Donald W. Pfaff, Ph.D.
Pfaff uses molecular, neuroanatomical, and neurophysiological methods to study the cellular mechanisms by which the vertebrate 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.
The Pfaff lab, which investigates the cellular control mechanisms for behavior, has two areas of focus: steroid hormones’ influence on the brain and generalized arousal of the central nervous system. Over several years, they solved the question of how hormone action in the brain regulates a specific social behavior.
Current work in Pfaff’s lab focuses on the question: How do animals or humans initiate any behavior at all? His work began to answer the question by framingthe concept of generalized arousal. Pfaff offered the first operational definition of GA, which activates all behavioral responses, enabling scientists to measure arousal quantitatively. In humans, deficits in GA contribute to a wide variety of cognitive and emotional problems, from depression to dementia.
Pfaff and physicist Jayanth Banavar have gathered large amounts of precise behavioral data to test their theory that rapid alterations between not/active and active/aroused act like a physical “phase transition.” The lab measured the behavior of individual mice in GA assay chambers at 20-millisecond resolution and described the behavioral changes preciselyin mathematical terms. On a longer, circadian time scale, the transition from light (not aroused) to dark (aroused) follows an entirely different equation precisely—and from dark back to light shows a surprising reverse symmetry.
The cellular origins of central nervous system arousal, GA, reside deep in the hindbrain, in the nucleus gigantocellularis (NGC). Using the developing mouse brain, the lab is investigating the transcriptional regulation responsible for NGC neuron birth and migration. Meanwhile, cultured NGC neurons are being recorded on multi-electrode arrays and lab members are working to reconstruct reticulospinal systems, which arise from the NGC, in vitro.
The Pfaff lab endeavors to derive these crucial neurons from mouse embryonic stem cells. So far they have determined the transcriptome of these GA master cells with special attention to mRNAs within axonal projections to the thalamus responsible for “waking up” the cerebral cortex. One transcript is unique to this subpopulation of NGC neurons,and several others suggest how these NGC neurons manage their metabolism to survive challenges and prevent GA failures.
The lab is testing the hypothesis that first expression of the delayed rectifier current using a class of potassium channel which they believe accounts for the initial burst of heightened excitability seen in young NGC neurons in the mouse and in culture. From postnatal day 3 to 6, pups’ arousal increases dramatically as does NGC excitability, suggesting delayed rectifier expression is responsible. Using the same patchclamp technology with individual NGC neurons, the Pfaff lab is starting to measure the effects o fspecific environmental toxins.