Molecular and cellular mechanisms of memory allocation in neuronetworks
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)
- et al.
Metaplasticity: The plasticity of synaptic plasticity
Trends in Neurosciences
(1996) - et al.
Chromatin acetylation, memory, and LTP are impaired in CBP mice: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration
Neuron
(2004) - et al.
Use of the whole-cell patch-clamp method in studies on the role of cAMP in regulating the spontaneous firing of locus coeruleus neurons
Journal of Neuroscience Methods
(1995) - et al.
CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation
Cell
(1998) - et al.
Aplysia CREB2 represses long-term facilitation: Relief of repression converts transient facilitation into long-term functional and structural change
Cell
(1995) - et al.
The many faces of CREB
Trends in Neurosciences
(2005) - et al.
Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins
Neuron
(2003) - et al.
Signaling routes to CREM and CREB: plasticity in transcriptional activation
Trends in Biochemical Sciences
(1999) - et al.
Transcriptional regulation by cyclic AMP-responsive factors
Progress in Nucleic Acid Research and Molecular Biology
(2000) - et al.
Deacetylase activity is required for cAMP activation of a subset of CREB target genes
Journal of Biological Chemistry
(2003)
Competing for memory: Hippocampal LTP under regimes of reduced protein synthesis
Neuron
CREM gene: Use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription
Cell
Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133
Cell
Defining the CREB regulon: A genome-wide analysis of transcription factor regulatory regions
Cell
CBP histone acetyltransferase activity is a critical component of memory consolidation
Neuron
Function and regulation of CREB family transcription factors in the nervous system
Neuron
Generation of silent synapses by acute in vivo expression of CaMKIV and CREB
Neuron
Synaptic economics: Competition and cooperation in synaptic plasticity
Neuron
CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period
Neuron
The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons
Neuron
Arc/Arg3.1: Linking gene expression to synaptic plasticity and memory
Neuron
52
CREB-binding protein and p300 in transcriptional regulation
Journal of Biological Chemistry
Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety
Biological Psychiatry
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
CREB as a memory modulator: Induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila
Cell
Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF
Science
Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex
Nature Structural Biology
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
Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREB
European Journal of Neuroscience
Depression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2
Science
CREB modulates excitability of nucleus accumbens neurons
Nature Neuroscience
The amygdala, fear, and memory
Annals of the New York Academy of Sciences
Epigenetic regulation of neural gene expression and neuronal function
Pediatric Research
Cited by (71)
The gut-brain axis involved in polystyrene nanoplastics-induced neurotoxicity via reprogramming the circadian rhythm-related pathways
2023, Journal of Hazardous MaterialsDysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment
2021, Experimental NeurologyCitation 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