Genome-wide Functional Analysis of CREB/Long-Term Memory-Dependent Transcription Reveals Distinct Basal and Memory Gene Expression Programs

Lakhina, Vanisha; Arey, Rachel N.; Kaletsky, Rachel; Kauffman, Amanda; Stein, Geneva M.; Keyes, William; Xu, Daniel; Murphy, Coleen T.

doi:10.1016/j.neuron.2014.12.029

Cited by 123 publications

(121 citation statements)

References 60 publications

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“…Moreover, transcription factor up-regulation might occur in response to the first phase of transcription occurring shortly after induction of mechanisms leading to long-term synaptic plasticity (117). Contribution of transcription factors could be detected during the second transcription phase necessary for memory gene expression program, as it was recently shown for CREB transcription factor activity, a hallmark of LTM (118). This suggestion is suitable for the network assembled around the proteins positively correlating with factor 2, showing enrichment of transcription, mRNA processing, and translation related gene enrichment (Suppl.…”

Section: Discussionmentioning

confidence: 93%

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Borovok

Nesher

Levin

et al. 2016

Molecular & Cellular Proteomics

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Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phasecurbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) Long-term synaptic plasticity is considered a cellular correlate of long-term memory (LTM) 1 . Contemporary understanding of memory formation is based on the initiation and maintenance of long-term synaptic plasticity (1-4), for which de novo protein synthesis is a vital requirement. De novo protein synthesis itself is secondary to activity-dependent changes in synapses that occur during learning processes. These activity changes trigger post-translational modifications of proteins initiating and sustaining multiple signal transduction pathways. In turn, these signaling pathways regulate changes in synaptic strength and connectivity by governing gene expression and protein translation (5-13). Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18). Multiple synaptic From the ‡Department

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Section: Discussionmentioning

confidence: 93%

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Borovok

Nesher

Levin

et al. 2016

Molecular & Cellular Proteomics

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“…We previously found that similar to Drosophila , mice, and other higher organisms[3], C. elegans ’ associative learning and memory also decline with age; this happens at a much faster rate than many other types of aging-associated neuronal dysfunctions[34, 35]. For example, unlike chemotaxis (Figures 5B–C naïve) and motility behaviors, which remain intact during the first 7 days of adulthood, long-term associative memory (16 hr) declines as early as day 4 in wild-type animals[34].…”

Section: Resultsmentioning

confidence: 99%

The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory

Lei

Arey

et al. 2016

Current Biology

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Summary Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging, and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, while upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2 signaling pathway, and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging, and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.

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“…Notably, CREB is required for long-term appetitive olfactory learning and long-term habituation in C. elegans as well as aversive imprinting (Kauffman et al, 2010; Timbers and Rankin, 2011); in each case, CREB is required for memory that lasts at least 24 hours. In long-term appetitive olfactory training, CREB changes the expression of over 1000 genes (Lakhina et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Distinct Circuits for the Formation and Retrieval of an Imprinted Olfactory Memory

Jin

Pokala

Bargmann

2016

Cell

121

181

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Summary Memories formed early in life are particularly stable and influential, representing privileged experiences that shape enduring behaviors. Here we show that exposing newly-hatched C. elegans to pathogenic bacteria results in persistent aversion to those bacterial odors, whereas adult exposure generates only transient aversive memory. Long-lasting imprinted aversion has a critical period in the first larval stage, and is specific to the experienced pathogen. Distinct groups of neurons are required during formation (AIB, RIM) and retrieval (AIY, RIA) of the imprinted memory. RIM synthesizes the neuromodulator tyramine, which is required in the L1 stage for learning. AIY memory retrieval neurons sense tyramine via the SER-2 receptor, which is essential for imprinted but not for adult-learned aversion. Odor responses in several neurons, most notably RIA, are altered in imprinted animals. These findings provide insight into neuronal substrates of different forms of memory, and lay a foundation for further understanding of early learning.

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Genome-wide Functional Analysis of CREB/Long-Term Memory-Dependent Transcription Reveals Distinct Basal and Memory Gene Expression Programs

Cited by 123 publications

References 60 publications

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory

Distinct Circuits for the Formation and Retrieval of an Imprinted Olfactory Memory

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