About Saper Lab Projects
Clifford B. Saper, James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School, and Department of Neurology, Beth Israel Deaconess Medical Center
The focus of the Saper laboratory is on hypothalamic circuitry that is responsible for basic life functions like regulation of wake-sleep cycles and circadian rhythms, including body temperature, locomotor activity, feeding, and corticosteroids. We use state-of-the-art genetic targeting of neurons in the brain to identify cell groups with specific functions by using optogenetic, chemogenetics, and genetically encoded toxins to manipulate genetically defined populations of neurons. We test their role in whole animal physiology (wake-sleep, thermoregulation, corticosteroid secretion) and behavior (aggression, feeding, drinking, locomotor activity). This work is augmented by our collaborator, Elda Arrigoni, who uses intracellular recordings in slice preparations, to determine the effects of specific neurotransmitters on identified cell populations in the hypothalamus.
Ongoing Projects
Sleep-Switching Circuitry
Our lab group has discovered many of the key cell groups involved in wake-sleep regulation, including and the role of the parabrachial nucleus1-3, dorsal raphe nucleus4 and supramammillary nucleus5 in maintaining wake, and the role of the ventrolateral preoptic nucleus in causing sleep6-8. We have also worked out many of the pathways that control the transition between slow wave or non-REM and REM sleep9-10.
References
- Kaur S, Wang JL, Ferrari L, Thankachan S, Kroeger D, Venner A, Lazarus M, Wellman A, Arrigoni E, Fuller PM, Saper CB. A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia. Neuron 2017;96:1153-67.e5.
- Fuller PM, Sherman D, Pedersen NP, Saper CB, Lu J. Reassessment of the structural basis of the ascending arousal system. J Comp Neurol 2011;519:933-56.
- Fischer DB, Boes AD, Demertzi A, Evrard HC, Laureys S, Edlow BL, Liu H, Saper CB, Pascual-Leone A, Fox MD, Geerling JC. A human brain network derived from coma-causing brainstem lesions. Neurology 2016;87:2427-34.
- Kaur S, de Luca R, Khanday MA, Bandaru SS, Thomas RC, Broadhurst RY, Venner A, Todd WD, Fuller PM, Arrigoni E, Saper CB. Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals. Nat Comm 2020;11:2769.
- Pedersen NP, Ferrari L, Venner A, Wang JL, Abbott SBG, Vujovic N, Arrigoni E, Saper CB, Fuller PM. Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun 2017;8:1405.
- Kroeger D, Absi G, Gagliardi C, Bandaru SS, Madara JC, Ferrari LL, Arrigoni E, Munzberg H, Scammell TE, Saper CB, Vetrivelan R. Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat Comm 2018;9:4129.
- Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010;68:1023-42.
- Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-63.
- Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature 2006;441:589-94.
- Vetrivelan R, Kong D, Ferrari LL, Arrigoni E, Madara JC, Bandaru SS, Lowell BB, Lu J, Saper CB. Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 2016;336:102-113.
Circadian Rhythms
Our lab has developed a model for the network by which the brain’s biological clock, the suprachiasmatic nucleus (SCN), controls a wide range of physiological functions, including wake-sleep cycles, to body temperature, feeding, locomotor activity, and corticosteroid secretion8,11,12. We are currently using mice with conditional genetic constructs to test the model in control of corticosteroid secretion and aggressive behavior13.
References
- Saper CB, Lu J, Chou TC, Gooley J. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005;28:152-7.
- Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms. Science 2008;320:1074-7.
- Todd WD, Fenselau H, Wang JL, et al. A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 2018;21:717-24.
Human Sleep and Circadian Rhythms
Because this basic circuitry is highly conserved, we are interested in the same brain circuitry in humans. We study the autopsy brains from subjects who have died after being carefully studied during life, to identify the fate of neurons and circuits that control basic life functions with immunohistochemistry. We have recently found that the loss of neurons in the ventrolateral preoptic during aging correlates with the amount of consolidated sleep that the individual achieves12. The ventrolateral preoptic galanin neurons are also damaged in Alzheimer’s disease, and the consequent sleep loss may further exacerbate the dementia. We also found that loss of suprachiasmatic VIP neurons with aging is correlated with reduced amplitude of circadian rhythms13. We are currently studying how Alzheimer pathology may affect both the circadian and sleep systems11.
References
- Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain 2014;137:2847-61.
- Wang JL, Lim AS, Chiang WY, Hseih WH, Lo MT, Schneider JA, Buchman AS, Bennett DA, Hu K, Saper CB. Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. Ann Neurol 2015;78:317-22.
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