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Stress-Induced Pathophysiology 255Prefrontal CortexXCognitive responses to stressICMAutonomic responses to stressStriatumNTSAccumbensCingulate cortexPrefrontal cortexBLACeAHypothalarnusD. motor n. vagusBNSIParabrachial n.Locus coeruleusSeptal nucleusFigure 11-1 The basolateral amygdala (BLA) and central amygdala (CeA) are proposedto regulate different aspects of the stress response. The BLA exhibits ascending projectionsto areas involved in the cognitive responses to stress. In contrast, the CeA projectsto regions that are more typically involved in the autonomic responses to stress. It is proposedthat the prefrontal cortex, acting via the inhibitory intercalated cell mass (ICM),will preferentially attenuate the CeA drive of autonomic systems, thereby preventing pathologicalconsequences from maintained increased autonomic drive.Based on these evidences, we proposed a model to account for why deficitsthat are present soon after birth do not lead to schizophrenia symptomatology untillate adolescence or early adulthood (Grace, 2004; Thompson et al., 2004). In thismodel, we proposed that an underlying deficit in prefrontal cortical function inadolescence makes the individual more susceptible to the deleterious influencesof stress. Therefore, the onset of schizophrenia, as outlined above, is due to two“hits:” a potentially genetically determined pathology within the prefrontal cortexthat leads to abnormal reactivity to stressors combined with a stressful environmentduring childhood. The central component of this model is the abnormalregulation of stress responses leading to activation of a positive feedback loop(figure 11-2). Thus, in a susceptible individual, the prefrontal cortex would beincapable of providing the normal suppressive influence over subcortical reactivityacross a number of circuits. We have proposed previously that the abnormallyheightened response of the dopamine system in the ventral striatum (Laruelle,1998) occurs secondary to a deficit in prefrontal cortical modulation of this system(Grace, 1991). This uncontrolled dopaminergic reactivity in itself is likely tobe highly stressful to the patient. In addition, a deficit in prefrontal cortical functionwould also attenuate the ability of the prefrontal cortex to modulate activationof the amygdala. The increase in amygdala responsivity, and consequentlyan amygdala-mediated activation of the locus coeruleus (Ramsooksingh et al.,2004), would also exacerbate the response to stress. The consequence is that there