Investigation into the synaptic origins of hippocampal replay

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Project Summary The aim of this project is to study the synaptic mechanisms that allow particular patterns of neural activity to become reinstated. In hippocampal circuits, the sequential pattern of neural activity observed during behavior is later replayed during oscillatory bursts of activity known as sharp-wave ripples (SPW-Rs). Computational models show that replay could arise due to plasticity of glutamatergic synapses onto excitatory neurons. However, such excitatory-excitatory connections are weak in hippocampal area CA1, where SPW-R replay is observed. Therefore, SPW-R replay in CA1 may be inherited from upstream region CA3, which has dense excitatory recurrents. Alternatively, it is possible that plasticity in inhibitory circuits supports changes in SPW-R dynamics. This grant will use SPW-R replay to study how neural patterns are learned and recalled. In the K99 Aims, I will examine whether neural activity is sufficient and synaptic plasticity necessary for subsequent neural reactivation during SPW-Rs. I will artificially induce patterns of activity in areas CA1 and CA3 and test whether those patterns are reactivated in the proceeding SPW-Rs and whether reactivation is restricted to recurrent-dense CA3. Next, I will test for the integrity of SPW-R replay while blocking synaptic consolidation in CA1 pyramidal cells. Replay disruptions would point to an unexpected role of CA1 plasticity in defining replay sequences. The R00 portion of the grant focuses on whether replay depends on synaptic plasticity in inhibitory circuits. First, I will establish whether the synaptic connectivity between CA1 pyramidal cells and interneurons changes with repetitive pairings in vivo. Next, I will block synaptic consolidation in CA1 GABAergic neurons to assess whether replay is also disrupted. Such a finding would demonstrate a novel role for plasticity in inhibitory circuits in defining network dynamics. Together, these experiments offer a direct test of the hypothesis that synaptic plasticity amongst a population of co-active neurons (excitatory and inhibitory) promotes subsequent reactivation of that population. To study how synaptic connectivity affects circuit dynamics, this grant combines, for the first time, cell-type specific control of synaptic consolidation and in vivo electrophysiology. The proposed training will set the foundation for a career that studies memory on the level of behavior, circuit dynamics, and synaptic function. The proposed experiments aim to inform clinical use of pharmacology and artificial neural stimulation to aid learning and recall in people with diseases that cause memory deficits.