Heads of Laboratories
Laboratory of Neurobiology and Behavior
Dr. Pfaff uses molecular, neuroanatomical, 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. Dr. Pfaff recently found that knocking out the gene for the estrogen receptor in animals prevents female reproductive behavior and maternal behaviors. 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. And fourth, Dr. Pfaff has shown that these gene products facilitate reproductive behavior. Together, these four advances proved how specific chemicals acting in specific parts of the brain determine individual behavioral responses.
In experiments uniting the immune, endocrine, and 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 directs the pituitary to stimulate the ovaries and testes. Dr. Pfaff’s lab discovered that GnRH – producing neurons emerge from in the olfactory epithelium and migrate up the nose and into the forebrain and that genetic interruption of that migration, especially in men, results in inadequate testosterone and loss of 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 and humans. In humans, deficits in arousal contribute to cognitive problems such as attention deficit/hyperactivity disorder, autism, and Alzheimer’s disease, and analyzing the mechanisms of arousal may lead to pharmacological methods to enhance alertness and sleep, as well as to the development of more precise anesthesiology. 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.
In conjunction with Alex Proekt, a visiting fellow in the lab, Dr. Pfaff and his team are using mathematical statistics to search for the quantitative properties of a brain emerging from a non-aroused state to an aroused state. Dr. Proekt demonstrated that the transition from inactivity to the activation of behavior follows a power law, and then showed that emergence from anesthetic-caused unconsciousness is not a smooth, monotonic process but instead requires the brain to dwell temporarily in dynamic “hub states.” The team is currently analyzing this finding, with the goal of understanding the temporal patterns of neural activity in arousal systems that explain a person’s emergence from anesthesia.
Finally, studies in the lab have indicated that the origins of central nervous system arousal reside in the activities of large neurons, deep in the hindbrain, called nucleus gigantocellularis. A postdoc in the lab, Inna Tabansky, is using stem cell technology to produce these neurons from mouse embryonic stem cells. In parallel, her team is studying the normal lineage of nucleus gigantocellularis in the developing mouse brain. Taken together, her studies will address questions on the origins of arousal and have implications for certain neurodevelopmental disorders.
Massachusetts Institute of Technology
Massachusetts Institute of Technology, 1965–1966
The Rockefeller University, 1966–1968
Staff Scientist, 1968–1969
Assistant Professor, 1969–1971
Associate Professor, 1971–1973
Associate Professor with Tenure, 1973–1978
The Rockefeller University
Award for Excellence in Professional and Scholarly Publishing, Association of American Publishers, 2005
Fondation IPSEN Prize in Neuronal Plasticity, 2010
Daniel S. Lehrman Lifetime Achievement Award, 2011
National Academy of Sciences
American Academy of Arts and Sciences
Hunter, R.G., et al. Stress and the dynamic genome: steroids, epigenetics, and the transposome. Proc. Natl. Acad. Sci. U.S.A. 112, 6828–6833 (2015).
Faustino, L.C., et al. Impact of thyroid hormones on estrogen receptor α-dependent transcriptional mechanisms in ventromedial hypothalamus and preoptic area. Neuroendocrinology 101, 331–346 (2015).
Davis, E.P. and Pfaff, D. Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder. Psychoneuroendocrinology 49, 11–25 (2014).
Clark S. et al. Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells. J. Steroid Biochem. Mol. Biol. 139, 45–53 (2014).
Gagnidze, K. et al. Early histone modifications in the ventromedial hypothalamus and preoptic area following oestradiol administration. J. Neuroendocrinol. 25, 939–955 (2013).