Amygdala Lesions Reduce Cataplexy in Orexin Knock-Out Mice

Burgess, Christian R.; Oishi, Yo; Mochizuki, Takatoshi; Peever, John H.; Scammell, Thomas E.

doi:10.1523/jneurosci.5632-12.2013

Cited by 101 publications

(87 citation statements)

References 69 publications

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“…This hypothesis explains dysregulated sleep/wake cycling associated with orexin neuron loss in NC, but does not explain cataplexy symptoms. How cataplexy relates to motivational or arousal functions of the orexin system is controversial, but a link to emotional arousal is clear 7,11,19,23,27–29 (Box 1). …”

Section: The Many Faces Of Orexin/hypocretin Functionmentioning

confidence: 99%

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Motivational activation: a unifying hypothesis of orexin/hypocretin function

et al. 2014

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Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processes under select circumstances. Orexins primarily mediate behavior under situations of high motivational relevance, such as during physiological need states, exposure to threats or reward opportunities. We hypothesize that many behavioral functions of orexins (including regulation of sleep/wake cycling) reflect a fundamentally integrated function for orexins in translating motivational activation into organized suites of psychological and physiological processes supporting adaptive behaviors. We also discuss how numerous forms of neural heterogeneity modulate this function, allowing orexin neurons to organize diverse, adaptive responses in a variety of motivationally relevant situations. Thus, the involvement of orexins in diverse behaviors may reflect a common underlying function for this peptide system.

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Section: The Many Faces Of Orexin/hypocretin Functionmentioning

confidence: 99%

“…Cataplexy involves brief episodes of muscle atonia (paralysis) with maintained consciousness, often triggered by strong positive emotional stimuli in humans and animals 3,6,8,11,28,29 .…”

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confidence: 99%

Motivational activation: a unifying hypothesis of orexin/hypocretin function

et al. 2014

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“…3 Inhibitory connections between the amygdala and "REM-off" area trigger cataplexy in response to positive stimuli in hypocretin knock-out (KO) mice with a decrease following bilateral amygdala lesions. 4 Human studies have shown that narcolepsy patients have altered responses to positive emotional stimuli and reward. 5,6 These studies suggest the amygdala and hypocretin neurons are active in response to positive emotional states.…”

Section: Discussionmentioning

confidence: 99%

“…4 Human studies have shown that narcolepsy patients have altered responses to positive emotional stimuli and reward. 5,6 These studies suggest the amygdala and hypocretin neurons are active in response to positive emotional states.…”

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confidence: 99%

Dramatic Cataplexy Improvement Following Right Parietal Surgery

Fam

Shammi

Mainprize

et al. 2015

Journal of Clinical Sleep Medicine

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This is the case of a 34-year-old woman with severe narcolepsy with cataplexy who experienced a dramatic reduction in cataplexy symptoms after resection of a right parietal astrocytoma. The patient underwent detailed neurological exam, neuropsychological testing, polysomnography and multiple sleep latency testing following surgery. Keywords: narcolepsy, cataplexy, astrocytoma, parietal lobe Citation: Fam DJ, Shammi P, Mainprize TG, Murray BJ. Dramatic cataplexy improvement following right parietal surgery. J Clin Sleep Med 2015;11(7):829-830.pii: jc-00471-14 http://dx.doi.org/10.5664/jcsm.4860 N arcolepsy is a disorder resulting in disrupted transition between sleep states from an orexin/hypocretin signaling impairment. Cataplexy is the emotionally triggered loss of motor tone, which is pathognomonic. Here we describe the fi rst reported case of dramatic improvement in cataplexy symptoms following resection of a right parietal astrocytoma. REPORT OF CASEA 34-year-old right-handed woman had 18 years of narcolepsy with cataplexy. Her symptoms began with multiple daily episodes of cataplexy triggered by virtually any emotional stimulus including the thought of humor. She had sleepiness, daily hypnogogic hallucinations, and sleep paralysis on awakening several times weekly.Investigations included a multiple sleep latency test (MSLT) showing a short sleep latency and multiple sleep onset REM periods (SOREMPS). She was positive for HLA DQB1*0602. She underwent several medication trials at an outside institution including methylphenidate, dextroamphetamine, modafi nil, and fl uoxetine. The last of these provided modest improvement in cataplexy. She discontinued all narcolepsy treatment in 2005. She found her symptoms greatly impaired social interactions.In July 2013, she had worsening occipital headaches. MRI brain showed a right parietal neoplasm. Surgical resection was performed in January 2014 and histology suggested a lowgrade astrocytoma (Figure 1).Immediately after surgery, she had a left homonymous inferior quadrantanopia and trouble performing rudimentary calculations. Despite this, the patient spontaneously reported that she was delighted to experience a dramatic reduction in cataplexy symptoms. For the fi rst several weeks there were no cataplexy events. There were no changes in her medications.Approximately four months after surgery, she described her cataplexy as at least 75% improved in both frequency and On initial examination, she remained fully alert. Affective range of expression was normal. There was an element of receptive dysprosody and diffi culty judging the emotional content of speech, including sarcasm. Language examination was normal. She had dyscalculia including diffi culty with serial 7's. She had some diffi culty with right-left discrimination and identifying her own individual fi ngers. Further testing for neglect, apraxia, graphesthesia, and stereognosis was unrevealing. Besides her visual fi eld defi cits, the remainder of her neurologic exam was normal.Repeat polysomnography and MSLT f...

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“…Thus, a vital flexibility of arousal is lost without orexin/hypocretin. In terms of robustness, it is well known that without orexin/hypocretin arousal can dip to inappropriately low levels (unconsciousness) upon disturbances such as laughter in humans or sight of delicious food in animals [2,117,118]. Without orexin/hypocretin, there is no appropriate tracking/adjustment of arousal state to internal and external state.…”

Section: Mapping Orexin/hypocretin Biology Onto Control Operationsmentioning

confidence: 99%

Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain

Schöne

Burdakov

2016

Current Topics in Behavioral Neurosciences

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An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via redundancy', wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/ hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wakepromoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm's law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin → histamine → noradrenaline/serotonin-orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops. KeywordsArousal; Brain state; Control theory; Hypocretin; Hypothalamus; Neurons; Orexin ✉ denis.burdakov@crick.ac.uk. Europe PMC Funders GroupAuthor Manuscript Curr Top Behav Neurosci. Author manuscript; available in PMC 2018 January 13. However, wakefulness also needs to be controlled on a much more rapid and unpredictable timescale than that controlled by the SCN. Most of us take this rapid wakefulness adjustment for granted, assuming that we will not fall asleep in the middle of laughing or talking. This is not so for patients suffering from the sleep-wake disorder narcolepsy, which affects about 1:2000 people and where sleep and paralysis suddenly and uncontrollably intrude into normal wakefulness [2,3]. Most cases of human narcolepsy are associated with reduced levels of orexin/hypocretin peptides in the CSF and lack of central orexin/ hypocretin-producing neurons in the brain [4][5][6][7]. Loss of orexin/hypocretin peptides in humans, dogs, mice and rats impairs arousal control, resulting in abnormally frequent and rapid loss of consciousness ('sleep attacks'). It seems that without the orexin/hypocre...

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Amygdala Lesions Reduce Cataplexy in Orexin Knock-Out Mice

Cited by 101 publications

References 69 publications

Motivational activation: a unifying hypothesis of orexin/hypocretin function

Motivational activation: a unifying hypothesis of orexin/hypocretin function

Dramatic Cataplexy Improvement Following Right Parietal Surgery

Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain

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