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Abstract

Hippocampal ripples, brief high-frequency (150-200Hz) oscillations occurring during quiet wakefulness or slow wave sleep (SWS), represent simultaneous discharge of a large neuronal population that is synchronized across the entire hippocampus. Learning experience increases frequency of ripple occurrence, which is predictive of memory recall, while ripple suppression impairs hippocampal-dependent learning. Experience-induced replay of neuronal ensembles occurs predominantly during ripples. These observations support the idea that ripples provide a neurophysiological substrate for ‘off-line’ memory consolidation by
facilitating synaptic plasticity within the learning-associated neuronal network. We hypothesized that noradrenaline (NE) release during ripples in subcortical and cortical targets of the Locus Coeruleus (LC) may be beneficial for memory consolidation. Rats implanted with linear electrode arrays for extracellular recording in cortex and hippocampus and a stimulating electrode in LC were trained on a spatial memory task. Neural activity was monitored for 1h immediately after each learning session. Ripples were detected on-line using a band-pass filtered (150-250Hz) extracellular voltage signal recorded in the CA1 region of hippocampus by applying a threshold-crossing algorithm. Trains of biphasic electrical pulses (0.4ms, 0.05mA) were delivered to LC at each ripple onset. Group1 received LC stimulation (5 pulses at 20Hz) that did not produce detectable changes in cortical or hippocampal neural activity. Group2 received LC stimulation (10-20 pulses at 50-100Hz) that induced a transient (1-2s) desynchronization of cortical EEG, during which both thalamocortical sleep spindles and hippocampal ripples were suppressed. Additional control groups included random LC
stimulation, stimulation outside of LC, and sham-operated animals. Ripple-triggered LC stimulation produced a spatial memory deficit exclusively in Group2 rats, while behavioral performance of other control rats did not differ from intact animals. The stimulation-induced discharge of LC neurons and concurrent NE release caused a transient state change in the thalamocortical network, which was not favorable for hippocampal-cortical communication. These results challenge the original hypothesis, yet support the findings of our recent fMRI study showing a remarkable dichotomy between ripple-associated cortical activation and
deactivation of many subcortical regions including thalamus and brain stem neuromodulatory centers (Logothetis et al., 2012).