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 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 use injection of adeno-associated viral vectors (AAVs) that express green fluorescent protein (GFP) only in cells that contain Cre recombinase into mice that express Cre under different promoters, to trace the projections of neurotransmitter-specific cell populations. 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 methods for using conditional knockin and knockout models as well as injections of conditional AAVs containing genes for artificial ligand-gated receptors to alter the neuronal activity in one chemically defined population of neurons in the brain at a time.. 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.