CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats.

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability.

A robust activity marking system for exploring active neuronal ensembles.

Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control.

Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling.

Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed.

Notch Intracellular Domain (NICD) Suppresses Long-Term Memory Formation in Adult Drosophila Flies.

Notch receptor signaling is evolutionarily conserved and well known for its roles in animal development. Many studies in Drosophila have shown that Notch also performs important functions in memory formation in adult flies. An intriguing observation is that increased expression of the full-length Notch receptor (Nfull) triggers long-term memory (LTM) formation even after very weak training (single training).

Spatio-temporal in vivo recording of dCREB2 dynamics in Drosophila long-term memory processing.

CREB (cAMP response element-binding protein) is an evolutionarily conserved transcription factor, playing key roles in synaptic plasticity, intrinsic excitability and long-term memory (LTM) formation. The Drosophila homologue of mammalian CREB, dCREB2, is also important for LTM. However, the spatio-temporal nature of dCREB2 activity during memory consolidation is poorly understood.

Time of day influences memory formation and dCREB2 proteins in Drosophila.

Many biological phenomena oscillate under the control of the circadian system, exhibiting peaks and troughs of activity across the day/night cycle. In most animal models, memory formation also exhibits this property, but the underlying neuronal and molecular mechanisms remain unclear. The dCREB2 transcription factor shows circadian regulated oscillations in its activity, and has been shown to be important for both circadian biology and memory formation.

From Drosophila development to adult: clues to Notch function in long-term memory.

Notch is a cell surface receptor that is well known to mediate inter-cellular communication during animal development. Data in the field indicate that it is also involved in the formation of long-term memory (LTM) in the fully developed adults and in memory loss upon neurodegeneration. Our studies in the model organism Drosophila reveal that a non-canonical Notch-protein kinase C activity that plays critical roles in embryonic development also regulates cyclic-AMP response element binding protein during LTM formation in adults.

ERK phosphorylation regulates sleep and plasticity in Drosophila.

Given the relationship between sleep and plasticity, we examined the role of Extracellular signal-regulated kinase (ERK) in regulating baseline sleep, and modulating the response to waking experience. Both sleep deprivation and social enrichment increase ERK phosphorylation in wild-type flies. The effects of both sleep deprivation and social enrichment on structural plasticity in the LNvs can be recapitulated by expressing an active version of ERK (UAS-ERK(SEM)) pan-neuronally in the adult fly using GeneSwitch (Gsw) Gsw-elav-GAL4.

Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation.

The transcription factor CREB is an important regulator of many adaptive processes in neurons, including sleep, cellular homeostasis, and memory formation. The Drosophila dCREB2 family includes multiple protein isoforms generated from a single gene. Overexpression of an activator or blocker isoform has been shown to enhance or block memory formation, but the molecular mechanisms underlying these phenomena remain unclear.

Notch-inducible hyperphosphorylated CREB and its ultradian oscillation in long-term memory formation.

Notch is a cell surface receptor that is known to regulate developmental processes by establishing physical contact between neighboring cells. Many recent studies show that it also plays an important role in the formation of long-term memory (LTM) in adults, implying that memory formation requires regulation at the level of cell-cell contacts among brain cells. Neither the target of Notch activity in LTM formation nor the underlying mechanism of regulation is known.

Developing BACE-1 inhibitors for FXS.

Fragile X syndrome (FXS) is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression. Two of the overexpressed proteins are amyloid-beta protein precursor (APP) and its metabolite amyloid-beta, which have been well-studied in Alzheimer's disease (AD).

dCREB2-mediated enhancement of memory formation.

CREB-responsive transcription has an important role in adaptive responses in all cells and tissue. In the nervous system, it has an essential and well established role in long-term memory formation throughout a diverse set of organisms. Activation of this transcription factor correlates with long-term memory formation and disruption of its activity interferes with this process.

In vivo circadian oscillation of dCREB2 and NF-κB activity in the Drosophila nervous system.

cAMP response element-binding protein (CREB) and nuclear factor kappa-B (NF-κB) are two ubiquitous transcription factors involved in a wide number of cellular processes, including the circadian system. Many previous studies on these factors use cellular assays that provide limited information on circadian activity or anatomical specificity. The ability to study transcription factors in defined tissue within intact animals will help to bridge the gap between cellular and in vivo data.

Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in drosophila.

Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral-ventral pacemaker neurons (LN(v)s) that secrete the neuropeptide PDF (pigment dispersing factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity.

Mg(2+) block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression.

NMDA receptor (NMDAR) channels allow Ca(2+) influx only during correlated activation of both pre- and postsynaptic cells; a Mg(2+) block mechanism suppresses NMDAR activity when the postsynaptic cell is inactive. Although the importance of NMDARs in associative learning and long-term memory (LTM) formation has been demonstrated, the role of Mg(2+) block in these processes remains unclear. Using transgenic flies expressing NMDARs defective for Mg(2+) block, we found that Mg(2+) block mutants are defective for LTM formation but not associative learning.

Cytoplasmic to nuclear localization of fatty-acid binding protein correlates with specific forms of long-term memory in Drosophila.

We recently reported evidence implicating fatty-acid binding protein (Fabp) in the control of sleep and memory formation. We used Drosophila melanogaster to examine the relationship between sleep and memory through transgenic overexpression of mouse brain-Fabp, Fabp7, or the Drosophila Fabp homolog, (dFabp). The key findings are that 1) a genetically induced increase in daytime consolidated sleep (naps) correlates with an increase in cognitive performance, and 2) a late "window" of memory consolidation occurs days after the traditionally understood "synaptic" consolidation.

A time-dependent history of mood disorders in a murine model of neuropathic pain.

Background: Chronic pain is clinically associated with the development of affective disorders. However, studies in animal models of neuropathic pain are contradictory and the relationship with mood disorders remains unclear. In this study, we aimed to characterize the affective consequences of neuropathic pain over time and to study potential underlying mechanisms.

Loss of PTB or negative regulation of Notch mRNA reveals distinct zones of Notch and actin protein accumulation in Drosophila embryo.

Polypyrimidine Tract Binding (PTB) protein is a regulator of mRNA processing and translation. Genetic screens and studies of wing and bristle development during the post-embryonic stages of Drosophila suggest that it is a negative regulator of the Notch pathway. How PTB regulates the Notch pathway is unknown.

Memory formation: filling in the gaps in flies.

Research in Drosophila has many advantages for the study of complex behavior. Two studies identify a new role for chemical and electrical signaling in the anterior paired lateral neurons during memory formation.

Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling.

Background: Mice lacking type 1 equilibrative nucleoside transporter (ENT1(-/-)) exhibit increased ethanol-preferring behavior compared with wild-type littermates. This phenotype of ENT1(-/-) mice appears to be correlated with increased glutamate levels in the nucleus accumbens (NAc). However, little is known about the downstream consequences of increased glutamate signaling in the NAc.

Fatty-acid binding proteins modulate sleep and enhance long-term memory consolidation in Drosophila.

Sleep is thought to be important for memory consolidation, since sleep deprivation has been shown to interfere with memory processing. However, the effects of augmenting sleep on memory formation are not well known, and testing the role of sleep in memory enhancement has been limited to pharmacological and behavioral approaches. Here we test the effect of overexpressing the brain-type fatty acid binding protein (Fabp7) on sleep and long-term memory (LTM) formation in Drosophila melanogaster.

Circadian rhythms and memory formation.

There has been considerable progress in elucidating the molecular mechanisms that contribute to memory formation and the generation of circadian rhythms. However, it is not well understood how these two processes interact to generate long-term memory. Recent studies in both vertebrate and invertebrate models have shown time-of-day effects on neurophysiology and memory formation, and have revealed a possible role for cycling molecules in memory persistence.

GLD2 poly(A) polymerase is required for long-term memory.

The formation of long-term memory is believed to require translational control of localized mRNAs. In mammals, dendritic mRNAs are maintained in a repressed state and are activated upon repetitive stimulation. Several regulatory proteins required for translational control in early development are thought to be required for memory formation, suggesting similar molecular mechanisms.

The cyclic AMP phenotype of fragile X and autism.

Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism.