Noradrenergic Modulation of Stress-Induced Deficits in Fear Extinction
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Date
2019-06-04
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Abstract
Early intervention strategies (e.g., psychological debriefing and exposure therapy) are thought to rely on extinction-like mechanisms to reduce pathological fear. These therapies attempt to reduce or prevent the development of stress- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Despite this, disorders of fear and anxiety are prevalent in our society, due in part to a lack of empirically-driven treatment options. For example, both animal models and human data suggest early interventions after a traumatic event may actually undermine long-term recovery. In the laboratory, Pavlovian fear conditioning procedures in rats have provided fundamental knowledge regarding the brain circuits mediating learned fear. However, less is known about the mechanisms of extinction learning, a process intended to reduce conditional fear, which is highly sensitive to stress. We aimed to examine how stress, and the stress hormone norepinephrine, act to impair extinction learning. We show that fear conditioning produces rapid and sustained changes in both the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA) which impinges upon extinction learning when extinction training occurs soon after conditioning, a phenomenon called the immediate extinction deficit (IED). We demonstrate that this stress-induced suppression of mPFC and simultaneous excitation in the BLA soon after conditioning can be normalized with systemic propranolol, a betablocker. In addition, we further show that local application of propranolol into the BLA, but not the mPFC, enables extinction learning under stress, where it normally fails. We point to a role for the locus coeruleus norepinephrine system (LC-NE) using cell-specific manipulations to alter NE release. LC excitation paired with a weak footshocks mimics stronger footshock activation of BLA activity, which may lead to extinction deficits. Lastly, we demonstrate that the LC-NE system is also involved in fear relapse.
That is, LC excitation resulted in elevated conditioned fear responses to a previously extinguished cue. Overall, the data suggest a complex circuit in which LC-NE modulates both the mPFC and BLA to toggle high and low fear states. The LC-NE system represents a promising therapeutic target for individuals suffering from stressor-and trauma-related disorders.
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norepinephrine, fear extinction