Yale Center for Genes and Behavior

The objective this new Center is to study genetic contributions to complex behavior under normal conditions and in disease states.

One major goal is to develop novel ways to induce genetic mutations in specific brain regions of laboratory animals, which can then be used to study the functional activity of specific genes. Two approaches are being used: inducible, targeted transgenic mice and viral-mediated gene transfer.

Inducible, targeted transgenic mice have been constructed by use of the tetracycline gene regulation system. This is a bigenic system. One gene encodes the tetracycline transactivator (tTA), which is a tetracycline inhibitable transcription factor. The other gene encodes the protein of interest under the control of the TetOp promoter, which is activated by tTA. To obtain brain-specific expression, tTA was placed under the control of the neuron-specific enolase (NSE) promoter. Depending on the insertion site of the NSE-tTA gene, various lines of these mice drive expression to specific brain regions, including striatum, CA1 region of hippocampus, cerebral neocortex, and cerebellum. We have used this system to obtain brain region-specific and inducible expression of three genes: one that encodes luciferase (a reporter protein) and others that encode deltaFosB or CREB, two transcription factors implicated in neural plasticity. Expression of these genes can be turned completely off by relatively low doses of doxycycline, a tetracycline derivative, and driven to very high levels in the absence of doxycycline. This system thereby provides novel tools with which to study the function of these (or potentially any other) gene in brain function.

We also have been using recombinant herpes viruses to induce overexpression of specific genes in highly localized regions of brain. This work has been carried out in collaboration with Dr. Rachael Neve in the Department of Genetics at Harvard Medical School. By injecting an HSV vector into a specific brain region, it is possible to induce overexpression of a protein of interest in that injected region in the absence of detectable toxicity. Work to date has focused on viral-mediated overexpression of glutamate receptor subunits and of CREB. See Carlezon et al., Science 277:812-814 (1997) for further information.

A second major goal of the Yale Center for Genes and Behavior is to develop a range of behavioral assays to screen animals with these various genetic mutations. Rather than focusing on a single behavioral abnormality, our objective is to gain a more global understanding of the behavioral consequences of alterations in a given gene or collection of genes.

By synthesizing these two goals, we hope to contribute to a gradual understanding of the ways in which a host of individual genes and their products affect complex behaviors associated with reinforcement, motivation, cognition, learning, memory, and affective state.

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