Graded persistent activity in entorhinal cortex neurons

발표자 : 심리학과 생물심리전공 설선혜

A.V.Egorov, B.N.Hamam, E.Fransen, M.E. Hsselmo, and A.A.Alonso

Introduction

Medial-temporal lobe memory system

Entorhinal cortex (EC) in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operation are essential.

EC is the crucial component of the medial temporal-lobe memory system.

(Kandel et al., Principles of Neural Science 4th ed.)

Introduction

Memory system and Working memory

(http://www.psy.ohio-state.edu/psy312/wrkmem.html)

Introduction

Activity of a cell in the Inferotemporal cortex of a monkey in a visual memory task (Fuster,1997)

Persistent neuronal activity is the elementary process underlying working memory

EC neurons also display persistent activity during the delay phase of delayed match or non-match tasks.

Introduction

What is the cellular basis of the persistent neuronal activity?

Synaptic reverberations in recurrent circuits

Vs

Intrinsic neuronal ability

Method

Individual neurons from layer V of the entorhinal cortex were recorded.

(Young et al., 1997)

Method

Intracellular recording method in a rat EC slice preparation

(Henze et al., 2000)

(Hammond, 2001,Cellular and Molecular Neurobiology)

(Klink and Alonso, 1997)

Result: Muscarinic dependent persistent activity

Figure 1: Muscarinic dependent persistent activity

a. CCh or muscarine could give rise to a plateau potential, which was blocked by atropine or pirenzepine.

muscarinic-dependent

b, c. increases in the stimulus duration or intensity led to an increase in the duration of the plateau potential.

activity dependent and self sustained

d. voltage dependence of persistent firing.

Result: Muscarinic dependent persistent activity

The muscarinic-dependent plateau potential were not caused by local circuit reverberation mechanisms.

Activities were recorded during glutamatergic and GABA-mediated neurotransmission block with cocktails consisting of a mixture of kynurenic acid and picrotoxin.

Nevertheless, the plateau activity could be induced equally well with synaptic stimulation during intact neurotransmission.

Intrinsic!

Result

Persistent activity for working memory can directly encode dimensions of input or output signals if it can maintain stable analogue values of activity.

(Seung et al., 2000)

Result: Graded persistent activity

Figure 2a : Repetitive depolarizing steps

Result: Graded persistent activity

Figure 2c: Repetitive hyperpolarizing steps

Result: Graded persistent activity

Figure 2b: Fourier analysis plots

Depolarizing step(15) Hyperpolarizing step(51)

Result: Graded persistent activity

Repetitive application of the sustained firing inducing input always led to well-defined increases of stable discharge rates. (Graded)

Once persistent firing was initiated it could only be turned off by prolonged membrane hyperpolarizations. (Persistent)

Repetitive application of hyperpolarizing current pulse steps lead to graded stable decreases in firing rate.

And then,

Could local synaptic activation also lead to a state of persistent firing?

Result: Synaptic induction of persistent activity

Figure 3a

Result: Synaptic induction of persistent activity

Figure 3b: stable increase in frequency by synaptic excitation

Result: Synaptic induction of persistent activity

Figure 3c: synaptic inhibition with 1mM kynurenic acid

Result: Synaptic induction of persistent activity

Muscarinic modulation of EC layer V neurons implements in these neurons the internal ability to generate truly persistent activity that can maintain multiple levels of stable firing rate.

It should be resistant to distracting inputs. stable firing frequency were not affected by relatively brief excitatory-inhibitory stimuli.

Result: Ionic mechanism

Ca2+ influx associated with spiking is an important element. Figure 4a: removal of extracellular Ca2+ completely and reversibly abolished muscarinic induced p

lateau potentials

Intracellular injection of the Ca2+ chelator EGTA had the similar effect.

The induction of the plateau potential depends on intracellular Ca2+ rises.

Result: Ionic mechanism

4b: nifedipine partially blocked the activity.

L-type channels are related.

4c: flufenamic acid completely blocked the persistent activity.

Ca2+ -activated non-specific cation current is important.

Spike-induced Ca2+ influx triggering a slow potential mediated by a cationic current can be a basic mechanism for the generation of persistent activity.

Conclusion

EC layer V neurons lie at the core of the hippocampal neocortical memory system, which implements the acquisition, storage and retrieval of memories for facts and events in a temporally organized and graded manner.

The single-cell mnemonic mechanism allows cells to ‘hold on’ to information for relatively prolonged periods of time enables the system to perform associational computations

It might be fundamental for the memory operations in the temporal lobe.

Conclusion

Working Memory

While working memory operations in prefrontal cortex may be important for monitoring familiar stimuli, the medial temporal lobe may be more important for matching and active maintenance of mew information during memory delays (Stern et al., 2001).

Perirhinal and entorhinal lesions impaired neuronal responses to visual paired associates in inferotemporal cortex (Higuchi and Miyashita, 1996).

The intrinsic persistent activity displayed by the EC layer V cells represents an ideal mechanism for sustaining information about a new stimulus for memory encoding and/or consolidation purposes.

Conclusion

Synaptic reverberations in recurrent circuits Vs Intrinsic neuronal ability

Conclusion

EC layer V neurons behave as analogue memory devices. muliple bits of information in the form of activity along a graded dimension determined by stimulu

s input.

※bistable neurons

(Marder et al.,1996)

This intrinsic cellular behavior constitutes an elementary form of mnemonic process on which associative network mechanisms could build to hold externally or internally driven sensory representations.

Conclusion

Memory in networks results from an ongoing interplay between changes in synaptic efficacy and intrinsic membrane properties. (Marder et al., 1996)

Changes in…

synaptic efficacy + intrinsic membrane properties Memory

References

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Supplementary Information

Supplementary Information

Appendix