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. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.

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. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system's versatility.

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. Exactly how Fabp-signaling may be involved in converting normal to enhanced long-term memory (LTM) is not known. Here we describe additional data which support relative subcellular compartmental localization of Fabp in regulating stage associations of different forms of memory in Drosophila. Anesthesia resistant memory (ARM) is a longer lasting memory that is produced by massed training, but unlike LTM produced by spaced training, it is insensitive to protein synthesis inhibitors and does not persist as long. We observed that the ratio of ARM to LTM performance index of Fabp7-transgenic flies is proportional to the relative cytoplasmic to nuclear Fabp7 expression level. These data suggest a common lipid-signaling cascade exists between phases of memory formation previously thought to be molecularly distinct.