Different molecular cascades in different sites of the brain control memory consolidation

doi:10.1016/j.tins.2006.07.005

Trends in Neurosciences

Volume 29, Issue 9, September 2006, Pages 496-505

https://doi.org/10.1016/j.tins.2006.07.005 Get rights and content

To understand cognition, it is important to understand how a learned response becomes a long-lasting memory. This process of memory consolidation has been modeled extensively using one-trial avoidance learning, in which animals (or humans) establish a conditioned response by learning to avoid danger in just one trial. This relies on molecular events in the CA1 region of the hippocampus that resemble those involved in CA1 long-term potentiation (LTP), and it also requires equivalent events to occur with different timings in the basolateral amygdala and the entorhinal, parietal and cingulate cortex. Many of these steps are modulated by monoaminergic pathways related to the perception of and reaction to emotion, which at least partly explains why strong and resistant consolidation is typical of emotion-laden memories. Thus memory consolidation involves a complex network of brain systems and serial and parallel molecular events, even for a task as deceptively simple as one-trial avoidance. We propose that these molecular events might also be involved in many other memory types in animals and humans.

Introduction

One-trial avoidance has been widely used for the study of memory consolidation. There have been many successful inferences from this task to other forms of memory, especially those of fear-motivated learning and spatial tasks. One-trial avoidance corresponds to many important examples of learning in humans, such as not to stick your fingertips into electric plug sockets, to look right rather than left when crossing a street in London, and to refrain from entering a suspicious-looking neighborhood.

The sequence of molecular mechanisms underlying long-term potentiation (LTP) in the CA1 region of the hippocampus has been proposed to underlie memory consolidation in that region 1, 2, 3, 4, 5, 6, 7, 8. This was shown to be indeed the case for one type of memory: one-trial avoidance learning 9, 10. However, at the same time, different sequences of molecular changes in other brain regions are also crucial for memory consolidation in this and other tasks 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. The main difference between the molecular changes in the hippocampus and the other structures (the basolateral amygdala, and the entorhinal and parietal cortex) is their timing and sequential order 9, 10, 11. Timing among its diverse underlying molecular events is a key factor in the build-up of LTP maintenance 1, 4, 10 and, as shown elsewhere 9, 10, 11, 12, 13, 14 and discussed here, in the build-up of consolidation. The sheer number of connections within and among various brain structures in LTP and in memory formation is the reason why these processes are so complex 1, 4, 9, 10, and why it is difficult to schematize them. Attempts have been made to devise schemes or blueprints for LTP 1, 4 and memory 2, 3, 9, 10. However, by the end of this article we hope to have persuaded readers that memory consolidation requires not only LTP (or a process very much like LTP) in the hippocampal CA1 sub-area but also different sequences of the same or of related signaling pathways in other cortical areas and the amygdala 9, 10, 17.

Section snippets

What is memory consolidation?

Most neuroscientists view consolidation as a process lasting a few hours through which memories are transformed from a labile into a more stable state 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. However, several authors favor the view that there is also another form of consolidation that lasts for many days or months, or even a lifetime [18]. No doubt memories can accrue or lose information over prolonged periods 9, 10. However, over days, months or years there are oscillations in the rate

Why one-trial avoidance

One-trial step-down or step-through inhibitory (‘passive’) avoidance in rodents 9, 10, 18, or one-trial peck avoidance in young chicks 19, 20, has long been a favorite model for biochemical and pharmacological studies of memory. In the rodent models, the animals learn that stepping down from a platform or stepping through a door is followed by a footshock; on subsequent exposures to the task they will stay much longer on the safe platform or on the safe side of the door before eventually

Main molecular events in CA1 LTP and in the consolidation of one-trial-avoidance memory

The main events in CA1 during consolidation of one-trial avoidance involve, like those in CA1 LTP 1, 2, 3, 4, 5, 6, 29, the initial activation of AMPA, metabotropic and particularly NMDA glutamate receptors 2, 5, 7, 9, 32, 33, 34, 35, 36. This causes an increase of intracellular Ca²⁺ concentration ([Ca²⁺]_i) 1, 5, followed by an enhancement of Ca²⁺/calmodulin-dependent kinase II (CaMKII) activity in the first 60 min 7, 37, 38, 39, which leads to phosphorylation of AMPA receptors 39, 40 and a

Main events in memory formation of one-trial learning in the basolateral amygdala, entorhinal cortex and posterior parietal cortex

Table 2, Table 3, Table 4 summarize the main published findings on memory consolidation in the basolateral amygdala, entorhinal cortex and posterior parietal cortex, respectively. There have been a few scattered findings on the posterior parietal cortex (a prolonged amnesic effect of the ERK1/2 inhibitor U0126 and of the GABA receptor agonist muscimol when given up to 3 h post-training [14]). Findings in other structures (e.g. the insular lobe and prefrontal areas) have been less consistent or

What forms of plasticity are involved in each structure?

Clearly, in CA1 the form of plasticity involved in memory consolidation is one closely similar to LTP, if not actual LTP 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In the other structures the sequences of molecular processes are different from those described for LTP. However, the receptors involved (particularly the NMDA receptor) 9, 10, 11, 14, 34, 36, 83 and the function of the enzymes involved (particularly their relationship to receptor activation, CREB phosphorylation, gene expression, protein

Why are emotionally-rich memories usually better consolidated?

The post-training hippocampal PKA activation and CREB phosphorylation, and memory consolidation itself, are highly sensitive to dopamine receptor agonists and to antagonists acting on D₁ receptors, β-adrenoceptors and 5HT_1A receptors [50] (Table 1, Table 3, Table 4). The pathways ending on dopamine D₁ receptors and β-adrenoceptors in the hippocampus and neocortex are well known to mediate alertness, emotion and anxiety levels. D₁ receptors and β-adrenoceptors enhance, and 5HT_1A receptors

Endogenous state dependency revisited

Table 1, Table 2, Table 3, Table 4 show that memory consolidation is accompanied and regulated by different neuromodulatory and molecular ‘states’. So is retrieval [89]. Memories, particularly those of an emotional type, have been suggested to rely on an endogenous state-dependent process 90, 91, 92, 93.

Both consolidation and retrieval of one-trial avoidance require PKA and ERK activity in the hippocampus, the entorhinal, parietal and cingulate cortex and the basolateral amygdala, and both are

A note on the parallel processing of immediate, short-term and long-term memory

STM is now known to last ∼3–6 h and is processed in parallel to the consolidation of LTM 21, 22. Before that, and as a precondition for both STM and LTM formation, working memory (WM) handles the information that is to be saved while it is being acquired and/or for a few seconds afterwards 9, 10, 11. The mechanisms of WM and STM are in general not directly related to those of LTM formation, and the interested reader is referred to Ref. [11] for a recent review of this topic.

Several of the

A caveat

The list of brain areas that participate in memory consolidation is certainly longer than the one we have discussed in this review. If CA1 and the entorhinal cortex participate, then surely the dentate gyrus and CA3 must be involved [33]. Recent evidence supports this [94]. The same stands for other molecules not specifically discussed here. For example, recent data point to a key role for the ubiquitin–proteasome system [96] and brain-derived neurotrophic factor (BDNF) 97, 98, 99 in STM and

Can a neural network be proposed?

The sequence of events in CA1 LTP has been worked out by several authors 1, 3, 4, 5, 6. However, beyond the early NMDA receptor activation, and the subsequent increase in [Ca²⁺]_i, activation of CaMKII and enhancement of AMPA receptor, PKC and PKA activity, things become blurred and it is difficult to be precise, especially about timing [44]. There could also be alternative connections between metabolic routes, particularly those involving signaling pathways and gene activation [7]. Indeed, LTP

Concluding remarks

Different chains of molecular events involving glutamate receptors, CaMKII, PKA, PKC and ERK1/2 are necessary for LTM formation in the CA1 region of the hippocampus, basolateral amygdala, entorhinal cortex, parietal cortex and cingulate cortex. The time course of the events in CA1 is similar but not identical to that which underlies LTP in this area. The timings of the molecular events in the other structures differ from each other and from those in CA1. Several of the biochemical events

Acknowledgements

This work was supported by grants from FAPERGS/CNPQ, Brazil, through the National Program for Nuclei of Excellence (PRONEX), by CONICET and ANPCyT, Argentina, and by NIH grant R21-TW007800-01.

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Trends in Neurosciences

OpinionDifferent molecular cascades in different sites of the brain control memory consolidation

Introduction

Section snippets

What is memory consolidation?

Why one-trial avoidance

Main molecular events in CA1 LTP and in the consolidation of one-trial-avoidance memory

Main events in memory formation of one-trial learning in the basolateral amygdala, entorhinal cortex and posterior parietal cortex

What forms of plasticity are involved in each structure?

Why are emotionally-rich memories usually better consolidated?

Endogenous state dependency revisited

A note on the parallel processing of immediate, short-term and long-term memory

A caveat

Can a neural network be proposed?

Concluding remarks

Acknowledgements

Behav. Brain Res.

Neuropharmacology

Neurobiol. Learn. Mem.

Trends Neurosci.

Neurosci. Biobehav. Rev.

Neurobiol. Learn. Mem.

Cortex

Behav. Neural Biol.

Brain Res.

Brain Res.

Neuroscience

Neurobiol. Learn. Mem.

Neurobiol. Learn. Mem.

Brain Res. Rev.

Brain Res.

Cell

Neuron

Curr. Opin. Neurobiol.

J. Biol. Chem.

Neuron

Neurobiol. Learn. Mem.

Brain Res. Rev.

Neuroscience

Mol. Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Behav. Neural Biol.

Neuroscience

Trends Neurosci.

Neuroscience

Curr. Opin. Neurobiol.

Behav. Brain Res.

Behav. Neural Biol.

Prog. Neurobiol.

Ageing Res. Rev.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Long-term potentiation – a decade of progress?

Science

Neuroscience: breaking down scientific barriers to the study of brain and mind

Science

Synaptic plasticity and memory: an evaluation of the hypothesis

Annu. Rev. Neurosci.

The long-term potential of LTP

Nat. Rev. Neurosci.

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

Philos. Trans. R. Soc. Lond. B Biol. Sci.

Behavioural pharmacology and its contribution to the molecular basis of memory consolidation

Behav. Pharmacol.

Molecular pharmacological dissection of short- and long-term memory

Cell. Mol. Neurobiol.

Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway

Behav. Pharmacol.

AMPA/kainate and group-I metabotropic receptor antagonists infused into different brain areas impair memory formation of inhibitory avoidance in rats

Behav. Pharmacol.

Retrograde amnesia induced by drugs acting on different molecular systems depends on how long after training these drugs are infused in selected brain areas

Behav. Neurosci.

Auditory thalamus, dorsal hippocampus, basolateral amygdala, and perirhinal cortex role in the consolidation of conditioned freezing to context and to acoustic conditioned stimulus in the rat

J. Neurosci.

Role of GABA during the multiple consolidation of memory

Drug Dev. Res.

Opinion
Different molecular cascades in different sites of the brain control memory consolidation