Heads of Laboratories
Dr. Pfaff uses neuroanatomical, neurochemical and neurophysiological methods to study the cellular mechanisms by which the brain controls behavior. His laboratory’s research has focused on steroid hormone effects on nerve cells as they direct natural, instinctive behaviors, as well as the influences of hormones and genes on generalized brain arousal.
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 to primates. This hormone-sensitive system apparently is a general feature of the vertebrate brain, and Dr. Pfaff recently found that knocking out the gene for the estrogen receptor in animals prevents female reproductive 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 that estrogens can turn on several genes in the forebrain. Fourth, Dr. Pfaff has shown that these gene products facilitate reproductive behavior. Turning on the gene for the progesterone receptor, for example, can stimulate the hormone estrogen to turn on another gene whose product is important for modulating mating behavior. Together, these four advances proved for the first time how specific chemicals acting in specific parts of the brain can determine individual behavioral responses.
In an experiment that lent support to the concept of the “unity of the body,” uniting the immune, the endocrine and the nervous systems with behavior, Dr. Pfaff and his colleagues were the first to genetically link the neuroimmune system to emotional behavior, showing that mast cells in the brain mediate anxious behavior in mice. They also found that the nervous system protein GnRH promotes reproductive behavior as well as directing 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 then found 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. Genetic interruption of that migration, especially in men, results in inadequate amounts of the sex hormone testosterone and a subsequent loss of sexual motivation, libido.
Dr. Pfaff’s study of generalized arousal, which activates all behavioral responses, led to the first operational definition of the term, enabling scientists to measure arousal quantitatively in laboratory animals as well as in human beings. In humans, deficits in arousal contribute to cognitive problems such 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 the development of more precise anesthesiology. Most recently, Dr. Pfaff and his colleagues pitted two forces of arousal — hunger and circadian rhythms — against each other, showing that these two pathways converge at the ventromedial hypothalamus and that this brain region is the first to register changes in food availability. Now they are searching for temporal patterns of neural activity in arousal systems that explain a person’s emergence from anesthesia.
Finally, Dr. Pfaff has made fundamental contributions to our understanding of how the administration of sex hormones can affect health. His lab 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. Actions of sex hormones are crucial, at both the level of the brain cell’s outer membrane and inside the nucleus where the cell’s DNA is housed, in triggering hormone-dependent gene expression and behavioral functions.
Dr. Pfaff graduated from Harvard College magna cum laude and 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.
Dr. Pfaff is a member of the 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 book, Brain Arousal and Information Theory. He is the recipient of a share of the 2010 Ipsen Foundation Prize in Neuronal Plasticity and received the Daniel S. Lehrman Lifetime Achievement Award in Behavioral Neuroendocrinology in 2011.
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