Abstract
Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF‐α) is an important neuroinflammation mediator. Here, we examined the effects of TNF‐α treatment on hypocretin expression in vivo and behaviour in mice. TNF‐α decreased hypocretin 1 and hypocretin 2 expression in a dose‐dependent manner in cultured hypothalamic neurons. TNF‐α decreased mRNA stability of prepro‐hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF‐α demonstrated decreased expression of prepro‐hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF‐α, prepro‐hypocretin mRNA decay was increased in hypothalamus. TNF‐α neutralizing antibody restored the expression of prepro‐hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF‐α challenged mice, supporting hypocretin system can be impaired by increased TNF‐α through decreasing hypocretin expression. Repeated TNF‐α challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF‐α neutralizing antibody blocked the effects of TNF‐α; in contrast, hypocretin receptor antagonist enhanced the effects of TNF‐α. The data support that TNF‐α is involved in the regulation of hypocretin expression, sleep and cognition. The findings shed some lights on the role of neuroinflammation in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Highlights
Hypocretin 1 and hypocretin 2 are important neuropeptides that were first described in 1998 almost simultaneously by two independent research groups.[1,2] Prepro‐hypocretin is the single precursor of hypocretin 1 and hypocretin 2, which generates hypocretin 1 and hypocretin 2 through proteolytic cleavage.[1,2] Prepro‐hypocretin is expressed mainly in hypothalamic neurons and in testis.[1-3]
It is less obvious about the direct role of hypocretins in neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD), as well as in patients with rapid eye movement (REM) sleep be‐ haviour disorder (RBD)
The present study has demonstrated that TNF‐α can impair the hypocretin system through decreasing mRNA stabil‐ ity of prepro‐hypocretin in cultured hypothalamic neurons in vitro and in hypothalamus in vivo in mice
Summary
Hypocretin 1 and hypocretin 2 (aka orexin A and B, OXA and OXB) are important neuropeptides that were first described in 1998 almost simultaneously by two independent research groups.[1,2] Prepro‐hypocretin is the single precursor of hypocretin 1 and hypocretin 2, which generates hypocretin 1 and hypocretin 2 through proteolytic cleavage.[1,2] Prepro‐hypocretin is expressed mainly in hypothalamic neurons and in testis.[1-3]. Two hypo‐ cretin receptors are identified, hypocretin receptor 1 (HcrtR1) and hypocretin receptor 2 (HcrtR2) (aka, orexin receptor 1/OX1R, and orexin receptor 2/OX2R, respectively); they are G‐protein‐ coupled receptors.[2,4,5]. Both receptors share over 60% homology in their amino acid sequences.[4]. Published data have linked the activation of TNF‐α signalling to multiple brain disorders, such as the development of narcolepsy, depression, neurodegenerative diseases such as AD and PD, and multiple sclerosis.[17-20]. The effects of TNF‐α on hypocretin expression in vivo, muscle activity during REM sleep (RBD), learning, cognition and mem‐ ory were examined in mice. The findings support an important role of TNF‐α in the regulation of hypocretin system, sleep, and cognition and learning. The findings shed some lights on the role of neuroinflammation on some aspects of neurodegen‐ erative diseases including Alzheimer's disease and Parkinson's disease
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