- Email: [email protected]
Waking under pressure
Sleep Medicine 14 (2013) 1045–1046
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Waking under pressure
We live in an exciting time in the history of puzzling together the brain circuits that control sleep and wakefulness. The outer edge is near completion and the middle pieces are coming together. Yet despite much progress, our knowledge of the detailed pathways remains incomplete. Corner pieces were laid in place by early investigators, such as von Economo [1], Bremer [2], Nauta [3], and Moruzzi and Magoun [4]. From their work, we know that the anterior hypothalamus promotes sleep and the posterior hypothalamus promotes wake and that fundamentally, arousal requires activating input from the brainstem. Subsequent work placed edge pieces to connect the corners by narrowing the search for the key neurons in each region. In the anterior hypothalamus, sleep-promoting inhibitory neurons were found in the median and ventrolateral preoptic nuclei [5,6]. The search for wake-consolidating posterior hypothalamic networks has rapidly advanced [7,8], and the source of the ascending reticular activating system was localized to the midbrain–pons junction in or near the parabrachial nucleus [9]. Meanwhile, several new puzzle pieces have fit together, as some unexpected brain regions were found to potently influence arousal [10]. These ‘‘middle’’ pieces include midbrain raphe dopamine neurons [11], the basal forebrain [9], the globus pallidus [12], and a cluster of inhibitory neurons at the pontomedullary junction [13]. Conversely, recent evidence has shown that several nuclei thought necessary for sleep–wake regulation either do not fit in the puzzle, or play a more ancillary role than previously presumed. These regions include the thalamus [9,14], cholinergic basal forebrain neurons [15], serotonergic dorsal raphe neurons [16], histaminergic neurons in the tuberomammillary nucleus [15,17], and noradrenergic neurons in the locus coeruleus [15,17,18]. Such findings are driving rapid evolution in what had been a fairly standard map of interconnected nodes thought to stimulate or inhibit wakefulness [10] and likewise for the regulation of rapid eye movement (REM) sleep [16]. In 2013 of Sleep Medicine, Chen et al. [19] add an interesting piece to this puzzle, the rostral ventrolateral medulla (RVLM) [19]. They electrically stimulated the RVLM, a key region for autonomic control, and found that it produces cortical arousal. It should be noted that Abbott et al. [20] recently produced arousal using a complementary approach, optogenetic stimulation of a subset of RVLM neurons. The RVLM is critical for several autonomic reflexes including baroreflex control of blood pressure and the counterregulatory response to hypoglycemia [21]. The importance of RVLM neurons to bodily homeostasis is well established; in fact, it is the reason Chen et al. [19] chose to stimulate this region. They hypothesized that 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.08.779
increases in blood pressure, triggered by stimulating the RVLM, would wake rats from sleep. This hypothesis was based in part on the finding that pharmacologic changes in blood pressure can awaken lambs from sleep [22]. In the present study [19], electrode location in the RVLM was confirmed by demonstrating the expected increase in blood pressure. As hypothesized, they observed electroencephalogram desynchronization with behavioral arousal from sleep throughout a 6-h period of intermittent stimulation (50 lA at 50 Hz, delivered for 3 min every 20 min). Stimulation was delivered during lights-on when rats spend most of their time asleep; yet, the RVLM-stimulated rats spent more than twice as much time awake compared with control rats. Increased wakefulness primarily occurred at the expense of REM sleep, though most stimulation epochs occurred during non-REM sleep bouts. The overwhelming majority of trials (>75%) produced behavioral arousal with electroencephalogram desynchronization. Little information is provided regarding stimulation during the few REM epochs, so it is worth noting that optogenetic stimulation was only half as effective during REM sleep in the recent study of Abbott et al. [20]. Importantly, the average latency to arousal after the onset of RVLM stimulation was less than 2 s, occurring well before blood pressure begins to rise (7 s to 10% increase). This time course argues against the hypothesis that it is the increase in blood pressure leading to arousal and it requires another explanation. As RVLM neurons can increase respiratory drive [20], a trivial alternative is that increased lung inflation and respiratory rate are sensed by stretch receptors in the lung and diaphragm and awaken animals from sleep via vagal or somatic sensory pathways. A more intriguing possibility is suggested by the underappreciated fact that, in addition to its well-known autonomic projections, the RVLM provides substantial input to brain regions that promote arousal. In fact a subpopulation of adrenergic and glutamatergic neurons here—the ‘‘C1’’/RVLM cells stimulated by Abbott et al. [20]—represent the brain’s most prominent source of excitatory input to noradrenergic neurons in the locus coeruleus [23,24]. In turn the locus coeruleus directly projects to the cerebral cortex [25]. Its neurons are activated by stress and they produce cortical arousal when stimulated [26]. In the future, it will be beneficial to learn if and to what extent cortical arousal following RVLM stimulation relies on this disynaptic pathway (C1/RVLM ? locus coeruleus ? cerebral cortex). In addition, among the physiologic stressors that stimulate the RVLM to produce autonomic reflexes, it will be interesting to learn which trigger arousal via the same neurons. It is important to note that in the absence of stressors C1/RVLM and locus coeruleus neurons probably do not play a central role in
1046
Editorial / Sleep Medicine 14 (2013) 1045–1046
sleep–wake control. This contention is supported by evidence from lesion and genetic studies. For example, separating the medulla from the forebrain does not alter the normal sleep–wake pattern other than to increase the amount of time spent awake [27]. Additionally, sleep–wake patterns are not significantly altered in mice lacking the gene for dopamine-b-hydroxylase, which is necessary for producing norepinephrine and epinephrine, or after lesions of the locus coeruleus [17,18]. On the other hand, these manipulations do abolish the increase in waking which typically is exhibited after stressors [18,28], suggesting that the arousal effect described by Chen et al. [19] plays a fundamental and clinically important role by alerting us to homeostatic perturbations. That is, in parallel with the autonomic reflex adjustments made via descending connections to the spinal cord, C1/RVLM neurons may produce arousal via ascending connections to the LC. What these new findings suggest is that the same pool of neurons which orchestrate life-saving autonomic and neuroendocrine responses on the inside may simultaneously ready us for adaptive behavioral responses on the outside, waking us from sleep or perhaps increasing arousal during quiet wakefulness like a security alarm so that we may initiate behaviors, such as eating, drinking, or fleeing threats. Coordinating arousal with autonomic reflex adjustments makes good sense, as it offers adaptive value in life-threatening situations. These implications are of no small relevance to human patients. For example, many obstructive sleep apnea patients exhibit prolonged cardiorespiratory abnormalities specifically during REM sleep, when optogenetic stimulation of C1/RVLM neurons in rats is less likely to provoke arousal [20]. In addition, inadequate arousal is a hallmark of hypoglycemia unawareness [29]. Low blood sugar normally evokes a coordinated neuroendocrine, autonomic, and behavioral response, but many insulin-dependent patients with diabetes mellitus fail to exhibit these important defenses and fail to seek and ingest carbohydrates [29]. During sleep, these patients have severely blunted arousal and autonomic responses to glucoprivation [30]. C1/RVLM neuron (under) activity may be central to the pathophysiology of hypoglycemia unawareness. Work on this topic may help us understand these and other arousal-related physiologic nuances and may provide ideas on how better to treat our patients in the future. For these reasons, the work of Chen et al. [19] and the report of Abbott et al. [20], who used a complementary technique, add an interesting and important new piece to the puzzle of sleep–wake brain circuitry. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.08.779.
References [1] von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249–59. [2] Bremer F. Nouvelles recherches sur le me´canisme du sommeil. C R Soc Biol 1936;122:460–4. [3] Nauta WJ. Hypothalamic regulation of sleep in rats; an experimental study. J Neurophysiol 1946;9:285–316. [4] Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455–73. [5] Lu J, Greco MA, Shiromani P, Saper CB. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci 2000;20:3830–42. [6] Szymusiak R, Gvilia I, McGinty D. Hypothalamic control of sleep. Sleep Med 2007;8:291–301.
[7] Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98:437–51. [8] Mochizuki T, Arrigoni E, Marcus JN, Clark EL, Yamamoto M, Honer M, et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci USA 2011;108:4471–6 [published online ahead of print February 28, 2011]. [9] 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. [10] Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010;68:1023–42. [11] Lu J, Jhou TC, Saper CB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci 2006;26:193–202. [12] Qiu MH, Vetrivelan R, Fuller PM, Lu J. Basal ganglia control of sleep–wake behavior and cortical activation. Eur J Neurosci 2010;31:499–507. [13] Anaclet C, Lin JS, Vetrivelan R, Krenzer M, Vong L, Fuller PM, et al. Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J Neurosci 2012;32:17970–6. [14] Vanderwolf CH, Stewart DJ. Thalamic control of neocortical activation: a critical re-evaluation. Brain Res Bull 1988;20:529–38. [15] Blanco-Centurion C, Gerashchenko D, Shiromani PJ. Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 2007;27:14041–8. [16] Lu J, Sherman D, Devor M, Saper CB. A putative flip–flop switch for control of REM sleep. Nature 2006;441:589–94. [17] Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep–wake control. J Neurosci 2002;22:7695–711. [18] Gompf HS, Mathai C, Fuller PM, Wood DA, Pedersen NP, Saper CB, et al. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci 2010;30:14543–51. [19] Chen C, Kuo T, Hsieh I, Yang C. Electrical stimulation of the rostral ventrolateral medulla promotes wakefulness in rats. Sleep Med 2013;14:1076–84. [20] Abbott SB, Coates MB, Stornetta RL, Guyenet PG. Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats. Hypertension 2013;61:835–41. [21] Guyenet PG, Stornetta RL, Bochorishvili G, Depuy SD, Burke PG, Abbott SB. Invited review EB 2012: C1 neurons: the body’s EMTs. Am J Physiol Regul Integr Comp Physiol 2013;305:R187–204 [published online ahead of print May 22, 2013]. [22] Horne RS, Berger PJ, Bowes G, Walker AM. Effect of sinoaortic denervation on arousal responses to hypotension in newborn lambs. Am J Physiol 1989;256:H434–40. [23] Ennis M, Aston-Jones G. A potent excitatory input to the nucleus locus coeruleus from the ventrolateral medulla. Neurosci Lett 1986;71:299–305. [24] Card JP, Sved JC, Craig B, Raizada M, Vazquez J, Sved AF. Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: implications for the central control of cardiovascular regulation. J Comp Neurol 2006;499:840–59. [25] Aston-Jones G, Foote SL, Segal M. Impulse conduction properties of noradrenergic locus coeruleus axons projecting to monkey cerebrocortex. Neuroscience 1985;15:765–77. [26] Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 2010;13:1526–33 [published online ahead of print October 31, 2010]. [27] Batini C, Moruzzi G, Palestini M, Rossi GF, Zanchetti A. Presistent patterns of wakefulness in the pretrigeminal midpontine preparation. Science 1958;128:30–2. [28] Hunsley MS, Palmiter RD. Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine. Sleep 2003;26:521–6. [29] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013;369:362–72. [30] Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 2003;52:1195–203.
⇑
Joel C. Geerling Department of Neurology at Beth Israel-Deaconess Medical Center, Boston, MA, USA Harvard Medical School, Boston, MA, USA ⇑ Tel.: +1 617 667 7000; fax: +1 617 735 3249. E-mail address: [email protected] Available online 30 August 2013
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Waking under pressure
We live in an exciting time in the history of puzzling together the brain circuits that control sleep and wakefulness. The outer edge is near completion and the middle pieces are coming together. Yet despite much progress, our knowledge of the detailed pathways remains incomplete. Corner pieces were laid in place by early investigators, such as von Economo [1], Bremer [2], Nauta [3], and Moruzzi and Magoun [4]. From their work, we know that the anterior hypothalamus promotes sleep and the posterior hypothalamus promotes wake and that fundamentally, arousal requires activating input from the brainstem. Subsequent work placed edge pieces to connect the corners by narrowing the search for the key neurons in each region. In the anterior hypothalamus, sleep-promoting inhibitory neurons were found in the median and ventrolateral preoptic nuclei [5,6]. The search for wake-consolidating posterior hypothalamic networks has rapidly advanced [7,8], and the source of the ascending reticular activating system was localized to the midbrain–pons junction in or near the parabrachial nucleus [9]. Meanwhile, several new puzzle pieces have fit together, as some unexpected brain regions were found to potently influence arousal [10]. These ‘‘middle’’ pieces include midbrain raphe dopamine neurons [11], the basal forebrain [9], the globus pallidus [12], and a cluster of inhibitory neurons at the pontomedullary junction [13]. Conversely, recent evidence has shown that several nuclei thought necessary for sleep–wake regulation either do not fit in the puzzle, or play a more ancillary role than previously presumed. These regions include the thalamus [9,14], cholinergic basal forebrain neurons [15], serotonergic dorsal raphe neurons [16], histaminergic neurons in the tuberomammillary nucleus [15,17], and noradrenergic neurons in the locus coeruleus [15,17,18]. Such findings are driving rapid evolution in what had been a fairly standard map of interconnected nodes thought to stimulate or inhibit wakefulness [10] and likewise for the regulation of rapid eye movement (REM) sleep [16]. In 2013 of Sleep Medicine, Chen et al. [19] add an interesting piece to this puzzle, the rostral ventrolateral medulla (RVLM) [19]. They electrically stimulated the RVLM, a key region for autonomic control, and found that it produces cortical arousal. It should be noted that Abbott et al. [20] recently produced arousal using a complementary approach, optogenetic stimulation of a subset of RVLM neurons. The RVLM is critical for several autonomic reflexes including baroreflex control of blood pressure and the counterregulatory response to hypoglycemia [21]. The importance of RVLM neurons to bodily homeostasis is well established; in fact, it is the reason Chen et al. [19] chose to stimulate this region. They hypothesized that 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.08.779
increases in blood pressure, triggered by stimulating the RVLM, would wake rats from sleep. This hypothesis was based in part on the finding that pharmacologic changes in blood pressure can awaken lambs from sleep [22]. In the present study [19], electrode location in the RVLM was confirmed by demonstrating the expected increase in blood pressure. As hypothesized, they observed electroencephalogram desynchronization with behavioral arousal from sleep throughout a 6-h period of intermittent stimulation (50 lA at 50 Hz, delivered for 3 min every 20 min). Stimulation was delivered during lights-on when rats spend most of their time asleep; yet, the RVLM-stimulated rats spent more than twice as much time awake compared with control rats. Increased wakefulness primarily occurred at the expense of REM sleep, though most stimulation epochs occurred during non-REM sleep bouts. The overwhelming majority of trials (>75%) produced behavioral arousal with electroencephalogram desynchronization. Little information is provided regarding stimulation during the few REM epochs, so it is worth noting that optogenetic stimulation was only half as effective during REM sleep in the recent study of Abbott et al. [20]. Importantly, the average latency to arousal after the onset of RVLM stimulation was less than 2 s, occurring well before blood pressure begins to rise (7 s to 10% increase). This time course argues against the hypothesis that it is the increase in blood pressure leading to arousal and it requires another explanation. As RVLM neurons can increase respiratory drive [20], a trivial alternative is that increased lung inflation and respiratory rate are sensed by stretch receptors in the lung and diaphragm and awaken animals from sleep via vagal or somatic sensory pathways. A more intriguing possibility is suggested by the underappreciated fact that, in addition to its well-known autonomic projections, the RVLM provides substantial input to brain regions that promote arousal. In fact a subpopulation of adrenergic and glutamatergic neurons here—the ‘‘C1’’/RVLM cells stimulated by Abbott et al. [20]—represent the brain’s most prominent source of excitatory input to noradrenergic neurons in the locus coeruleus [23,24]. In turn the locus coeruleus directly projects to the cerebral cortex [25]. Its neurons are activated by stress and they produce cortical arousal when stimulated [26]. In the future, it will be beneficial to learn if and to what extent cortical arousal following RVLM stimulation relies on this disynaptic pathway (C1/RVLM ? locus coeruleus ? cerebral cortex). In addition, among the physiologic stressors that stimulate the RVLM to produce autonomic reflexes, it will be interesting to learn which trigger arousal via the same neurons. It is important to note that in the absence of stressors C1/RVLM and locus coeruleus neurons probably do not play a central role in
1046
Editorial / Sleep Medicine 14 (2013) 1045–1046
sleep–wake control. This contention is supported by evidence from lesion and genetic studies. For example, separating the medulla from the forebrain does not alter the normal sleep–wake pattern other than to increase the amount of time spent awake [27]. Additionally, sleep–wake patterns are not significantly altered in mice lacking the gene for dopamine-b-hydroxylase, which is necessary for producing norepinephrine and epinephrine, or after lesions of the locus coeruleus [17,18]. On the other hand, these manipulations do abolish the increase in waking which typically is exhibited after stressors [18,28], suggesting that the arousal effect described by Chen et al. [19] plays a fundamental and clinically important role by alerting us to homeostatic perturbations. That is, in parallel with the autonomic reflex adjustments made via descending connections to the spinal cord, C1/RVLM neurons may produce arousal via ascending connections to the LC. What these new findings suggest is that the same pool of neurons which orchestrate life-saving autonomic and neuroendocrine responses on the inside may simultaneously ready us for adaptive behavioral responses on the outside, waking us from sleep or perhaps increasing arousal during quiet wakefulness like a security alarm so that we may initiate behaviors, such as eating, drinking, or fleeing threats. Coordinating arousal with autonomic reflex adjustments makes good sense, as it offers adaptive value in life-threatening situations. These implications are of no small relevance to human patients. For example, many obstructive sleep apnea patients exhibit prolonged cardiorespiratory abnormalities specifically during REM sleep, when optogenetic stimulation of C1/RVLM neurons in rats is less likely to provoke arousal [20]. In addition, inadequate arousal is a hallmark of hypoglycemia unawareness [29]. Low blood sugar normally evokes a coordinated neuroendocrine, autonomic, and behavioral response, but many insulin-dependent patients with diabetes mellitus fail to exhibit these important defenses and fail to seek and ingest carbohydrates [29]. During sleep, these patients have severely blunted arousal and autonomic responses to glucoprivation [30]. C1/RVLM neuron (under) activity may be central to the pathophysiology of hypoglycemia unawareness. Work on this topic may help us understand these and other arousal-related physiologic nuances and may provide ideas on how better to treat our patients in the future. For these reasons, the work of Chen et al. [19] and the report of Abbott et al. [20], who used a complementary technique, add an interesting and important new piece to the puzzle of sleep–wake brain circuitry. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.08.779.
References [1] von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249–59. [2] Bremer F. Nouvelles recherches sur le me´canisme du sommeil. C R Soc Biol 1936;122:460–4. [3] Nauta WJ. Hypothalamic regulation of sleep in rats; an experimental study. J Neurophysiol 1946;9:285–316. [4] Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455–73. [5] Lu J, Greco MA, Shiromani P, Saper CB. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci 2000;20:3830–42. [6] Szymusiak R, Gvilia I, McGinty D. Hypothalamic control of sleep. Sleep Med 2007;8:291–301.
[7] Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98:437–51. [8] Mochizuki T, Arrigoni E, Marcus JN, Clark EL, Yamamoto M, Honer M, et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci USA 2011;108:4471–6 [published online ahead of print February 28, 2011]. [9] 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. [10] Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010;68:1023–42. [11] Lu J, Jhou TC, Saper CB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci 2006;26:193–202. [12] Qiu MH, Vetrivelan R, Fuller PM, Lu J. Basal ganglia control of sleep–wake behavior and cortical activation. Eur J Neurosci 2010;31:499–507. [13] Anaclet C, Lin JS, Vetrivelan R, Krenzer M, Vong L, Fuller PM, et al. Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J Neurosci 2012;32:17970–6. [14] Vanderwolf CH, Stewart DJ. Thalamic control of neocortical activation: a critical re-evaluation. Brain Res Bull 1988;20:529–38. [15] Blanco-Centurion C, Gerashchenko D, Shiromani PJ. Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 2007;27:14041–8. [16] Lu J, Sherman D, Devor M, Saper CB. A putative flip–flop switch for control of REM sleep. Nature 2006;441:589–94. [17] Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep–wake control. J Neurosci 2002;22:7695–711. [18] Gompf HS, Mathai C, Fuller PM, Wood DA, Pedersen NP, Saper CB, et al. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci 2010;30:14543–51. [19] Chen C, Kuo T, Hsieh I, Yang C. Electrical stimulation of the rostral ventrolateral medulla promotes wakefulness in rats. Sleep Med 2013;14:1076–84. [20] Abbott SB, Coates MB, Stornetta RL, Guyenet PG. Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats. Hypertension 2013;61:835–41. [21] Guyenet PG, Stornetta RL, Bochorishvili G, Depuy SD, Burke PG, Abbott SB. Invited review EB 2012: C1 neurons: the body’s EMTs. Am J Physiol Regul Integr Comp Physiol 2013;305:R187–204 [published online ahead of print May 22, 2013]. [22] Horne RS, Berger PJ, Bowes G, Walker AM. Effect of sinoaortic denervation on arousal responses to hypotension in newborn lambs. Am J Physiol 1989;256:H434–40. [23] Ennis M, Aston-Jones G. A potent excitatory input to the nucleus locus coeruleus from the ventrolateral medulla. Neurosci Lett 1986;71:299–305. [24] Card JP, Sved JC, Craig B, Raizada M, Vazquez J, Sved AF. Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: implications for the central control of cardiovascular regulation. J Comp Neurol 2006;499:840–59. [25] Aston-Jones G, Foote SL, Segal M. Impulse conduction properties of noradrenergic locus coeruleus axons projecting to monkey cerebrocortex. Neuroscience 1985;15:765–77. [26] Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 2010;13:1526–33 [published online ahead of print October 31, 2010]. [27] Batini C, Moruzzi G, Palestini M, Rossi GF, Zanchetti A. Presistent patterns of wakefulness in the pretrigeminal midpontine preparation. Science 1958;128:30–2. [28] Hunsley MS, Palmiter RD. Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine. Sleep 2003;26:521–6. [29] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013;369:362–72. [30] Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 2003;52:1195–203.
⇑
Joel C. Geerling Department of Neurology at Beth Israel-Deaconess Medical Center, Boston, MA, USA Harvard Medical School, Boston, MA, USA ⇑ Tel.: +1 617 667 7000; fax: +1 617 735 3249. E-mail address: [email protected] Available online 30 August 2013