We are interested in the brain and how memories are formed, stabilized, and retrieved. We are also interested in the human diseases that affect learning and memory, including Alzheimer’s, schizophrenia, bipolar disorder, autism, and ADHD. We study learning and memory at the genetic level to understand the structure, regulation, evolution and biological function of genes that are required for normal learning and memory. Studies at the cellular level help us to understand how the gene products involved in learning and memory mediate physiological changes in the neurons that encode memories. We also focus effort at the level of anatomy to understand the pathways of information flow in the brain for normal learning to occur, and at the behavioral level to probe the complexities of memory formation.

Numerous genes important for learning in Drosophila have been studied extensively. Some of these include dunce, rutabaga, DCO, and CREB. Flies defective in the expression of any of these genes exhibit poor memory formation for olfactory conditioning tasks. Molecular cloning has demonstrated that dunce codes for the enzyme, cAMP phosphodiesterase; rutabaga codes for adenylyl cyclase; DCO codes for the catalytic subunit of protein kinase A, and CREB a transcription factor that is phosphorylated and activated by protein kinase A. These results demonstrate that the cAMP signaling system is critical for altering the physiological state of the neurons that mediate this type of learning. Other studies have shown that a family of proteins called 14-3-3 are involved in learning along with interesting cell adhesion molecules of the integrin family and the immunoglobulin superfamily. Moreover, we have studied several biogenic amine receptors, including dopamine receptors that are involved in the acquisition of initial memories. By studying the expression of these genes, the neurons that mediate learning have been identified. These include the mushroom body cells. All of the genes discussed above are preferentially expressed in these neurons. Our current goals include understanding these and other genes and the role of mushroom body neurons in further detail.

We have developed a powerful new imaging technology that allows us to visualize changes that occur in the brain of Drosophila due to learning. Using this technology, we have discovered several of these changes, or memory traces, in different neurons of the brain (Figure). Some changes occur immediately after learning and persist for only a few minutes; others form with a delay of up to several hours and likely persist for days. Thus, behavioral memory may be due to the effects of multiple memory traces, each controlling behavior over discrete windows of time after learning.

It is important to determine whether the genes identified from model systems like Drosophila also serve mammalian behavior. To approach this, we have cloned mouse homologs of some of the aforementioned genes and have genetically studied their role in mammalian behavior. Of high interest are the knockouts of certain integrin genes, which produce an impairment of working memory without affecting other types of memory. These knockouts may be important models for human brain diseases that affect working memory including Alzheimer’s Disease, schizophrenia, autism, and ADHD.

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