Molecular and cellular mechanisms of memory allocation in neuronetworks

https://doi.org/10.1016/j.nlm.2007.08.017Get rights and content

Abstract

Determining how neuronal networks encode memories is a key goal of neuroscience. Although neuronal circuit processes involved in encoding, storing and retrieving memory have attracted a great deal of attention, the processes that allocate individual memories to specific neurons within a network have remained elusive. Recent findings unraveled the first insights into the processes that modulate memory allocation in neuronetworks. They showed that neurons in the lateral amygdala compete to take part in auditory fear conditioned memory traces and that the levels of the transcription factor CREB (cAMP-response element binding protein) can affect the probability of a neuron to be recruited into a given memory representation. CREB-mediated transcriptional regulation involves several signaling pathways, known to mediate nuclear responses to diverse behavioral stimuli, along with coordinated interactions with multiple other transcription activators, coactivators and repressors. Moreover, activation of CREB triggers an autoinhibitory feedback loop, a metaplastic process that could be used to allocate memories away from cells that have been recently involved in memory. Beyond CREB, there may be a host of other processes that dynamically modulate memory allocation in neuronetworks by shaping cooperation and competition among neurons.

Section snippets

Memory allocation: A competitive process

Memory depends on specific sets of connected neurons which together support the ‘memory trace’ (McGaugh, 1972, Thompson, 2005). Electrophysiological and cellular imaging studies demonstrated that only a portion of neurons are involved in a given memory (Repa et al., 2001, Rumpel et al., 2005). Despite numerous studies on the nature and properties of memory traces, little is known about how memories are allocated into specific subsets of neurons in a given neuronetwork.

Activity-dependent

Role of CREB in competitive memory allocation

CREB, a member of a family of structurally related transcription factors, is widely expressed in the brain and its activity is induced in response to calcium, neurotrophin, and cytokine signals as well as a variety of cellular stresses (Carlezon et al., 2005, Lonze and Ginty, 2002, Mayr and Montminy, 2001, Shaywitz and Greenberg, 1999, Silva et al., 1998). Membrane depolarization or/and an elevation of cAMP strongly induce the phosphorylation of CREB at serine 133, and thereby activate

What are the mechanisms underlying CREB-mediated competitive memory allocation?

How do neurons with higher levels/activity of CREB gain a competitive edge during memory allocation? CREB regulates a diverse array of genes, and many CREB targets (e.g., c-fos, JunD, C/EBPβ, Egr1, Nurr1, etc.) are themselves transcription factors that regulate other genes. Multiple CREB target genes could contribute to the coordinate regulation of the memory allocation process. Much effort has been invested on identifying the CREB ‘transcriptome’ or ‘regulon’, a complex that includes all genes

Potential molecular pathways regulating memory allocation

The finding that neurons with higher levels of CREB activity become memory attractors, while those with low levels are less likely to participate in a given memory trace, suggest that some or all of the cooperating and antagonizing signaling pathways known to regulate CREB activity (Fig. 2) might also affect the competitive memory allocation process.

CREB is crucial for translating diverse behavioral stimuli into transcriptional responses in the nucleus. Several intracellular signaling pathways

Metaplasticity in memory allocation

It is possible that the acquisition of a memory changes the activity of CREB (activation followed by repression due to the transcription of CREB repressors such as inducible cAMP early repressor, ICER), which then decreases the probability that the cells engaged in the first memory participate in a second memory some time later. Memories created very close in time are a special challenge because of the high likelihood that there will be common attributes and overlapping contexts. Dynamic memory

Reconsolidating the allocation of stored memories

Transgenic studies with inducible CREB mice showed that CREB plays a key role in the reconsolidation as well as consolidation of memory (Kida et al., 2002). It would be exciting to examine whether reconsolidation, just as consolidation, involves the reallocation of memories, and whether CREB plays a role in this process. The levels and activities of CREB in each neuron might differ dramatically during acquisition and retrieval. Therefore, reactivation of memory circuits during retrieval and

Concluding remarks

Recent findings show that competition between neurons, which has been demonstrated to be necessary for refining neural circuits during development, may be important for selecting the neurons that participate in encoding memories in the adult brain. They also suggest that CREB mediates the competition between neuronal cells that leads to the formation of memory traces. Yet, there are both competing as well as cooperating pathways regulating CREB activity in neurons (Carlezon et al., 2005, Lonze

Acknowledgments

We would like to thank Silva lab members for comments on the manuscript. This work was supported by grants from the NIH (AG013622 and MH077972).

References (67)

  • R. Fonseca et al.

    Competing for memory: Hippocampal LTP under regimes of reduced protein synthesis

    Neuron

    (2004)
  • N.S. Foulkes et al.

    CREM gene: Use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription

    Cell

    (1991)
  • G.A. Gonzalez et al.

    Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133

    Cell

    (1989)
  • S. Impey et al.

    Defining the CREB regulon: A genome-wide analysis of transcription factor regulatory regions

    Cell

    (2004)
  • E. Korzus et al.

    CBP histone acetyltransferase activity is a critical component of memory consolidation

    Neuron

    (2004)
  • B.E. Lonze et al.

    Function and regulation of CREB family transcription factors in the nervous system

    Neuron

    (2002)
  • H. Marie et al.

    Generation of silent synapses by acute in vivo expression of CaMKIV and CREB

    Neuron

    (2005)
  • K.D. Miller

    Synaptic economics: Competition and cooperation in synaptic plasticity

    Neuron

    (1996)
  • T.A. Pham et al.

    CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period

    Neuron

    (1999)
  • T.A. Pham et al.

    The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons

    Neuron

    (2001)
  • A.V. Tzingounis et al.

    Arc/Arg3.1: Linking gene expression to synaptic plasticity and memory

    Neuron

    52

    (2006)
  • N. Vo et al.

    CREB-binding protein and p300 in transcriptional regulation

    Journal of Biological Chemistry

    (2001)
  • T.L. Wallace et al.

    Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety

    Biological Psychiatry

    (2004)
  • X. Wu et al.

    Calmodulin kinase II attenuation of gene transcription by preventing cAMP response element-binding protein (CREB) dimerization and binding of the CREB-binding protein

    Journal of Biological Chemistry

    (2001)
  • J.C. Yin et al.

    CREB as a memory modulator: Induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila

    Cell

    (1995)
  • R.J. Cabelli et al.

    Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF

    Science

    (1995)
  • G. Canettieri et al.

    Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex

    Nature Structural Biology

    (2003)
  • H. Cha-Molstad et al.

    Cell-type-specific binding of the transcription factor CREB to the cAMP-response element

    Proceedings of the National Academy of Science United States of America

    (2004)
  • J.R. Chao et al.

    Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREB

    European Journal of Neuroscience

    (2002)
  • W.G. Chen et al.

    Depression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2

    Science

    (2003)
  • Y. Dong et al.

    CREB modulates excitability of nucleus accumbens neurons

    Nature Neuroscience

    (2006)
  • M.S. Fanselow et al.

    The amygdala, fear, and memory

    Annals of the New York Academy of Sciences

    (2003)
  • J. Feng et al.

    Epigenetic regulation of neural gene expression and neuronal function

    Pediatric Research

    (2007)
  • Cited by (71)

    • Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment

      2021, Experimental Neurology
      Citation Excerpt :

      Previous studies report that phosphorylation and activation of the nuclear transcription factor cAMP-response element binding protein (CREB) at Ser133 induces transcription of CRE-related genes and protein synthesis. CRE-related genes are essential for long-lasting synaptic plasticity and memory; however, their activity is impaired by oAβ in AD (Gong et al., 2006; Pugazhenthi et al., 2011; Won and Silva, 2008). Notably, CREB phosphorylation is not sufficient for CREB-dependent gene transcription (Briand et al., 2015; Impey et al., 1996), it requires recruitment of specific coactivators including CREB binding protein (CBP)/p300 and other phosphorylation sites.

    • The up and down of sleep: From molecules to electrophysiology

      2019, Neurobiology of Learning and Memory
    View all citing articles on Scopus
    View full text