Basic questions remain as to how information is conveyed by neural activity. In the hippocampus, the firing rate of single cells and the temporal ordering of those cells relative to one another correlate with experienced and planned spatial trajectories. These correlations suggest that the hippocampus supports memory function using both a rate code and a temporal code, but a causal link between temporal coding and memory is lacking. To establish if the temporal ordering of cells conveys information to the rest of the brain, it is necessary to perform simultaneous recordings from the hippocampus and an output region. Here, I propose three experiments in which I will record and optogenically stimulate the hippocampus while recording from one of its main post- synaptic cortical targets, the subiculum.
Specific Aim 1 is to provide correlative evidence that, in the absence of stimulation, subicular cells are sensitive to hippocampal temporal coding. Statistical modeling of subicular activity wil test whether a significant amount of variance in firing rate can be explained by sequences of activity in area CA1 of the hippocampus.
Specific Aim 2 will test whether subicular firing patterns are affected by disruptions to the hippocampal temporal code that is defined by small differences in spike timing. Spike-timing disruption will be achieved either directly by expressin light-activated opsins that excite pyramidal cells, or indirectly by expressing light-activated opsins that silence interneurons. If alterations in subicular activity occur when spike-timing in the hippocampus is disrupted, this would provide strong evidence that the temporal code can bias the activity of post-synaptic targets and therefore likely conveys information. Finally, Specific Aim 3 seeks to link disruption of fine spike-timing to memory. In this experiment, broader optogenetic stimulation of CA1 will be used and memory will be tested in a delayed alternation paradigm that depends upon the hippocampus. I predict that stimulations during the delay that disrupt the order in which hippocampal cells fire will also affect memory.
The aim of these experiments is to show that information is conveyed from the hippocampus to downstream regions using a temporal code. Confirming a causal link between temporal coding and memory would greatly expand estimates of the hippocampal storage capacity and may offer insights into stimulation protocols that enhance memory.
Neural stimulation can ameliorate memory in some conditions though interfere in others. Given the exciting potential of recovering memory function for those with neurological or psychiatric disorders, it is imperative to find stimulation protocol that provide maximal therapeutic value. The proposed experiments will directly contribute to this search by testing whether the sequence in which cells fire in a key memory center influences downstream neural activity to support learning and memory.
| McKenzie, Sam (2018) Inhibition shapes the organization of hippocampal representations. Hippocampus 28:659-671 |
| English, Daniel Fine; McKenzie, Sam; Evans, Talfan et al. (2017) Pyramidal Cell-Interneuron Circuit Architecture and Dynamics in Hippocampal Networks. Neuron 96:505-520.e7 |
| McKenzie, Sam; Keene, Christopher S; Farovik, Anja et al. (2016) Representation of memories in the cortical-hippocampal system: Results from the application of population similarity analyses. Neurobiol Learn Mem 134 Pt A:178-191 |
