Mechanisms underlying working memory for novel information

doi:10.1016/j.tics.2006.09.005

Trends in Cognitive Sciences

Volume 10, Issue 11, November 2006, Pages 487-493

https://doi.org/10.1016/j.tics.2006.09.005 Get rights and content

In this Opinion article we describe a theory that the brain mechanisms underlying working memory for novel information include a buffer in parahippocampal cortices. Computational modeling indicates that mechanisms for maintaining novel information in working memory could differ from mechanisms for maintaining familiar information. Electrophysiological data suggest that the buffer for novel information depends on acetylcholine. Acetylcholine activates single-cell mechanisms that underlie persistent spiking of neurons in the absence of synaptic transmission, allowing maintenance of information without prior synaptic modification. fMRI studies and lesion studies suggest that parahippocampal regions mediate working memory for novel stimuli, and the effects of cholinergic blockade impair this function. These intrinsic mechanisms in parahippocampal cortices provide an important alternative to theories of working memory based on recurrent synaptic excitation.

Introduction

Research has demonstrated the existence of multiple memory systems, including working memory, which is defined as a limited capacity system for the temporary storage and manipulation of information for cognitive tasks 1, 2. Many initial fMRI studies of working memory in humans used highly familiar stimuli such as letters and words, and focused primarily on a system that includes prefrontal cortex and parietal cortex 1, 2, 3. However, electrophysiological and lesion studies in animals and recent imaging studies suggest that temporal lobe structures play a crucial role in working memory 4, 5, 6. Here we present the theory that working memory for novel information differs from working memory for familiar information, proposing that novel stimuli require additional cellular mechanisms within the entorhinal and perirhinal cortex, whereas prefrontal and parietal systems are sufficient for maintaining familiar stimuli in working memory. We are not proposing a double dissociation between the systems, but instead we suggest that the prefrontal–parietal system alone is insufficient for maintaining information that has no prior representation in the brain. We hypothesize that cholinergic activation of these single neuron mechanisms results in persistent spiking activity without excitatory synaptic transmission between neurons (Figure 1 and Box 1). This theory provides an alternative to many physiological models of working memory that use recurrent excitation between neurons to maintain persistent spiking [7]. Those other models, based on recurrent excitation, can only maintain information consistent with previously formed representations (i.e. familiar information).

In this article, we evaluate experimental data 6, 8, 9, 10 and computational modeling 11, 12, 13 that support the proposal that working memory for novel stimuli requires additional cellular mechanisms activated by acetylcholine in the entorhinal cortex and other parahippocampal cortices and that differ substantially from the mechanisms required for working memory for familiar stimuli. In each section we first evaluate evidence for the role of this cellular mechanism in the active maintenance of novel stimuli for working memory, and, if evidence is available, we consider a role for this mechanism in encoding long-term memories.

Section snippets

Working memory

Lesion studies suggest an important role for parahippocampal regions in working memory for novel stimuli. Although cortical regions including prefrontal cortex and parietal cortex show activity during working memory for novel stimuli [14], these regions do not seem to be sufficient to perform working memory for novel stimuli at normal levels when parahippocampal regions are lesioned, although they are sufficient to maintain normal working memory for familiar stimuli. Many studies test working

Working memory

Functional neuroimaging studies support the idea that working memory for novel stimuli requires the additional recruitment of parahippocampal regions. Early functional neuroimaging studies of working memory emphasized the role of prefrontal and parietal cortices, and most studies were carried out using highly familiar stimuli, including letters, words, simple objects and spatial locations [26]. Surprisingly, these early fMRI studies of working memory did not report activity within

Working memory

Studies of the behavioral effects of drugs that block muscarinic acetylcholine receptors support a role for cholinergic modulation in the entorhinal cortex in the short-term retention of novel memories. Systemic injections of muscarinic acetylcholine blockers such as scopolamine impair DMS performance in monkeys at delays on the order of several seconds [31], and impair the arm choice behavior of rats in an eight-arm radial maze when there is a delay between the individual choices [32]. In

Cellular physiology

The proposal of a working memory system for novel stimuli presented here was initially motivated by intracellular single-cell recordings of memory mechanisms 8, 47. Recordings in the laboratory of Angel Alonso demonstrated that single neurons in layer II of slice preparations of the entorhinal cortex, isolated from other neurons by pharmacological blockade of excitatory and inhibitory synaptic transmission, can maintain memory for prior input in the form of persistent spiking activity (Figure 3

Recording of spiking activity during behavior

The theory that the Alonso current in the entorhinal cortex contributes to the maintenance of working memory is supported by recordings of the spiking activity of single neurons in animals performing delayed matching tasks. Sustained spiking activity during delay periods has been shown for neurons in parahippocampal cortices, including the entorhinal cortex, in rats performing a continuous DNMS task with odors [10] and in monkeys during performance of DMS tasks with complex visual stimuli [30].

Summary and future directions

The experimental data and computational modeling reviewed here support the hypothesis that intrinsic single neuron mechanisms in parahippocampal cortices mediate working memory for novel stimuli. Studies using techniques at several different levels support this hypothesis. However, further work at the behavioral level is needed to test whether blockade of cholinergic receptors will selectively impair active maintenance of novel but not familiar stimuli in the same task in humans, possibly by

Acknowledgements

This work was supported by NINDS 41636, NIMH 60013, NIMH 61492, NIMH 60450, NSF Science of Learning Center SBE0354378 and NIDA 16454 as part of the joint NSF/NIH program for Collaborative Research in Computational Neuroscience (CRCNS).

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Trends in Cognitive Sciences

OpinionMechanisms underlying working memory for novel information

Introduction

Section snippets

Working memory

Working memory

Working memory

Cellular physiology

Recording of spiking activity during behavior

Summary and future directions

Acknowledgements

The episodic buffer: a new component of working memory?

Trends Cogn. Sci.

From Conditioning to Conscious Recollection: Memory Systems of the Brain

Memory networks in the prefrontal cortex

Prog. Brain Res.

Directing the mind's eye: prefrontal, inferior and medial temporal mechanisms for visual working memory

Curr. Opin. Neurobiol.

Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli

Hippocampus

Scopolamine reduces persistent activity related to long-term encoding in the parahippocampal gyrus during delayed matching in humans

J. Neurosci.

Neurocomputational models of working memory

Nat. Neurosci.

Muscarinic modulation of the oscillatory and repetitive firing properties of entorhinal cortex layer II neurons

J. Neurophysiol.

Graded persistent activity in entorhinal cortex neurons

Nature

Memory representation within the parahippocampal region

J. Neurosci.

Storage of 7 ± 2 short-term memories in oscillatory subcycles

Science

Novel lists of 7 ± 2 known items can be reliably stored in an oscillatory short-term memory network: interaction with long-term memory

Learn. Mem.

Simulations of the role of the muscarinic-activated calcium-sensitive nonspecific cation current INCM in entorhinal neuronal activity during delayed matching tasks

J. Neurosci.

Neural activity in the primate prefrontal cortex during associative learning

Neuron

Preserved recognition memory for small sets, and impaired stimulus identification for large sets, following rhinal cortex ablations in monkeys

Eur. J. Neurosci.

Complementary roles of the orbital prefrontal cortex and the perirhinal entorhinal cortices in an odor-guided delayed-nonmatching-to-sample task

Behav. Neurosci.

Lasting consequences of bilateral medial temporal lobectomy: clinical course and experimental findings in HM

Semin. Neurol.

Monkeys (Macaca fascicularis) with rhinal cortex ablations succeed in object discrimination learning despite 24-hr intervals and fail at matching to sample despite double sample presentations

Behav. Neurosci.

The medial temporal lobe

Annu. Rev. Neurosci.

Working memory for conjunctions relies on the medial temporal lobe

J. Neurosci.

Visual working memory is impaired when the medial temporal lobe is damaged

J. Cogn. Neurosci.

Doubts about double dissociations between short- and long-term memory

Trends Cogn. Sci.

The animal model of human amnesia: long-term memory impaired and short-term memory intact

Proc. Natl. Acad. Sci. U. S. A.

Modeling goal-directed spatial navigation in the rat based on physiological data from the hippocampal formation

Neural Netw.

Hippocampal sequence-encoding driven by a cortical multi-item working memory buffer

Trends Neurosci.

A parametric study of prefrontal cortex involvement in human working memory

Neuroimage

Medial temporal lobe activity associated with active maintenance of novel information

Neuron

Neural mechanisms for detecting and remembering novel events

Nat. Rev. Neurosci.

Persistence of parahippocampal representation in the absence of stimulus input enhances long-term encoding: a functional magnetic resonance imaging study of subsequent memory after a delayed match-to-sample task

J. Neurosci.

Object and place memory in the macaque entorhinal cortex

J. Neurophysiol.

Opinion
Mechanisms underlying working memory for novel information