavior may be mediated by the amygdala, BNST, and motor cortex. There are some inconsistencies in findings between lesion studies and neuroimaging studies in nonhuman primates, such as the role of the hippocampus in cortisol reactivity. These inconsistencies may be because neuroimaging studies are more specific and can pinpoint activity in a particular subregion of a brain region, whereas lesion studies typically encompass the entire region, which may have mixed effects. Additionally, anxious temperament is a complex phenotype based on three individual components–freezing, cortisol, and cooing–which is likely mediated by a network of brain regions, rather than a single brain region. 2.8. Rodent Models of Inhibited Temperament Several rodent models of inhibited temperament have been developed and have been used to replicate behavioral and physiological findings in humans (for a review on the Wistar Kyoto rat model of inhibited temperament, see: Jiao et al., 2011a, pp. 95?10). Individual differences in rodent inhibited temperament can be elicited by exposing rats to a novel environment (Cavigelli and McClintock, 2003) or to a natural predator (i.e., ferret; Qi et al., 2010). Inhibited temperament in rodent models is stable over time and has been associated with increased anxiety-like behavior throughout development and increased corticosterone response to novelty (Cavigelli and McClintock, 2003; Clinton et al., 2011; Jiao et al., 2011b; Qi et al., 2010). Similar to findings in humans with anxiety disorders, inhibited rats exhibit alterations in avoidance learning. During avoidance learning, more inhibited rats had less activation of the medial prefrontal cortex, but no differences in amygdala activation (Perrotti et al., 2013). Inhibited behaviors in rats can be reduced by diazepam administration, a common treatment for anxiety in humans, (Qi et al., 2010). In rats, inhibited temperament was associated with increased immediate early gene expression in the hippocampus and hypothalamus in response to a predator threat, but not in the amygdala (Qi et al., 2010). Additionally, inhibited tem.