The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the mouse lateral amygdala via cholecystokinin

Abstract

Although fear memory formation is essential for survival and fear-related mental disorders, the neural circuitry and mechanism are incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory in mice. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. We adopted both loss-of-function and gain-of-function experiments to demonstrate that release of the cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons project from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of the auditory response in the LA and formation of trace fear memory. In summary, high-frequency activation of EC neurons triggers the release of CCK in their projection terminals in the LA, potentiating auditory response in LA neurons. The neural plasticity in the LA leads to trace fear memory formation.

Cholecystokinin B Receptor Antagonists for the Treatment of Depression via Blocking Long-term Potentiation in the Basolateral Amygdala

“…LFS induces long-term depression (LTD) when both the number of stimulation pulses (typically 900 pulses) and the current of stimulation are large (Collingridge, Peineau et al 2010). As previously reported, we concluded that HFS induced the release of CCK from the presynaptic terminals, leading to LTP in the neocortex and amygdala (Chen, Li et al 2019, Feng, Su et al 2021). We then hypothesize that the application of the CCKBR agonist (CCK4) induces LTP in the BLA even under the LFS paradigm.…”

“…The fear memory can be inactivated and reactivated by LTD and LTP (Nabavi, Fox et al 2014). Recently, we found that activating CCK-positive projection from the EC to LA by a high-frequency laser stimulation modulated the neuronal plasticity, and potentiated auditory response in LA neurons (Feng, Su et al 2021). We implanted an optical ber in the BLA after virus injection into the EC of CCK-Cre mice (AAV-EF1a-DIO-ChETA-EYFP in the experimental group, ChETA; AAV-EF1a-DIO-EYFP in the control group, EYFP; g. 2 a b).…”

“…CCK is the most abundant neuropeptide in the brain (REHFELD and JF 1978). Mice lacking the CCK gene exhibit poor performance in passive avoidance tasks and display impaired spatial (Lo, Samuelson et al 2008), associative and fear memories (Chen, Li et al 2019, Feng, Su et al 2021). The MTL sends a "plasticity-enabled" signal to the neocortex to switch on the encoding of new associations, evidence suggests that the plasticity-enabled signal is CCK from the EC (Chen, Guo et al 2013, Li, Yu et al 2014, Chen, Li et al 2019.…”

“…No LTP, the physiological trace of memory, was induced in the neocortex of CCK-KO mice, while it was readily induced in their wild-type control (Chen, Li et al 2019). The BLA mediates fear conditioning, and recent evidence implicates that the CCK projection neurons in the EC enable LTP and fear memory-encoding in the lateral amygdala (LA) using CCK as the chemical signal (Feng, Su et al 2021). CCKBR antagonist blocks thetaburst stimulation (TBS) induced LTP in the neocortex (Chen, Li et al 2019).…”

“…CCKBR antagonist blocks thetaburst stimulation (TBS) induced LTP in the neocortex (Chen, Li et al 2019). The amygdala shows abundant CCKBR expression (Honda, Wada et al 1993, Feng, Su et al 2021). We hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the BLA, enhancing the development of depression.…”