Cortical HFS-induced neo-Hebbian local plasticity enhances efferent output signal and strengthens afferent input connectivity.

Abstract

High-frequency stimulation (HFS)-induced long-term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site, rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also non-specifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin (CCK) release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons, rather than solely at their projection terminals.Significance Statement This manuscript reveals that cortical HFS triggers the local release of CCK, a crucial neuromodulator for cortical plasticity, which is released at the HFS site from other cortical efferents rather than in a homosynaptic manner. Therefore, cortical HFS influences long-range cortical efferents through changes at the HFS location, not at the projection terminals. Additionally, the HFS-triggered locally released CCK strengthens long-range afferent synapses to the HFS site. This evidence suggests that a CCK-dependent neo-Hebbian mechanism underlies cortical plasticity.