Impact of music intervention on endoscopic retrograde cholangiopancreatography patients' pain, anxiety, and vital signs: a randomized controlled trial.

The hippocampal CA3 has been implicated in sequence learning. Sequence learning requires linking memories of adjacent events in a sequence by shared ensemble cells. It has been proposed that the may link two neuronal ensembles representing two temporally separated episodes in the hippocampal CA1 area. This mechanism, however, is unlikely to make a memory link in the CA3 recurrent network, in which episodic memories are represented by orthogonal (nonoverlapping) neuronal ensembles. It remains unknown how the CA3 network links memory ensembles to encode memory of sequential events while maintaining ensemble orthogonality. CA3 pyramidal cells (CA3-PCs) receive synaptic inputs from mossy fibers (MFs) and perforant pathway (PP) at proximal and distal apical dendrites, respectively. MFs make sparse but strong synapses on proximal apical dendrites of CA3-PCs, while PP densely innervates distal apical dendrites with relatively weak synaptic strength. In addition, CA3-PCs are recurrently connected via associational/commissural (A/C) fibers. Based on this network architecture, it has been proposed that MF inputs contribute to nonoverlapping memory representation during memory encoding, while PP inputs to the reactivation of memory ensembles during cued retrieval of memories. This prediction has been supported by behavioral consequences after lesioning afferent inputs to the CA3 area. High frequency MF inputs to a CA3-PC lead to a sustained high excitability state of distal apical dendrites, whereby primes the CA3-PC for subsequent PP inputs. This high excitability state is mediated by downregulation of dendritic Kv1.2 channels, which carry D-type K current (). is activated on low depolarization from resting membrane potential (RMP), and thus plays an important role in opposing Na-spike firing. Kv1.2 channels are expressed not only on axonal initial segments but also on apical dendrites of CA3-PCs. Moreover, apical dendritic expressions of both Kv1.2 and Na channels in CA3-PCs are polarized to distal apical dendrites. High frequency MF inputs or a train of 10 Hz somatic action potentials (APs) elevate dendritic [Ca] via back-propagating APs and L-type Ca channels, leading to tyrosine kinase-dependent endocytosis of dendritic Kv1.2. Such downregulation of dendritic Kv1.2 channels facilitates activation of dendritic Na spikes preferentially at distal apical dendrites because of the polarized expression of dendritic Na channels, resulting in heterosynaptic long-term potentiation (LTP) of PP-induced EPSPs (PP-EPSPs) and lowering somatic input conductance (), called LTP of intrinsic excitability (LTP-IE). MF-induced LTP-IE results in EPSP-to-spike (E-S) potentiation of PP inputs. Because homosynaptic LTP at PP-to-CA3 synapses (PP-LTP) displays the features of Hebbian synapses, LTP-IE lowers the threshold of PP input strength necessary for induction of homosynaptic PP-LTP. Recently, we showed that high-frequency PP inputs to MF-primed CA3-PCs not only induce homosynaptic PP-LTP but also restore the hyperexcitability state to baseline. Dendritic Ca signaling activates both tyrosine kinase and phosphatase in CA3-PCs, and it can be induced by both high-frequency MF and PP inputs to CA3-PCs. However, dendritic Zn signaling, which inhibits tyrosine phosphatase, can be induced by MF inputs but not by non-MF (A/C or PP) inputs. Therefore, MF inputs are privileged to activate tyrosine kinases without opposing phosphatase action, leading to LTP-IE, while subsequent non-MF inputs can reverse LTP-IE through Ca-dependent activation of tyrosine phosphatase.