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 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 include:

1. 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 and supramammillary nucleus4 in maintaining wake, and the role of the ventrolateral preoptic nucleus in causing sleep5,6.  We have also worked out many of the pathways that control the transition between slow wave or non-REM and REM sleep7,8.

References: 
  1. Kaur S, Wang JL, Ferrari L, et al. A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia. Neuron 2017;96:1153-67.e5.
  2. 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.
  3. Fischer DB, Boes AD, Demertzi A, et al. A human brain network derived from coma-causing brainstem lesions. Neurology 2016;87:2427-34.
  4. Pedersen NP, Ferrari L, Venner A, et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun 2017;8:1405.
  5. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010;68:1023-42.
  6. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-63.
  7. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature 2006;441:589-94.
  8. . Vetrivelan R, Kong D, Ferrari LL, et al. Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 2016;336:102-113. 
Figure 1 Saper Lab



Figure 1. A summary of the components of the wake-promoting pathways in the ascending arousal system. The golden pathway from the pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei uses acetylcholine (Ach) to activate the thalamus.  The glutamatergic neurons in the parabrachial nucleus (PB) and supramammillary nucleus (SUM) are the main sources of the red arousal pathways that traverses the hypothalamus. It is joined by monoamine inputs from the locus coeruleus (LC), raphe, periaqueductal gray, and tuberomammillary nucleus, and activates cholinergic, GABAergic, and glutamatergic neurons in the basal forebrain (BF) that arouse the cerebral cortex.  Modified 2018.6 ©C.B. Saper

 

Figure 2 Saper Lab

 

 

 

 

Figure 2. A summary of the sleep promoting pathways (purple) from the ventrolateral preoptic nucleus (VLPO) and the parafacial zone (PFZ) to the major components of the  ascending arousal system.  Modified 2018.6 ©C.B. Saper

 

 

 

Figure 3 Saper Lab
 
 
 

Figure 3. The wake- and sleep-promoting systems each innervate and inhibit the other.  This mutual inhibition results in the conditions for a “flip-flop switch,” in which if either system gains the upper hand, it turns off the other.  This relationship results in brisk, complete transitions from wake to sleep or vice versa.  Modified 2018.6 ©C.B. Saper

 

2. 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 secretion6,9,10.  We are currently using mice with conditional genetic constructs to test the model in control of corticosteroid secretion and aggressive behavior11.

References: 

 9.  Saper CB, Lu J, Chou TC, Gooley J. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005;28:152-7.
10. Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms. Science 2008;320:1074-7.
11. Todd WD, Fenselau H, Wang JL, et al. A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 2018;21:717-24

Figure 4 Saper Lab

 

Figure 4. The circadian timing system.  Neurons in the suprachiasmatic nucleus (SCN) have relatively few outputs directly to the systems they control.  Rather, they mainly send their output to the tan zone, the subparaventricular nucleus (SPZ).  The SPZ in turn sends outputs on to key areas like the paraventricular, dorsomedial, and ventromedial nuclei of the hypothalamus, where they control circadian rhythms of physiology and behavior.9

 

3. 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:

11. Todd WD, Fenselau H, Wang JL, et al. A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 2018;21:717-24.
12. Lim AS, Ellison BA, Wang JL, et al. 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.
13. Wang JL, Lim AS, Chiang WY, et al. Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. Ann Neurol 2015;78:317-22.

Publications from the Saper lab: http://www.ncbi.nlm.nih.gov/pubmed?term=saper cb 

 
Figure 5 Saper Lab
 
 
 
 
Figure 5. The ventrolateral preoptic nucleus in the human brain can be identified because it stains immunohistochemically for galanin.  In this section through a human hypothalamus, the paraventricular (PVN) and supraoptic nuclei also contain galanin neurons.  This galanin cell group had previously been called the intermediate nucleus (IN) in earlier work.  This brain comes from a study in which the subjects wore wrist actigraphs, which recorded the movements of their non-dominant wrist for 7-10 days in the year before they died.  The neurons can be counted, and the number of surviving neurons was compared to the wake-sleep behavior of the same individual. 12