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We use molecular techniques to analyze (1) how the mammalian brain manages specific natural behaviors and (2) hormonal and genetic influences on generalized brain arousal. While some of this work can be done in nerve cell lines, it is also necessary to study nerve cells in their normal synaptic context to see how, in the governance of behavior, the brain's special connectivity interacts with the types of molecular mechanisms seen in other tissues.

Hormone effects on brain and behavior build upon some of the best studied examples of eukaryotic transcription control. Steroid sex hormones and stress hormones have massive developmental effects, and in the adult brain they control a variety of instinctive behaviors. For example, sex hormone actions around the time of birth determine behavioral sex differences, and early stresss hormone exposure influences later responses to stress.

To analyze at the molecular level, we have shown significant effects of estrogens on the transcription of the genes for the progesterone receptor and for the opioid peptide enkephalin. These hormone effects occur in specific parts of the brain and are required for normal reproductive behavior. They are strong in females but not males, again correlated with behavioral results. These transcriptional effects are due to the binding of estrogen receptors to their cognate DNA sequences, "estrogen response elements," in the promoters of the progesterone receptor and enkephalin genes.

Other transcriptional systems that are hormone sensitive in the brain include the genes for oxytocin, the oxytocin receptor, the delta opioid receptor, the alpha adrenergic receptor, GnRH (LHRH) and the GnRH receptor. We now use microarrays to discover new hormone-sensitive genes in the brain.

Interestingly, other transcription factors can interact with the estrogen receptor in the brain to influence the estrogen effects on gene expression and behavior. That is, thyroid hormone receptors, themselves transcriptionally active, can interfere with estrogen-dependent transcription and behavior. In doing so, thyroid hormones and their receptors bring reproductive controls into concordance with environmental signals, particularly environmental temperature.

The explosion in the number of interesting genetically altered mice is giving us new insights into the relationship between mammalian gene expression and behavior. Using estrogen receptor knockout mice, we showed that the effect of a specific gene on a specific behavior can depend upon the gender in which that gene is expressed as well as upon exactly when and where it is expressed. Functional genomics for these problems constitutes biophysical and behavioral assays in knockout mice. In turn, the combination of mouse gene knockouts with neuropharmacology and antisense DNA technology offers the chance to open a new era, understanding mechanisms connecting gene expression to mammalian behavior.