Locus Coeruleus-Amygdala Circuit Disrupts Prefrontal Control to Impair Fear Extinction

BackgroundStress undermines extinction learning and hinders exposure-based clinical therapies for a variety of neuropsychiatric disorders. In both animals and humans, dysfunction in the ventromedial prefrontal cortex (vmPFC) contributes to stress-impaired extinction, but the neural circuit by which stress modulates vmPFC function is not known. We hypothesize that the locus coeruleus (norepinephrine system (LC-NE) undermines extinction learning by recruiting projections from the basolateral amygdala (BLA) to vmPFC. MethodsWe combined chemogenetics, calcium imaging, and fiber photometry to examine how the LC-NE system influences fear extinction, with special interest to LC[->]BLA projections. We infused viral vectors into the LC, BLA, and ventromedial prefrontal cortex (vmPFC) to express designer receptors (hM3Dq) or calcium indicators (GCaMP). The LC was globally or selectively (LC[->]BLA projections) stimulated, while vmPFC and BLA activity was monitored during different stages of memory processing. Intra-BLA propranolol infusions were used to block {beta}-adrenergic receptors to test their role in LC-driven effects. ResultsWe found that chemogenetic activation of the LC increased freezing behavior, suppressed vmPFC neuronal activity, and mimicked the effects of footshock. LC stimulation impaired both delayed and immediate extinction learning, while activation of the LC[->]BLA pathway alone was sufficient to drive the immediate extinction deficit. LC activation increased activity in BLA neurons projecting to vmPFC, and this effect, as well as vmPFC suppression, was prevented by {beta}-adrenergic blockade with propranolol in the BLA. Overall, LC-driven NE release in the BLA disrupted vmPFC activity and dynamics, promoted a high-stress stated and impaired fear extinction. ConclusionThis study demonstrates that stress and LC activation promote NE release in the BLA, which disrupts vmPFC activity and impairs fear extinction. These findings identify the LC-BLA-vmPFC circuit as a key pathway through which stress undermines extinction learning, highlighting BLA {beta}-adrenergic receptors as potential therapeutic targets for stress-related disorders like PTSD.