145 Indeed, CRH has been found to be elevated in cerebrospinal fluid of PSTD patients.147,148 PTSD patients have normal resting (nonprovoked) Akt inhibitor levels of amygdala activity, but the amygdala is highly responsive to anxiety

provocation.149-152 While most of these studies do not demonstrate an abnormal response of the amygdala per se, particularly because normal humans Inhibitors,research,lifescience,medical also demonstrate increased amygdala activity to fearful or aversive stimuli (however, they do suggest that the amygdala has a lower threshold for responding to fearful stimuli in anxiety disorder patients).153 While focus here has been on the amygdala and, to a lesser extent, on the BNST, a fundamental part of fear circuitry is the prefrontal cortex (eg, refs 27,154,155). The medial prefrontal cortex (mPFC), for example, plays a role in inhibition of fear responses and extinction.154,156 There is evidence that regions of the prefrontal cortex regulate glucocorticoid responses to duress.157-159 The prefrontal cortex has Inhibitors,research,lifescience,medical relatively dense expression of glucocorticoid receptors in most regions, including the infralimbic cortical areas and CRH neurons are also located in most regions of the

prefrontal cortex,49,50 Rosen and Schulkin, unpublished Inhibitors,research,lifescience,medical data. Chronic glucocorticoid treatment has been shown to alter apical dendrites of medial prefrontal neurons.137 Conclusions Although the amygdala has been known to be involved in the emotion of fear since the seminal studies of Kluver and Bucy160 showed a taming effect of amygdala lesions Inhibitors,research,lifescience,medical in monkeys, research in the last two decades has produced great advances in determining the neuroanatomy of fear circuits. Not only has the amygdala been found to be critical for many types of fear, but fear circuits that connect the amygdala to many other brain regions

Inhibitors,research,lifescience,medical have been described, which suggests that these circuits have evolved to function as neurobehavioral systems for particular kinds of cognitive and behavioral strategies. Understanding the neural circuitry that underlies fear/anxiety leads one to be in a better position for clinical judgment about treatment for states such anxious depression. Normal fear is an adaptation to danger; chronic anxiety and depression are the overexpression 3-mercaptopyruvate sulfurtransferase of the neural systems involved in adaptation to danger. Coping with anxious depression is metabolically expensive; expectations of adversity predominate. Moreover, anxious depression is a condition in which there can be both high systemic Cortisol and elevated CRH in the cerebrospinal fluid118,125,161,162 Anxious depressed patients also tend to have increased glucose metabolic rates in the amygdala.118,134 The Cortisol that regulates CRH gene expression in the amygdala may underlie the fear and anxiety of the anxiously depressed person.