Dr. Pfaff’s research has proceeded through four steps to demonstrate how steroid hormone effects on nerve cells can direct natural, instinctive behaviors. First, Dr. Pfaff is known for discovering exact cellular targets for steroid hormones in the brain. A system of hypothalamic and limbic forebrain neurons with sex hormone receptors, discovered in rodents, was later found to be present in species ranging from fish through primates. This hormone-sensitive system apparently is a general feature of the vertebrate brain, and Dr. Pfaff has recently found that knocking out the gene for the estrogen receptor in animals prevents female reproductive behavior. The deletion results both in masculinizing female animals and, counterintuitively, feminizing males’ behavior.

Second, Dr. Pfaff’s lab has worked out the neural circuitry for hormone-dependent female reproductive behavior, the first behavior circuit elucidated for any mammal. Third, they have demonstrated several genes that are turned on by estrogens in the forebrain. Fourth, Dr. Pfaff has shown that these gene products facilitate reproductive behavior. For example, the induction of one of them, the gene for the progesterone receptor, showed that the hormone estrogen could turn on another transcription factor important, in turn, for behavioral control.

Taken together, these four advances have proved that specific chemicals acting in specific parts of the brain could determine individual behavioral responses. While two genetic transcription factors, estrogen receptor and progesterone receptor, cooperate to promote reproductive behavior, another transcription factor, thyroid hormone receptor, interferes with estrogenic actions. Seasonal environmental changes that raise thyroid hormone levels can therefore block reproductive behaviors when they would be biologically inappropriate.

In an experiment that lent support to the concept of the “unity of the body,” Dr. Pfaff found that the nervous system protein GnRH promotes reproductive behavior as well as directs the pituitary to stimulate the ovaries and testes. This action of GnRH renders instinctive behaviors congruent with the physiology of reproductive organs elsewhere in the body. Dr. Pfaff’s lab subsequently discovered that GnRH-producing neurons are not actually born in the brain as other neurons are, but are born in the olfactory epithelium, and then migrate up the nose and into the forebrain. In humans, interruption of that migration, especially in men, results in inadequate amounts of the sex hormone testosterone.

Dr. Pfaff’s study of generalized arousal, responsible for activating all behavioral responses, has led to the first operational definition of nervous system arousal, enabling scientists to measure arousal quantitatively in laboratory animals as well as in human beings. In humans, deficits in arousal contribute to such cognitive problems as attention deficit hyperactivity disorder, autism and Alzheimer’s disease. Analyzing the mechanisms of arousal may lead to the development of pharmacological methods to enhance alertness during the day and sleep at night, as well as to the development of more precise anesthesiology.

Finally, Dr. Pfaff has made fundamental contributions to our understanding of how the administration of sex hormones can affect health. His lab recently showed that giving hormone doses in pulses, rather than as a steady exposure, may maximize the benefits and limit the side effects now associated with hormone therapies. In studies of rats, the scientists showed the actions of the hormone are crucial, at both the level of the brain cell’s protective outer membrane and inside the nucleus where the cell’s DNA is housed, in triggering hormone-dependent gene expression and female mating behavior. By limiting the estrogen exposure to short pulses, the total dose can be kept smaller, reducing negative effects.

CAREER

Dr. Pfaff received his Ph.D. from the Massachusetts Institute of Technology in 1965. He joined Rockefeller in 1966 as a postdoc and was named assistant professor in 1969. He was granted tenure in 1973 and promoted to full professor in 1978.

He is a member of the U.S. National Academy of Sciences and a fellow of the American Academy of Arts and Sciences. The author of several books on the brain and behavior, he received the 2005 Award for Excellence in Professional and Scholarly Publishing (medical science category) of the Association of American Publishers for his most recent book, Brain Arousal and Information Theory. He was the recipient of a National Institutes of Health Merit Award in 2003.