Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex

Sürmeli, Gülşen; Marcu, Daniel-Cosmin; McClure, Christina; Garden, Derek L. F.; Pastoll, Hugh; Nolan, Matthew F.

doi:10.1016/j.neuron.2015.10.041

Cited by 97 publications

(178 citation statements)

References 53 publications

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“…1A-D, H and fig. S1A-D), indicating that MEC-Va cells have extensive projections to the neocortex and BLA (23). We then sought to inhibit these specific projections by bilaterally injecting adeno-associated virus 8 (AAV 8 )-calcium/calmodulindependent protein kinase II (CaMKII):eArchT-enhanced yellow fluorescent protein (eYFP) in the deep layers of the MEC in wild-type (WT) mice with bilaterally implanted optic fibers above the PFC, cACC, or RSC ( Fig.…”

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confidence: 99%

Engrams and circuits crucial for systems consolidation of a memory

Kitamura

Ogawa

Roy

et al. 2017

Science

838

898

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Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation remain unknown. We found that neocortical prefrontal memory engram cells, critical for remote contextual fear memory, were rapidly generated during initial learning via inputs from both hippocampal-entorhinal cortex and basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, are maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.Memories are thought to be initially stored within the hippocampal-entorhinal cortex (HPC-EC) (recent memory) and over-time are slowly consolidated within the neocortex for permanent storage (remote memory) (1-7). Systems memory consolidation models suggest that the interaction between the HPC-EC and the neocortex during and after an experience is crucial (8)(9)(10)(11)(12). Experimentally, prolonged inhibition of hippocampal or neocortical networks during the consolidation period produces deficits in remote memory formation (13-15). However, little is known regarding specific neural circuit mechanisms underlying the formation and maturation of neocortical memories through interactions with the HPC-EC network. By employing activity-dependent cell labeling technology (16-18) combined with viral vector-based transgenic, anatomical (19, 20), and optogenetic strategies (19, 21) for We first traced entorhinal projections to frontal cortical structures (the medial prefrontal cortex (PFC), caudal anterior cingulate cortex (cACC), retrosplenial cortex (RSC)) involved in contextual fear memory, and the basolateral amygdala (BLA), with injections of the retrograde tracer cholera toxin subunit B (CTB)-Alexa555 into these regions ( fig. S1). CTB injections resulted in labeling in the medial entorhinal cortex (MEC) specifically in cells in layer Va (Fig. 1A-D, H and fig. S1A-D (Fig. 1F). Terminal inhibition during memory recall tests did not affect memory retrieval (Fig. 1G). Finally, terminal inhibition in the cACC or RSC during CFC or recall had no effect on memory throughout these periods (Fig. 1J-L and fig. S2G-I).The above results suggest that MEC-Va input into the PFC during CFC is crucial for the eventual formation of remote memory. This hypothesis was supported by several findings. First, CFC increased the number of c-Fos + cells in the PFC compared to that of homecage mice ( Fig. 1M-O), whereas context only exposure did not increase c-Fos activity in the PFC (Fig. 1O). Second, optogenetic terminal inhibition of MEC-Va projections within the PFC during CFC inhibited the observed incr...

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confidence: 99%

Engrams and circuits crucial for systems consolidation of a memory

Kitamura

Ogawa

Roy

et al. 2017

Science

838

898

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“…B) (Hamam et al, ), which received clearly identifiable input from CA1. Recent evidence indicates that these cells are presumably LVb principal neurons (Sürmeli et al, ). Resting membrane potential (RMP) of CA1‐coupled neurons was −70 ± 2 mV and input resistance was 68 ± 8 MΩ ( n = 9).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the different organization of the mEC and the hippocampus proper suggest basic differences in network mechanisms. For example, afferent fibers from CA1 selectively innervate principal neurons in layer Vb of the mEC (Sürmeli et al, ), while output to the major telencephalic targets of the mEC is mediated by layer Va. This segregation of input and output components suggests additional signal computation within deep layers.…”

Section: Discussionmentioning

confidence: 99%

Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro

et al. 2016

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The entorhinal cortex (EC) is a critical component of the medial temporal lobe (MTL) memory system. Local networks within the MTL express a variety of state-dependent network oscillations that are believed to organize neuronal activity during memory formation. The peculiar pattern of sharp wave-ripple complexes (SPW-R) entrains neurons by a very fast oscillation at ∼200 Hz in the hippocampal areas CA3 and CA1 and then propagates through the "output loop" into the EC. The precise mechanisms of SPW-R propagation and the resulting cellular input patterns in the mEC are, however, largely unknown. We therefore investigated the activity of layer V (LV) principal neurons of the medial EC (mEC) during SPW-R oscillations in horizontal mouse brain slices. Intracellular recordings in the mEC were combined with extracellular monitoring of propagating network activity. SPW-R in CA1 were regularly followed by negative field potential deflections in the mEC. Propagation of SPW-R activity from CA1 to the mEC was mostly monosynaptic and excitatory, such that synaptic input to mEC LV neurons directly reflected unit activity in CA1. Comparison with propagating network activity from CA3 to CA1 revealed a similar role of excitatory long-range connections for both regions. However, SPW-R-induced activity in CA1 involved strong recruitment of rhythmic synaptic inhibition and corresponding fast field oscillations, in contrast to the mEC. These differences between features of propagating SPW-R emphasize the differential processing of network activity by each local network of the hippocampal output loop. © 2016 Wiley Periodicals, Inc.

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“…From an anatomical point of view, both scenarios seem plausible. On the one hand, grid-cell activity requires excitatory drive from the hippocampus [102], which projects to the deep layers of the mEC [103, 104] where grid cells are found [23, 60]. On the other hand, parasubicular inputs target layer II of the mEC [61, 105–108] where grid cells are most abundant [23, 60].…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that multiple sites of origin exist, and that grid-like tuning is inherited—and even sharpened—via feed-forward projections from the deep to the superfical layers [115–119] or from the superficial to the deep layers [104]. …”

Section: Discussionmentioning

confidence: 99%

A single-cell spiking model for the origin of grid-cell patterns

D'Albis

Kempter

2017

PLoS Comput Biol

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Spatial cognition in mammals is thought to rely on the activity of grid cells in the entorhinal cortex, yet the fundamental principles underlying the origin of grid-cell firing are still debated. Grid-like patterns could emerge via Hebbian learning and neuronal adaptation, but current computational models remained too abstract to allow direct confrontation with experimental data. Here, we propose a single-cell spiking model that generates grid firing fields via spike-rate adaptation and spike-timing dependent plasticity. Through rigorous mathematical analysis applicable in the linear limit, we quantitatively predict the requirements for grid-pattern formation, and we establish a direct link to classical pattern-forming systems of the Turing type. Our study lays the groundwork for biophysically-realistic models of grid-cell activity.

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Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex

Cited by 97 publications

References 53 publications

Engrams and circuits crucial for systems consolidation of a memory

Engrams and circuits crucial for systems consolidation of a memory

Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro

A single-cell spiking model for the origin of grid-cell patterns

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