Orexins Regulate Fear Through Type 1 Receptors on Excitatory Neurons in the Basolateral Amygdala
The inability to extinguish fear memories is tied to psychiatric dysfunction, like that observed in post-traumatic stress disorder (PTSD). Individuals with PTSD learn to associate non-threatening stimuli with fearful and traumatic events. Understanding the neurocircuitry involved in the consolidation, retrieval, and extinction of fear learning can direct therapeutic intervention in PTSD sufferers. Orexins are neuropeptides produced in the lateral/dorsomedial-perifornical hypothalamus (LH/DMH-PeF) and are associated with motivation and arousal. As neuromodulators, orexins target several brain areas eliciting cellular effects through two different receptors: type 1 (Orx1) and type 2 (Orx2). One target area for orexins is the amygdala, an important brain area for the formation and interpretation of emotional information. A subregion of the amygdala, the basolateral amygdala (BLA), undergoes molecular and cellular changes during fear learning events. In a preclinical mouse model, we conditioned test animals to associate a tone with intense social stress from a larger aggressive mouse. After two days of conditioning, we administered an Orx1 antagonist (SB-674042) bilaterally into the BLA of test mice before experiencing two more (days 3 and 4) fear conditioning sessions. On day 5, mice were tested for contextual and cued fear responses in the absence of a social aggressor. Acute administration of the Orx1 antagonist reduced both contextual and cued fear responses compared to vehicle-treated animals. Brain analyses identified high Orx1 mRNA levels in the DMH and BLA, and low levels in predominantly GABA-rich areas, like the intercalated cell regions of the amygdala. Further, glutamatergic (CAMKII+) projection neurons in the BLA were identified as expressing Orx1 receptors. Together, these results characterize a mechanism by which orexins regulate fear learning responses and offer insight into potential therapeutic inventions for disorders like PTSD by targeting Orx1 receptors.
Jacobs, Benjamin, "Orexins Regulate Fear Through Type 1 Receptors on Excitatory Neurons in the Basolateral Amygdala" (2020). IdeaFest. 137.