Precisely timed theta oscillations are selectively required during the encoding phase of memory

Quirk, Clare R; Zutshi, Ipshita; Srikanth, S.; Fu, Maylin L.; Marciano, Naomie Devico; Wright, Morgan; Parsey, Darian F; Liu, Stanley; Siretskiy, Rachel E; Huynh, Tiffany L; Leutgeb, Jill K.; Leutgeb, Stefan

doi:10.1038/s41593-021-00919-0

Cited by 28 publications

(25 citation statements)

References 62 publications

(114 reference statements)

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“…By contrast, it is not clear why from the purely Hebbian learning framework that disrupting the theta cycle should impair that form of learning. Intriguingly, a recent report appears to be consistent with the predictions of our model: Quirk et al (2021) found that a highly selective disruption of the timing of the theta cycle produced selective deficits in learning. Even more selective tests of the specific temporal dynamics associated with the CA3 and CA1 could more specifically test our model.…”

Section: Novel Predictionssupporting

confidence: 91%

Correcting the Hebbian Mistake: Toward a Fully Error-Driven Hippocampus

Zheng

Liu

Nishiyama

et al. 2021

Preprint

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The hippocampus plays a critical role in the rapid learning of new episodic memories. Many computational models propose that the hippocampus is an autoassociator that relies on Hebbian learning (i.e., “cells that fire together, wire together”). However, Hebbian learning is computationally suboptimal as it modifies weights unnecessarily beyond what is actually needed to achieve effective retrieval, causing more interference and resulting in a lower learning capacity. Our previous computational models have utilized a powerful, biologically plausible form of error-driven learning in hippocampal CA1 and entorhinal cortex (EC) (functioning as a sparse autoencoder) by contrasting local activity states at different phases in the theta cycle. Based on specific neural data and a recent abstract computational model, we propose a new model called Theremin (Total Hippocampal ERror MINimization) that extends error-driven learning to area CA3 — the mnemonic heart of the hippocampal system. In the model, CA3 responds to the EC monosynaptic input prior to the EC disynaptic input through dentate gyrus (DG), giving rise to a temporal difference between these two activation states, which drives error-driven learning in the EC→CA3 and CA3↔CA3 projections. In effect, DG serves as a teacher to CA3, correcting its patterns into more pattern-separated ones, thereby reducing interference. Results showed that Theremin, compared with our original model, has significantly increased capacity and learning speed. The model makes several novel predictions that can be tested in future studies.

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Section: Novel Predictionssupporting

confidence: 91%

Correcting the Hebbian Mistake: Toward a Fully Error-Driven Hippocampus

Zheng

Liu

Nishiyama

et al. 2021

Preprint

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“…PV interneurons in the hippocampus have previously been reported to be part of a microcircuit essential in regulating memory consolidation 64,65 , and our optogenetic manipulations could be associated with silencing of these cells to some extent. Moreover, although we did not observe changes in frequency bands other than theta, we cannot exclude that CA1 pyramidal neuron spike timing could be drastically altered when scrambling theta oscillations, while 8 Hz stimulation were shown to not result in increased hippocampal activity 17 , which could explain the differential effects of those stimulation patterns on working memory performance. The memory impairments we observed were likely non-cholinergic: firstly, in our immunohistological experiments we found virtually no expression of ChrimsonR in ChAT neurons of the MS. Secondly, our optogenetic stimulations were not associated with changes in hippocampal ripples, while previous reports indicate that ChAT neurons stimulation is associated with reduced ripple frequency 44,57 .…”

Section: Discussioncontrasting

confidence: 60%

“…While complete MS optogenetic inhibition has been associated with spatial memory impairments 13 , these effects could potentially be attributed to disruption of cholinergic functions 14,15 , which are known to be critical for memory function. The exact role of non-cholinergic MS PV cells in memory encoding and retrieval remains an active area of research and has only been described recently 16,17 . Since the MS provides the largest subcortical inputs to the hippocampus and is essential in generating and maintaining theta rhythms, disruption of MS activity is likely to impact downstream hippocampal physiology and working memory 18 .…”

Section: Introductionmentioning

confidence: 99%

Optogenetic frequency scrambling of hippocampal theta oscillations dissociates working memory retrieval from hippocampal spatiotemporal codes

Etter

Veldt

Choi

et al. 2021

Preprint

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The precise temporal coordination of activity in the brain is thought to be fundamental for memory encoding and retrieval. The medial septum (MS) provides the largest source of innervation to the hippocampus (HPC), and its inhibitory neurons play a major role in controlling HPC theta (~8 Hz) oscillations. While pharmacological inhibition of the MS is associated with memory impairment, the exact role of MS inhibitory neurons in HPC function and memory is not fully understood. While HPC place cells were previously reported to not depend on MS inputs, the exact role of MS inputs on HPC temporal codes is still a matter of debate. Moreover, pharmacological manipulations do not have the temporal resolution to distinguish the role of MS activity on working memory encoding, retention and retrieval. Here we stimulated the MS with optogenetics to either pace or ablate theta, while recording large hippocampal assemblies over time using calcium imaging along with local field potentials to monitor theta control. Using scrambled light stimulation, we could robustly ablate theta signals, which was associated with direct modulation of a subpopulation of neurons in the HPC. We found that such stimulation led to decreased working memory retrieval, but not encoding in both a delayed non-match to sample task and a novel place object recognition task. Strikingly, scrambled stimulations were not associated with disrupted spatiotemporal codes. Importantly, we show that our opsin did not transfect cholinergic cells and stimulation did not disrupt HPC ripple activity or running speed, suggesting a specific role for MS GABAergic cells in memory maintenance and retrieval that is independent from these other potential confounding mechanisms. Our study suggests that theta signals play a specific and essential role in supporting working memory retrieval and maintenance while not being necessary for hippocampal spatiotemporal codes.

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“…Microstimulation or optogenetic manipulations in animals hold the potential to modulate synchrony in a more spatially precise manner, testing the role of synchrony in maintaining specific representations. Indeed, rodent studies have reported selective modulation of synchrony by optogenetic methods ( Kidder et al, 2021 ; Quirk et al, 2021 ). Once we better understand the role of synchrony, the ability to selectively manipulate it could provide treatments for neural disorders ( Sreeraj et al, 2019 ).…”

Section: Manipulation Of Inter-areal Synchrony Alters Working Memory Performancementioning

confidence: 99%

Dependence of Working Memory on Coordinated Activity Across Brain Areas

Rezayat

Clark

Dehaqani

et al. 2022

Front. Syst. Neurosci.

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Neural signatures of working memory (WM) have been reported in numerous brain areas, suggesting a distributed neural substrate for memory maintenance. In the current manuscript we provide an updated review of the literature focusing on intracranial neurophysiological recordings during WM in primates. Such signatures of WM include changes in firing rate or local oscillatory power within an area, along with measures of coordinated activity between areas based on synchronization between oscillations. In comparing the ability of various neural signatures in any brain area to predict behavioral performance, we observe that synchrony between areas is more frequently and robustly correlated with WM performance than any of the within-area neural signatures. We further review the evidence for alteration of inter-areal synchrony in brain disorders, consistent with an important role for such synchrony during behavior. Additionally, results of causal studies indicate that manipulating synchrony across areas is especially effective at influencing WM task performance. Each of these lines of research supports the critical role of inter-areal synchrony in WM. Finally, we propose a framework for interactions between prefrontal and sensory areas during WM, incorporating a range of experimental findings and offering an explanation for the observed link between intra-areal measures and WM performance.

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Precisely timed theta oscillations are selectively required during the encoding phase of memory

Cited by 28 publications

References 62 publications

Correcting the Hebbian Mistake: Toward a Fully Error-Driven Hippocampus

Correcting the Hebbian Mistake: Toward a Fully Error-Driven Hippocampus

Optogenetic frequency scrambling of hippocampal theta oscillations dissociates working memory retrieval from hippocampal spatiotemporal codes

Dependence of Working Memory on Coordinated Activity Across Brain Areas

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