Graded persistent activity in entorhinal cortex neurons A.V.Egorov, B.N.Hamam, E.Fransen, M.E. Hsselmo, and A.A.Alonso 발표자: 심리학과 생물심리전공 설선혜

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 (Hammond, 2001,Cellular and Molecular Neurobiology) (Klink and Alonso, 1997) (Henze et al., 2000)

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(15) Hyperpolarizing step(51)

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 plateau 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 stimulus 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

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