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Clifford Saper Laboratory

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, particularly regulation of wake-sleep cycles and circadian rhythms, including body temperature, locomotor activity, feeding, and corticosteroids. 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 cutting edge conditional genetic constructs and viral vectors to manipulate these systems, and identify the roles played by specific neurotransmitter systems. 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 has developed a flip-flop model of the circuitry controlling the transitions from sleep to wakefulness, and from NREM to REM sleep (Figs. 1-3). Most of those circuits use either GABA or glutamate as major transmitters. We are currently using mice with conditional genetic constructs for the vesicular GABA and glutamate transporters, so that we can use viral vectors containing the gene for Cre recombinase to delete the ability of neurons at specific sites in the brain to use these neurotransmitters, and study the effects of these manipulations on wake-sleep function.

References:

Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. (2011) Sleep state switching. Neuron 68: 1023.
Lu J, Sherman D, Devor M, Saper CB (2006) A putative fip-flop switch for control of REM sleep. Nature 441: 589.
Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257.

2. Circadian rhythms.

Our lab has developed a model for the pathways from the suprachiasmatic nucleus of the hypothalamus (SCN), which we think are important for imposing the circadian rhythms derived from the SCN on a variety of physiological functions, ranging from wake-sleep cycles, to body temperature, feeding, locomotor activity, and corticosteroid secretion (Fig. 4). We are currently using mice with conditional genetic constructs for either clock genes or neurotransmitters involved in this pathway, to test the model, and examine the effects of manipulating the different limbs of the pathway on circadian rhythms of different physiological functions.

References:

Fuller PM, Lu J, Saper CB (2008) Differential rescue of light- and food-entrainable circadian rhythms. Science 320: 1074.
Gooley JJ, Schomer A, Saper CB (2006) The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nature Neurosci 9:398.
Saper CB, Lu J, Chou TC, Gooley J (2005) The hypothalamic integrator for circadian rhythms. TINS 28: 152.

3. Arousal from sleep apneas.

Patients with obstructive sleep apnea have airway collapse that obstructs breathing during sleep. This causes an arousal, which involves EEG desynchronization (behavioral arousal), re-establishing airway patency (respiratory arousal), and an increase in sympathetic tone (cardiovascular arousal). We are studying the way in which the elevated C02 or fall in O2 that occurs during sleep apnea activates the neuronal circuitry for these arousal responses. We are using mice with conditional gene constructs for the vesicular glutamate transporter 2 to test the hypothesis that glutamatergic neurons at several brain sites contribute to this response.

Reference:

Fuller PM, Sherman D, Pedersen NP, Saper CB, Lu J (2011) Reassessment of the structural basis of the ascending arousal system. J Comp Neurol 519:933.

4. Human sleep and circadian rhythms.

We receive autopsy brain material from an ongoing clinical study of normal aging (the Rush Memory and Aging Project, in Chicago), in which all subjects have had wrist actigraphy (measuring movements) and have donated DNA (which has been analyzed on a 900 K SNP chip). We are using the actigraphy data to derive information on the wake-sleep and circadian behavior of those subjects in their home environment, and then are examining wake-sleep and circadian circuitry in their hypothalamus post-mortem. We also are examining genetic correlates of different circadian phenotypes in this cohort.

Reference:


Gaus SE, Strecker RE, Tate BA, Parker RA, Saper CB (2002). Ventrolateral preoptic nucleus contains galaninergic, sleep-active neurons in multiple mammalian species. Neurosci. 115:285.

Publications from the Saper lab: http://www.ncbi.nlm.nih.gov/pubmed?term=saper%20cb



Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep State Switching. Neuron 2010; 68: 1023-42Fig. 1. Brain arousal pathways (from Saper et al., Neuron, 2011).

Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. (2011) Sleep state switching. Neuron 68: 1023.Fig. 2. During sleep, preoptic neurons inhibit the arousal system (from Saper et al., Neuron 2011).


Fig. 3. A flip-flop switch model for wake-sleep regulation. Preoptic sleep-promoting neurons inhibit the arousal systems during sleep and are inhibited by the arousal systems during wake. As a result, the two mutually inhibitory systems form a flip-flop switch that is stable in either state, but switches rapidly between them (from Saper et al., Nature, 2005).

DMHFig. 4. Summary of pathways by which the suprachiasmatic nucleus imposes circadian rhythms on a variety of important functions (from Saper et al., TINS, 2005).

Gaus et al., Neuroscience, 2002Fig. 5. Neurons of the ventrolateral preoptic nucleus in the human brain (arrow) contain galanin mRNA seen on the right in this darkfield image of an in situ hybridization autoradiograph (from Gaus et al., Neuroscience, 2002).