FIGURE 1.

Stress-integrative circuitry intact and adaptive. Under normal physiological conditions, the HPA axis is regulated by negative feedback (A). The activation of the HPA axis and subsequent synthesis and release of glucocorticoids from the adrenal glands feed back onto anatomical substrates such as the PVN and mPFC to terminate the stress response. Peripheral, acute CRF signaling and response by the CRF Receptor 1 on immune cells suppress the immune response. In parallel, negative feedback mechanisms of the central stress-integrative circuitry are intact and allow for adaptive responses to stressful stimuli. Under acute stress, FAAH activity is upregulated and AEA levels are decreased, enabling the activation of the HPA axis (Hill et al., 2009). The transient stress induced AEA levels in the amygdala plays an important role in balancing AEA signaling (Hill et al., 2010), and suggests that AEA tonically inhibits BLA activity in the absence of stressors (Hill et al., 2011a). Based on a series of neuroanatomical and biochemical experiments, we have put forth the idea that CB₁r is strategically localized to presynaptic terminals of CRF-containing neurons that arise in the amygdala as a mechanism of regulating input from the amygdala to the LC. The peri-LC contains a majority of excitatory synapses, while the core LC possesses mostly inhibitory synapses. This supports the idea that amygdalar CRF afferents are modulated by the eCB system to adapt to emotional stimuli during the stress response (B).