Binette, A. | Search bioRxiv

bioRxiv2025

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.

neuroscience↗

bioRxiv2022

Sex differences in the immediate extinction deficit and renewal of extinguished fear in rats

Extinction learning is central to exposure-based behavioral therapies for reducing fear and anxiety in humans. However, patients with fear and anxiety disorders are often resistant to extinction. Moreover, trauma and stress-related disorders are highly prone to relapse and are twice as likely to occur in females compared to males, suggesting that females may be more susceptible to extinction deficits and fear relapse phenomena. In this report, we tested this hypothesis by examining sex differences in a stress-induced extinction learning impairment, the immediate extinction deficit (IED), and renewal, a common form of fear relapse. In contrast to our hypothesis, there were no sex differences in the magnitude of the immediate extinction deficit in two different rat strains (Long-Evans and Wistar). However, we did observe a sex difference in the renewal of fear when the extinguished conditioned stimulus was presented outside the extinction context. Male Wistar rats exhibited significantly greater renewal than female rats, a sex difference that has previously been reported after appetitive extinction. Collectively, these data reveal that stress-induced extinction impairments are similar in male and female rats, though the context-dependence of extinction is more pronounced in males.

animal behavior and cognition↗