Locus Ceruleus and Anterior Cingulate Cortex Sustain Wakefulness in a Novel Environment

Gompf, Heinrich S.; Mathai, Christine; Fuller, Patrick M.; Wood, David А.; Pedersen, Nigel P.; Saper, Clifford B.; Lü, Jun

doi:10.1523/jneurosci.3037-10.2010

Cited by 158 publications

(126 citation statements)

References 41 publications

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“…In addition, the PGCL is thought to contain the human homologue of the preBotzinger complex, the central rhythm generator of respiration (Feldman et al, 2013;Schwarzacher et al, 2011). The locus coeruleus of the rostral pons was analyzed because it contains neuronal cell bodies that produce norepinephrine (NE), likewise important for homeostatic regulation and arousal (Aston- Jones and Cohen, 2005;Gompf et al, 2010;Li and Nattie, 2006). With diffusion tractography, we were not able to delineate 5-HT-or NE-specific fiber pathways within the raphe/extra-raphe and locus coeruleus pathways, respectively; nevertheless, the connectivity of these brainstem regions of interest (ROIs) as a whole was a surrogate for the transmitter-specific subsets.…”

Section: Brainstem Seeds and Forebrain Targetsmentioning

confidence: 99%

The Structural Connectome of the Human Central Homeostatic Network

et al. 2016

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Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.

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Section: Brainstem Seeds and Forebrain Targetsmentioning

confidence: 99%

The Structural Connectome of the Human Central Homeostatic Network

et al. 2016

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“…The view against their wake-promoting role was largely based on the fact that lesions limited to the LC only exert small effects on the amount of wakefulness (49). However, Dbh -/-mice, which lack endogenous noradrenaline, have been reported to exhibit reduced wakefulness as well as REM sleep (50).…”

Section: Roles Of Orexin Receptor Activation Of Dr Serotonergic Neuromentioning

confidence: 99%

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways

Hasegawa¹,

Yanagisawa²,

Sakurai³

et al. 2014

J. Clin. Invest.

147

125

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The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy. IntroductionThe neuropeptides orexin A and orexin B (also termed hypocretin-1 and hypocretin-2, respectively) are implicated in feeding, the reward system, and sleep/wake regulation (1). They act on the G protein-coupled receptors orexin receptor type 1 (OX1R) and OX2R. Degenerative loss of orexin neurons in humans is associated with narcolepsy, a debilitating neurological disorder that provides a unique perspective on the mechanisms of sleep/wakefulness control (2). The syndrome consists of excessive daytime sleepiness that often results in sleep attacks (sudden onset of non-rapid eye movement [NREM] sleep), cataplexy (sudden bilateral skeletal muscle weakening triggered by emotions, without consciousness impairment), hypnagogic hallucinations, and sleep paralysis.The symptoms of narcolepsy can be divided into 2 independent pathological phenomena (1, 2). The first is dysregulation of NREM sleep onset: the inability to maintain a consolidated awake period, characterized by abrupt transitions from wakefulness to NREM sleep. This phenomenon manifests clinically as excessive daytime sleepiness or sleep attacks. The second is dysregulation of rapid eye movement (REM) sleep onset: the pathological intrusion of REM sleep or REM atonia into wakefulness or at sleep onset. It is during these periods that patients may experience cataplexy, hypnagogic hallucinations, and sleep paralysis.Similarly, mice with targeted deletion of the prepro-orexin gene (orexin -/-mice), mice in which orexin neurons are specifically ablated (orexin/ataxin-3 mice), and mice that lack both orexin receptors (Ox1r -/-Ox2r ...

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“…Careful studies of the inputs to the core of the locus coeruleus reveal that it receives a very restricted range of inputs, mainly from the rostral ventrolateral and paramedian medulla (including major inputs from the C1 and C3 adrenergic cell group, as well as from non-catecholaminergic neurons) and from the lateral hypothalamic area, paraventricular nucleus and ventrolateral preoptic nucleus (Aston- Jones et al, 1986;Aston-Jones, 1986, 1987;Guyenet and Young, 1987;Pieribone et al, 1988;Astier et al, 1990;Luppi et al, 1995;Sherin et al, 1998;Lu et al, 2002;Reyes et al, 2005;Abbott et al, 2012;Sevigny et al, 2012b). However, studies focusing on inputs to the more distal dendrites of the locus coeruleus neurons have demonstrated afferents from other components of the central autonomic system, including the medial prefrontal cortex, bed nucleus of the stria terminalis, central nucleus of the amygdala (including a dynorphin/CRF containing afferent pathway), and nucleus of the solitary tract (Van Bockstaele et al, 1996;Van Bockstaele et al, 1999a, 1999bBajic et al, 2000;Reyes et al, 2008Reyes et al, , 2011Gompf et al, 2010).…”

Section: Locus Coeruleusmentioning

confidence: 99%

“…The firing of the LC is also related to pupil diameter, and LC stimulation increases pupil diameter, probably through projections to the parasympathetic Edinger-Westphal nucleus (Breen et al, 1983;Samuels and Szabadi, 2008). This activity profile suggests a role in the maintenance of alertness or attention (Aston- Jones and Cohen, 2005;Corbetta et al, 2008;Sara, 2009;Gompf et al, 2010). Although, lesions of the locus coeruleus produce only minor changes in the amount of wakefulness and circadian rhythms of sleep-wake cycles in cats and rats (Cirelli and Tononi, 2004;BlancoCenturion et al, 2007;Gompf et al, 2010), LC neurons are needed to maintain wakefulness when animals are exposed to novel stimuli during their normal sleep period (Gompf et al, 2010).…”

Section: Locus Coeruleusmentioning

confidence: 99%