Publications by authors named "Clifford B Saper"

169 Publications

What Are the Odds?

Authors:
Clifford B Saper

Ann Neurol 2021 01 24;89(1):11-12. Epub 2020 Nov 24.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1002/ana.25960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753583PMC
January 2021

Symptomatic Hydrocephalus with Normal Cerebrospinal Pressure and Alzheimer's Disease.

Ann Neurol 2020 10 31;88(4):685-687. Epub 2020 Aug 31.

Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1002/ana.25871DOI Listing
October 2020

Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.

Nat Commun 2020 06 2;11(1):2769. Epub 2020 Jun 2.

Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.

During obstructive sleep apnea, elevation of CO during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBel neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DR neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DR terminals in the PBel. This effect was mediated by 5HT receptors which are expressed by PBel neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT receptors is critical for modulating the sensitivity of the PBel neurons that cause arousal to rising levels of blood CO.
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http://dx.doi.org/10.1038/s41467-020-16518-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265411PMC
June 2020

EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever.

J Neurosci 2020 03 20;40(12):2573-2588. Epub 2020 Feb 20.

Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPO neurons). To investigate the identity of MnPO neurons, we first used hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPO but few from MnPO neurons to a key site for fever production, the raphe pallidus. Ablation of MnPO but not MnPO neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPO neurons being GABAergic. Body temperature is regulated by the CNS. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses.
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http://dx.doi.org/10.1523/JNEUROSCI.2887-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083539PMC
March 2020

Critical Dynamics and Coupling in Bursts of Cortical Rhythms Indicate Non-Homeostatic Mechanism for Sleep-Stage Transitions and Dual Role of VLPO Neurons in Both Sleep and Wake.

J Neurosci 2020 01 6;40(1):171-190. Epub 2019 Nov 6.

Keck Laboratory for Network Physiology, Department of Physics, Boston University, Boston, Massachusetts 02215,

Origin and functions of intermittent transitions among sleep stages, including brief awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing sleep on scales of seconds and minutes results from intrinsic non-equilibrium critical dynamics. We investigate θ- and δ-wave dynamics in control rats and in rats where the sleep-promoting ventrolateral preoptic nucleus (VLPO) is lesioned (male Sprague-Dawley rats). We demonstrate that bursts in θ and δ cortical rhythms exhibit complex temporal organization, with long-range correlations and robust duality of power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, features typical of non-equilibrium systems self-organizing at criticality. We show that such non-equilibrium behavior relates to anti-correlated coupling between θ- and δ-bursts, persists across a range of time scales, and is independent of the dominant physiologic state; indications of a basic principle in sleep regulation. Further, we find that VLPO lesions lead to a modulation of cortical dynamics resulting in altered dynamical parameters of θ- and δ-bursts and significant reduction in θ-δ coupling. Our empirical findings and model simulations demonstrate that θ-δ coupling is essential for the emerging non-equilibrium critical dynamics observed across the sleep-wake cycle, and indicate that VLPO neurons may have dual role for both sleep and arousal/brief wake activation. The uncovered critical behavior in sleep- and wake-related cortical rhythms indicates a mechanism essential for the micro-architecture of spontaneous sleep-stage and arousal transitions within a novel, non-homeostatic paradigm of sleep regulation. We show that the complex micro-architecture of sleep-stage/arousal transitions arises from intrinsic non-equilibrium critical dynamics, connecting the temporal organization of dominant cortical rhythms with empirical observations across scales. We link such behavior to sleep-promoting neuronal population, and demonstrate that VLPO lesion (model of insomnia) alters dynamical features of θ and δ rhythms, and leads to significant reduction in θ-δ coupling. This indicates that VLPO neurons may have dual role for both sleep and arousal/brief wake control. The reported empirical findings and modeling simulations constitute first evidences of a neurophysiological fingerprint of self-organization and criticality in sleep- and wake-related cortical rhythms; a mechanism essential for spontaneous sleep-stage and arousal transitions that lays the bases for a novel, non-homeostatic paradigm of sleep regulation.
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http://dx.doi.org/10.1523/JNEUROSCI.1278-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939478PMC
January 2020

Reply to "Medicare for All?"

Authors:
Clifford B Saper

Ann Neurol 2020 01 6;87(1):156. Epub 2019 Nov 6.

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http://dx.doi.org/10.1002/ana.25630DOI Listing
January 2020

Reassessing the Role of Histaminergic Tuberomammillary Neurons in Arousal Control.

J Neurosci 2019 11 23;39(45):8929-8939. Epub 2019 Sep 23.

Department of Neurology, Beth Israel Deaconess Medical Center and Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts 02215,

The histaminergic neurons of the tuberomammillary nucleus (TMN) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMN neurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMN neurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMN neurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMN neurons coexpressed VGAT. Acute chemogenetic activation of TMN neurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMN neurons in arousal control. Further, if TMN neurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMN neurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions. The histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMN) have long been thought to promote arousal. Additionally, TMN neurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMN neurons does not impact sleep-wake amounts and that few TMN neurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMN neurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMN neurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.
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http://dx.doi.org/10.1523/JNEUROSCI.1032-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832676PMC
November 2019

Regulation of hippocampal dendritic spines following sleep deprivation.

J Comp Neurol 2020 02 9;528(3):380-388. Epub 2019 Sep 9.

Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Accumulating evidence supports the role of sleep in synaptic plasticity and memory consolidation. One line of investigation, the synaptic homeostasis hypothesis, has emphasized the increase in synaptic strength during waking, and compensatory downsizing of (presumably less frequently used) synapses during sleep. Conversely, other studies have reported downsizing and loss of dendritic spines following sleep deprivation. We wanted to determine the effect of sleep deprivation on dendritic spines of hippocampal CA1 neurons using genetic methods for fluorescent labeling of dendritic spines. Male Vglut2-Cre mice were injected with an AAV-DIO-ChR2-mCherry reporter in CA1 hippocampus. Gentle handling was used to sleep deprive mice for 5 hr, from lights on (7 am) to 12 noon. Control and sleep-deprived mice were euthanized at 12 noon and processed for quantification of dendritic spines. We used confocal microscope imaging and three-dimensional (3D) analysis to quantify thin, mushroom, and stubby spines from CA1 dendrites, distinguishing between branch segments. We observed significantly greater density of spines in CA1 of sleep-deprived mice, driven primarily by greater numbers of thin spines, and significantly larger spine volume and head diameter. Branch and region-specific analysis revealed that spine volume was greater in primary dendrites of apical and basal segments, along with proximal segments on both apical and basal dendrites, and spine density was increased in secondary branches and distal segments on apical dendrites following sleep deprivation. Our 3D quantification suggests sleep contributes to region- and branch-specific synaptic downscaling in the hippocampus, supporting the theory of broad but selective synaptic downscaling during sleep.
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http://dx.doi.org/10.1002/cne.24764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328436PMC
February 2020

Why "Medicare for All" would be a disaster.

Authors:
Clifford B Saper

Ann Neurol 2019 10;86(4):475-476

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http://dx.doi.org/10.1002/ana.25580DOI Listing
October 2019

Neural Circuitry Underlying Waking Up to Hypercapnia.

Front Neurosci 2019 26;13:401. Epub 2019 Apr 26.

Department of Neurology, Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.

Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway collapse, followed by brief arousals that help re-establish the airway patency. These repetitive arousals which can occur hundreds of times during the course of a night are the cause of the sleep-disruption, which in turn causes cognitive impairment as well as cardiovascular and metabolic morbidities. To prevent this potential outcome, it is important to target preventing the arousal from sleep while preserving or augmenting the increase in respiratory drive that reinitiates breathing, but will require understanding of the neural circuits that regulate the cortical and respiratory responses to apnea. The parabrachial nucleus (PB) is located in rostral pons. It receives chemosensory information from medullary nuclei that sense increase in CO2 (hypercapnia), decrease in O2 (hypoxia) and mechanosensory inputs from airway negative pressure during apneas. The PB area also exerts powerful control over cortical arousal and respiration, and therefore, is an excellent candidate for mediating the EEG arousal and restoration of the airway during sleep apneas. Using various genetic tools, we dissected the neuronal sub-types responsible for relaying the stimulus for cortical arousal to forebrain arousal circuits. The present review will focus on the circuitries that regulate waking-up from sleep in response to hypercapnia.
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http://dx.doi.org/10.3389/fnins.2019.00401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497806PMC
April 2019

Brain Circuitry for Arousal from Apnea.

Cold Spring Harb Symp Quant Biol 2018 23;83:63-69. Epub 2019 Apr 23.

Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

We wanted to understand the brain circuitry that awakens the individual when there is elevated CO or low O (e.g., during sleep apnea or asphyxia). The sensory signals for high CO and low O all converge on the parabrachial nucleus (PB) of the pons, which contains neurons that project to the forebrain. So, we first deleted the vesicular glutamate transporter 2, necessary to load glutamate into synaptic vesicles, from neurons in the PB, and showed that this prevents awakening to high CO or low O We then showed that PB neurons that express calcitonin gene-related peptide (CGRP) show cFos staining during high CO Using CGRP-Cre-ER mice, we expressed the inhibitory opsin archaerhodopsin just in the PB neurons. Photoinhibition of the PB neurons effectively prevented awakening to high CO, as did photoinhibition of their terminals in the basal forebrain, amygdala, and lateral hypothalamus. The PB neurons are a key mediator of the wakening response to apnea.
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http://dx.doi.org/10.1101/sqb.2018.83.038125DOI Listing
April 2019

Passages 2019.

Authors:
Clifford B Saper

Ann Neurol 2019 01;85(1):1-11

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http://dx.doi.org/10.1002/ana.25397DOI Listing
January 2019

Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice.

Nat Commun 2018 10 8;9(1):4129. Epub 2018 Oct 8.

Department of Neurology, Program in Neuroscience and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.

The preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neurons in the ventrolateral preoptic nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POA neurons was shown to paradoxically cause waking, not sleep. Here we report that photostimulation of VLPO neurons in mice promotes sleep with low frequency stimulation (1-4 Hz), but causes conduction block and waking at frequencies above 8 Hz. Further, optogenetic inhibition reduces sleep. Chemogenetic activation of VLPO neurons confirms the increase in sleep, and also reduces body temperature. In addition, chemogenetic activation of VLPO neurons induces short-latency sleep in an animal model of insomnia. Collectively, these findings establish a causal role of VLPO neurons in both sleep induction and heat loss.
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http://dx.doi.org/10.1038/s41467-018-06590-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175893PMC
October 2018

Is it time to reconsider the classic neurological examination?

Authors:
Clifford B Saper

Ann Neurol 2018 10 4;84(4):483-484. Epub 2018 Oct 4.

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http://dx.doi.org/10.1002/ana.25339DOI Listing
October 2018

A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia.

Curr Biol 2018 07 12;28(14):2291-2301.e5. Epub 2018 Jul 12.

Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA. Electronic address:

Stress elicits a variety of autonomic responses, including hyperthermia (stress fever) in humans and animals. In this present study, we investigated the circuit basis for thermogenesis and heat conservation during this response. We first demonstrated the glutamatergic identity of the dorsal hypothalamic area (DHA) neurons that innervate the raphe pallidus nucleus (RPa) to regulate core temperature (Tc) and mediate stress-induced hyperthermia. Then, using chemogenetic and optogenetic methods to manipulate this hypothalamomedullary circuit, we found that activation of DHA neurons potently drove an increase in Tc, but surprisingly, stress-induced hyperthermia was only reduced by about one-third when they were inhibited. Further investigation showed that DHA neurons activate brown adipose tissue (BAT) but do not cause vasoconstriction, instead allowing reflex tail artery vasodilation as a response to BAT-induced hyperthermia. Retrograde rabies virus tracing revealed projections from DHA neurons to RPa, but not to RPa neurons, and identified a set of inputs to DHA → RPa neurons that are likely to mediate BAT activation. The dissociation of the DHA thermogenic pathway from the thermoregulatory vasoconstriction (heat-conserving) pathway may explain stress flushing (skin vasodilation but a feeling of being too hot) during stressful times.
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http://dx.doi.org/10.1016/j.cub.2018.05.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085892PMC
July 2018

Connectivity of sleep- and wake-promoting regions of the human hypothalamus observed during resting wakefulness.

Sleep 2018 09;41(9)

Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA.

The hypothalamus is a central hub for regulating sleep-wake patterns, the circuitry of which has been investigated extensively in experimental animals. This work has identified a wake-promoting region in the posterior hypothalamus, with connections to other wake-promoting regions, and a sleep-promoting region in the anterior hypothalamus, with inhibitory projections to the posterior hypothalamus. It is unclear whether a similar organization exists in humans. Here, we use anatomical landmarks to identify homologous sleep- and wake-promoting regions of the human hypothalamus and investigate their functional relationships using resting-state functional connectivity magnetic resonance imaging in healthy awake participants. First, we identify a negative correlation (anticorrelation) between the anterior and posterior hypothalamus, two regions with opposing roles in sleep-wake regulation. Next, we show that hypothalamic connectivity predicts a pattern of regional sleep-wake changes previously observed in humans. Specifically, regions that are more positively correlated with the posterior hypothalamus and more negatively correlated with the anterior hypothalamus correspond to regions with the greatest change in cerebral blood flow between sleep-wake states. Taken together, these findings provide preliminary evidence relating a hypothalamic circuit investigated in animals to sleep-wake neuroimaging results in humans, with implications for our understanding of human sleep-wake regulation and the functional significance of anticorrelations.
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http://dx.doi.org/10.1093/sleep/zsy108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454456PMC
September 2018

Role of the median preoptic nucleus in the autonomic response to heat-exposure.

Temperature (Austin) 2018 6;5(1):4-6. Epub 2018 Feb 6.

Department of Neurology, Beth Israel-Deaconess Medical Center - Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1080/23328940.2017.1413155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902207PMC
February 2018

A hypothalamic circuit for the circadian control of aggression.

Nat Neurosci 2018 05 9;21(5):717-724. Epub 2018 Apr 9.

Department of Neurology, Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ transmission phase-dependently increases aggression. Finally, SPZ-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
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http://dx.doi.org/10.1038/s41593-018-0126-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920747PMC
May 2018

Passages 2018.

Authors:
Clifford B Saper

Ann Neurol 2018 01;83(1):1-9

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http://dx.doi.org/10.1002/ana.25135DOI Listing
January 2018

Reply to is there even such a thing as "idiopathic normal pressure hydrocephalus"?

Authors:
Clifford B Saper

Ann Neurol 2017 12 4;82(6):1033. Epub 2017 Dec 4.

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http://dx.doi.org/10.1002/ana.25098DOI Listing
December 2017

Supramammillary glutamate neurons are a key node of the arousal system.

Nat Commun 2017 11 10;8(1):1405. Epub 2017 Nov 10.

Department of Neurology, Beth Israel Deaconess Medical Center, Bostan, MA, 02215, USA.

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuM) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuM neurons. Inhibition of SuM neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuM neurons include a subpopulation containing both glutamate and GABA (SuM) and another also expressing nitric oxide synthase (SuM). Activation of SuM neurons produces minimal wake and optogenetic stimulation of SuM terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuM neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuM neurons as a key node of the wake-sleep regulatory system.
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http://dx.doi.org/10.1038/s41467-017-01004-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680228PMC
November 2017

A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia.

Neuron 2017 Dec 2;96(5):1153-1167.e5. Epub 2017 Nov 2.

Department of Neurology, Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address:

The precise neural circuitry that mediates arousal during sleep apnea is not known. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) play a critical role in arousal to elevated CO2 or hypoxia. Because many of the PBel neurons that respond to CO2 express calcitonin gene-related peptide (CGRP), we hypothesized that CGRP may provide a molecular identifier of the CO2 arousal circuit. Here, we report that selective chemogenetic and optogenetic activation of PBel neurons caused wakefulness, whereas optogenetic inhibition of PBel neurons prevented arousal to CO2, but not to an acoustic tone or shaking. Optogenetic inhibition of PBel terminals identified a network of forebrain sites under the control of a PBel switch that is necessary to arouse animals from hypercapnia. Our findings define a novel cellular target for interventions that may prevent sleep fragmentation and the attendant cardiovascular and cognitive consequences seen in obstructive sleep apnea. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720904PMC
December 2017

Is there even such a thing as "Idiopathic normal pressure hydrocephalus"?

Authors:
Clifford B Saper

Ann Neurol 2017 10 10;82(4):514-515. Epub 2017 Oct 10.

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http://dx.doi.org/10.1002/ana.25053DOI Listing
October 2017

Median preoptic glutamatergic neurons promote thermoregulatory heat loss and water consumption in mice.

J Physiol 2017 10 13;595(20):6569-6583. Epub 2017 Sep 13.

Department of Neurology, Beth Israel-Deaconess Medical Center - Harvard Medical School, Boston, MA, USA.

Key Points: Glutamatergic neurons in the median preoptic area were stimulated using genetically targeted Channelrhodopsin 2 in transgenic mice. Stimulation of glutamatergic median preoptic area neurons produced a profound hypothermia due to cutaneous vasodilatation. Stimulation also produced drinking behaviour that was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap.

Abstract: The median preoptic nucleus (MnPO) serves an important role in the integration of water/electrolyte homeostasis and thermoregulation, but we have a limited understanding these functions at a cellular level. Using Cre-Lox genetic targeting of Channelrhodospin 2 in VGluT2 transgenic mice, we examined the effect of glutamatergic MnPO neuron stimulation in freely behaving mice while monitoring drinking behaviour and core temperature. Stimulation produced a strong hypothermic response in 62% (13/21) of mice (core temperature: -4.6 ± 0.5°C, P = 0.001 vs. controls) caused by cutaneous vasodilatation. Stimulating glutamatergic MnPO neurons also produced robust drinking behaviour in 82% (18/22) of mice. Mice that drank during stimulation consumed 912 ± 163 μl (n = 8) during a 20 min trial in the dark phase, but markedly less during the light phase (421 ± 83 μl, P = 0.0025). Also, drinking during stimulation was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Both hypothermia and drinking during stimulation occurred in 50% of mice tested. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Thus, activation of separate but overlapping populations of glutamatergic MnPO neurons produces effects on drinking and autonomic thermoregulatory mechanisms, providing a structural basis for their frequently being coordinated (e.g. during hyperthermia).
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http://dx.doi.org/10.1113/JP274667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638873PMC
October 2017

A translational approach to capture gait signatures of neurological disorders in mice and humans.

Sci Rep 2017 06 12;7(1):3225. Epub 2017 Jun 12.

Department of Neurology, Division of Movement Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species. In mice, we represented spatial and temporal gait parameters as a function of velocity and established regression models that reproducibly capture the signatures of these relationships during walking. In experimental parkinsonism models, regression curves representing these relationships shifted from baseline, implicating changes in gait signatures, but with marked differences between models. Gait parameters in healthy human subjects followed similar strict velocity dependent relationships which were altered in Parkinson's patients in ways that resemble some but not all mouse models. This novel approach is suitable to quantify qualitative walking abnormalities related to CNS circuit dysfunction across species, identify appropriate animal models, and it provides important translational opportunities.
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http://dx.doi.org/10.1038/s41598-017-03336-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468293PMC
June 2017

Wake-sleep circuitry: an overview.

Curr Opin Neurobiol 2017 06 31;44:186-192. Epub 2017 May 31.

Department of Neurology, Program in Neuroscience, and Division of Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.

Although earlier models of brain circuitry controlling wake-sleep focused on monaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutmate and GABA. We review here recent advances in understanding the role these systems play in controlling sleep and wakefulness.
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http://dx.doi.org/10.1016/j.conb.2017.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531075PMC
June 2017

An open letter to those who write dean's letters.

Authors:
Clifford B Saper

Ann Neurol 2016 12;80(6):795-796

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http://dx.doi.org/10.1002/ana.24823DOI Listing
December 2016

A human brain network derived from coma-causing brainstem lesions.

Neurology 2016 Dec 4;87(23):2427-2434. Epub 2016 Nov 4.

From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.

Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network.

Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness.

Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks.

Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.
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http://dx.doi.org/10.1212/WNL.0000000000003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177681PMC
December 2016

A changing of the guard.

Authors:
Clifford B Saper

Ann Neurol 2016 11 19;80(5):643. Epub 2016 Oct 19.

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http://dx.doi.org/10.1002/ana.24785DOI Listing
November 2016