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. In four distinct steps, previous work in his lab has shown how specific chemicals, the steroid hormones, act in certain parts of the brain to direct natural, instinctive behaviors. First, he identified in rodents the exact cellular targets in the hypothalamic and limbic forebrain for steroid hormones, opening the door for the discovery of similar sex hormone receptor systems in species ranging from fish to primates.
Second, Pfaff’s lab worked out the neural circuitry for hormone-dependent female reproductive behavior, the first behavior circuit elucidated for any vertebrate. Third, they followed up on this discovery by using estrogens to turn on several genes in the forebrain. Fourth, Pfaff has shown these gene products facilitate reproductive behavior. For example, knocking out the estrogen receptor gene prevents female reproductive and maternal behaviors.
Current work in Pfaff’s lab focuses on the question: Why do animals or humans do anything at all? His work seeks an answer through the concept of generalized arousal (GA). He 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 suggesting the onset of GA is a phase transition. Now the lab is following individual mice through this phase transition at 20-millisecond resolution to describe the behavioral change in mathematical terms, and to follow up on a preliminary discovery of a striking sex difference.
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 the dish.
Lee-Ming Kow is testing the hypothesis that first expression of the delayed rectifier, a class of potassium channel, 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.
Meanwhile, Inna Tabansky is endeavoring to derive these crucial neurons from mouse embryonic stem cells. Collaborating with the Friedman lab, she has 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. She has so far uncovered one transcript unique to this subpopulation of NGC neurons and several that suggest how these NGC neurons manage their metabolism to survive challenges and prevent GA failures.