Optogenetic pacing of medial septum parvalbumin-positive cells disrupts temporal but not spatial firing in grid cells

Lepperød, Mikkel Elle; Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Buccino, Alessio Paolo; Yu, Jinxin; Fyhn, Marianne; Hafting, Torkel

doi:10.1126/sciadv.abd5684

Cited by 18 publications

(24 citation statements)

References 83 publications

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“…Previous research has shown that inactivation of the MSA and subsequent reduction of theta amplitude has a selective effect on reducing the spatial firing of grid cells while other hippocampal and mEC cell types remain intact 25 , 26 . Interestingly, our results and a recently published study 47 do not show any substantial alterations to grid or head-direction coding in mEC when manipulating the timing of septal oscillations. In contrast to the lack of effects with septal pacing, previous studies with pharmacological inactivation of the MSA caused a large reduction of not only theta oscillations, but also of firing rates of principal cells in the entorhino-hippocampal circuit 25 , 26 , 48 .…”

Section: Discussionsupporting

confidence: 53%

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

et al. 2021

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Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6–9 Hz), which are controlled by pacemaker cells in the medial septal area (MSA). Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive MSA neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

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Section: Discussionsupporting

confidence: 53%

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

et al. 2021

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“…Although it was reported that time (but not place) cells could depend directly on the medial entorhinal cortex (MEC) inputs 61 , recent experimental evidence suggests that MEC lesions do not lead to any alterations in hippocampal time cell physiology 62 . Notably, a more recent investigation found that optogenetic pacing of the MS did not disrupt the spatial codes of grid cells in the entorhinal cortex 63 , further suggesting that MS activity is not directly involved in spatial codes within the hippocampal formation. Together with our results, this indicates that temporal codes could either be the result of MS-dependent computations within the entorhinal cortex 63 (1) or be generated intrinsically within the hippocampus itself (2).…”

Section: Discussionmentioning

confidence: 96%

“…Notably, a more recent investigation found that optogenetic pacing of the MS did not disrupt the spatial codes of grid cells in the entorhinal cortex 63 , further suggesting that MS activity is not directly involved in spatial codes within the hippocampal formation. Together with our results, this indicates that temporal codes could either be the result of MS-dependent computations within the entorhinal cortex 63 (1) or be generated intrinsically within the hippocampus itself (2).…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2023

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The precise temporal coordination of activity in the brain is thought to be fundamental for memory function. Inhibitory neurons in the medial septum provide a prominent source of innervation to the hippocampus and play a major role in controlling hippocampal theta (~8 Hz) oscillations. While pharmacological inhibition of medial septal neurons is known to disrupt memory, the exact role of septal inhibitory neurons in regulating hippocampal representations and memory is not fully understood. Here, we dissociate the role of theta rhythms in spatiotemporal coding and memory using an all-optical interrogation and recording approach. We find that optogenetic frequency scrambling stimulations abolish theta oscillations and modulate a portion of neurons in the hippocampus. Such stimulation decreased episodic and working memory retrieval while leaving hippocampal spatiotemporal codes intact. Our study suggests that theta rhythms play an essential role in memory but may not be necessary for hippocampal spatiotemporal codes.

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“…While it was reported that time (but not place) cells could depend directly on medial entorhinal cortex (MEC) inputs 61 , other studies show that MEC lesions do not lead to any alterations in hippocampal time cell physiology 62 . Notably, a more recent investigation found that optogenetic pacing of the MS did not disrupt the spatial codes of grid cells in the entorhinal cortex 63 , further suggesting that MS activity is not directly involved in spatial codes within the hippocampal formation. Together with our results, this indicates that temporal codes could either be the result of MS-dependent computations within the entorhinal cortex 63 (1), or be generated intrinsically within the hippocampus itself (2).…”

Section: Discussionmentioning

confidence: 96%

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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Optogenetic pacing of medial septum parvalbumin-positive cells disrupts temporal but not spatial firing in grid cells

Cited by 18 publications

References 83 publications

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

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

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

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

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