CRCNS - Neuromodulation of Hippocampal Synaptic Plasticity in Waking & REM Sleep

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DESCRIPTION (provided by applicant): The proposed experiments and simulation studies investigate one of the first feasible mechanisms for memory consolidation during sleep. The results will elucidate particular roles for the Schaffer Collateral and temporo-ammonic inputs to the hippocampal CA1 region in memory processing and how NE and 5-HT gate these pathways during waking and Rapid Eye Movement (REM) sleep. During REM sleep, we have found that reactivation of hippocampal cells changes over the course of several days as the animals became familiar with an environment. Cells with place fields in an initially novel environment switch from firing near the theta rhythm peaks to firing near the theta troughs during REM, while maintaining their theta peak activity during waking exploration. Theta trough firing during REM may uniquely facilitate depotentiation of intra-hippocampal synapses which are associated with now familiar, cortically-consolidated memories and allow for learning of new information and the integration of novel information with old memories. This proposal seeks to test the role of the uniquely REM-suppressed neurotransmitters norepinephrine (NE) and serotonin (5-HT) in theta phase reversal, potentiation of TA-CA1 inputs, depotentiation of SC-CA1 synapses and hippocampus-dependent learning and memory. Specifically, experimental and modeling studies are proposed to investigate the hypothesis that the absence of NE and 5-HT during REM reactivation provides an environment wherein TA-CA1 synapses may be strengthened and SC-CA1 synapses may be weakened, thus indicating a unique role for REM sleep in learning and memory. Understanding the mechanisms underlying memory consolidation during sleep should lead to sleep-specific treatments for learning disabled persons and the elderly. The results will also indicate effects of commonly prescribed anti-depressants, such as selective noradrenergic (SNRIs) and serotonergic (SSRIs) re-uptake inhibitors, on learning and memory.