Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK −/− mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. Highfrequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after lowfrequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory. cholecystokinin | NMDA receptor | long-term potentiation | memory | entorhinal cortex M emory is stored in neural networks through changes in synaptic strength (1). Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity that are believed to represent a neural basis of memory in different brain regions (2-5). The major form of LTP in the hippocampus and neocortex is induced through theta burst stimulation or highfrequency stimulation (HFS) (2, 3). Previous studies have shown that NMDA receptors (NMDARs) play a crucial role in HFSinduced LTP in the hippocampus (6-9) and neocortex (2, 10), and in the formation and consolidation of associative memory (11,12).Serving as the gateway from the hippocampus to the neocortex, the entorhinal cortex forms strong reciprocal connections with the neocortex (13, 14) and shows extensive cholecystokinin (CCK) labeling (15-17) with projections to neocortical areas, including the auditory cortex (13,14,18). CCK is the most abundant cortical neuropeptide (19), and mice lacking the CCK gene exhibit poor performance in a passive avoidance task and display impaired spatial memory (20). Although many studies have focused on GABAergic CCK neurons (21-24), many glutamatergic neurons in the neocortex express CCK (25, 26). We previously found that local infusion of CCK into the auditory cortex of anesthetized rats induces plastic changes that enable auditory cortical neurons to start responding to a light stimulus after its pairing with an auditory stimulus (18). Activation of the entorhinal cortex potentiates neuronal responses in the auditory cortex, and this effect is suppressed by infusion of a CCK-B receptor (CCKBR) antagonist (18), suggesting that the entorhinal cortex enables neocortical plasticity via CCK-containing neurons projecting to the neocortex.If CCK enables cortical neuroplasticity and associative memory formation, then we would expect CCK-induced neuroplasticity to affect LTP. The release of neuropeptides occurs slowly in response to repetitive firing (27,28)....

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.

Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.

Depression is a common mental disorder. Evidence suggested a substantial causal relationship between stressful life events and the onset of episodes of major depression. Here, we investigated how CCK and CCKBR in the basolateral amygdala (BLA) are implicated in stress-mediated depressive-like behavior. The BLA mediates emotionally charged memory and long-term potentiation (LTP) is a trace of memory. Cholecystokinin knockout (CCK-KO) mice lacked LTP in the BLA; while the application of CCK4 induced LTP after low-frequency stimulation (LFS). Optogenetic activation of CCK fibers from the entorhinal cortex (EC) to BLA promoted stress susceptibility. CCK-B receptor knockout (CCKBR-KO) mice showed LTP deficits in the BLA; CCKBR antagonists blocked high-frequency stimulation (HFS) induced LTP in the BLA. CCK-KO and CCKBR-KO mice showed significantly lower levels of depression-related behaviors than wild-type control mice. Notably, CCKBR antagonists displayed a reduction in depressive-like behaviors in the acute tail suspension test (TST) and open field test (OFT), chronic social defeat stress (CSDS) model of mice. Together, these results indicate that CCKBR is a potential target to treat depression.

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