FIGURE 2.

Allostatic overload renders stress-responsive circuits vulnerable to neuronal injury and degeneration. During states of chronic or pathological stress, the HPA axis, LC, and associated stress integrative circuitry no longer respond to negative feedback inhibition, resulting in aberrant, unregulated, activity of the entire system (B). Chronic stress related psychiatric behavioral symptoms are the result of complex, between- and within- network adaptations. While large-scale cortical networks become less intrinsically connected, and the microcircuitry that comprise them retract in dendritic density and complexity, there is correspondingly less top-down regulation of limbic circuitry. GABA-ergic interneurons of the BLA are disinhibited by decreased cortical input, leading to greater activity in limbic regions such as the central nucleus of the amygdala (CeA). Further shifts away from cortical control and toward limbic control occur as CeA afferents release increasing amounts of CRF in high frequency onto locus coeruleus (LC) neurons, rendering them more susceptible to stress-related excitotoxicity. A predominance of CB₁r are found on cholecystokin (CCK)-positive GABAergic interneurons in the BLA. The inhibition of the BLA via CCK-positive GABAergic interneurons may be able to restore homeostatic LC tone by inhibiting CeA projections to the LC. In effect, this would silence HPA hyperactivation and halt the propagation of BLA excitability in a state of allostatic overload (A).