Clifford Saper Lab: Research
Clifford B. Saper, James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School, and Chair, Department of Neurology, Beth Israel Deaconess Medical Center.
The focus of the Saper laboratory is on the integrated functions maintained by the hypothalamus, including regulation of wake-sleep cycles, body temperature, and feeding and their interactions with to external stressors, ranging from immune stimuli, to food or sleep deprivation, to behavioral stress. The goal of our laboratory is to identify the neuronal circuitry that is involved in regulating these responses. To do this, we use a wide range of methodologies. To establish specific circuitry, we often use morphological methods, particularly combining axonal tracer methods with in situ hybridization and immunohistochemistry to determine the chemical phenotypes of neurons. We also examine the changes in gene expression in these neurons under different physiological conditions, such as changes in feeding, wake-sleep, and after applying immune stressors. At the same time, we also employ a wide range of physiological chronic recording methods, including wake-sleep, body temperature, activity, feeding, hormone levels, etc. to correlate the changes in gene expression in the brain with the changes in behavior. We then use both cell-specific lesion methods, as well as genetic knockouts, and intracerebral application of drugs to manipulate these systems, and identify the roles played by specific neurotransmitter systems. This work is augmented by our use of intracellular recordings in slice preparations, to determine the effects of specific neurotransmitters on identified cell populations in the hypothalamus.
Most recently, we have been developing conditional knockin and knockout models for specific genes involved in neurotransmission, ranging from receptors (such as orexin or prostaglandin E2) to transporters (such as vesicular GABA or glutamate transporters) involved in these responses. We have developed viral vectors containing Cre recombinase that allows us to manipulate these genes in specific cell populations, and to test the roles played by those neurotransmitters at those site. Finally, in addition to identifying this circuitry in experimental animals, we also are interested in determining the homologous circuitry in human brains, and in determining how it may be disrupted in specific neurological and psychiatric disorders. We study these neurotransmitter systems in tissue from humans with Parkinson’s disease, Alzheimer’s disease, Tourette syndrome, schizophrenia, Prader-Willi syndrome, and other conditions.
The sleep switch
Hypothalamic control of sleep and wakefulness
VLPO
Localization of sleep active neurons and galanin-containing neurons in the rat VLPO
DMH
Major DMH pathways regulating circadian timing of sleep, wakefulness, and hormone secrection
Peri-fornical
Region
Orexin-immunoreactive (brown) and MCH mRNA containing (blue) neurons in the perifornical region of a rat
