OBJECTIVE Dorsal raphe nucleus(DRN) is the largest single collection of neurons containing5-HT in the entire brain and particularly attractive in a wide variety of complex physiological and behavioral processes,such a...OBJECTIVE Dorsal raphe nucleus(DRN) is the largest single collection of neurons containing5-HT in the entire brain and particularly attractive in a wide variety of complex physiological and behavioral processes,such as sleep-wake regulation. Calmodulin dependent kinaseⅡ(CaMKⅡ) and protein kinase C(PKC)are important signal-transducing molecules activated by Ca^(2+). Since the Ca^(2+)modulation in DRN plays an important role in sleep-wake regulation,it should be presumed that the intracellular CaMKⅡ/PKC signaling in DRN may be involved in the regulation of sleep-wake. METHODS The polysomnogram consisting of EEG and EMG was recorded for analyzing sleep architecture. Immunohistochemisrty and Western-blotting methods were used in this study to investigate the roles of Ca^(2+),CaMKⅡ and PKC in sleep-wake regulation in rat DRN. RESULTS Ca^(2+)in the DRN exert arousal effects by reducing the NREMs,SWS and REMs via up-regulating serotonergic functions and activating CaMK Ⅱ-PKC.However,inhibition of PKC leads to significant promotion of total sleep time especial y the NREM sleep,but there were no changes in sleep parameters after the inhibition of CaMKⅡ by its inhibitor KN-93 in DRN.CONCLUSION The molecular,pharmacological,and behavioral findings of this study demonstrate a novel wake promoting and sleep-suppressing role for the Ca^(2+)/CaMK Ⅱ/PKC signaling pathway in DRN. Abnormalities in CaMK Ⅱ are found in patients with several neurological disorders that are associated with disturbed sleep,such as schizophrenia,depression,and Alzheimer′s disease. Several psychotropic drugs modulate CaMK Ⅱ activity. In addition,PKC is a cellular target of most current mood stabilizing and anti-manic agents and involved in bipolar disorder. The data of the present study raise the question whether PKC or CaMKⅡ modulations may also be effective on the sleep disorders or the mood disorders associated with sleep disorders.展开更多
基金The project supported by National Natural Science Foundation of China(81573407,81302746,81202511,81173031)National Mega-project of Scicence Research of China for New Drug Development(2009ZX09103-124)Research Fund for the Doctoral Program of Higher Eductaion of China(20100001110048)
文摘OBJECTIVE Dorsal raphe nucleus(DRN) is the largest single collection of neurons containing5-HT in the entire brain and particularly attractive in a wide variety of complex physiological and behavioral processes,such as sleep-wake regulation. Calmodulin dependent kinaseⅡ(CaMKⅡ) and protein kinase C(PKC)are important signal-transducing molecules activated by Ca^(2+). Since the Ca^(2+)modulation in DRN plays an important role in sleep-wake regulation,it should be presumed that the intracellular CaMKⅡ/PKC signaling in DRN may be involved in the regulation of sleep-wake. METHODS The polysomnogram consisting of EEG and EMG was recorded for analyzing sleep architecture. Immunohistochemisrty and Western-blotting methods were used in this study to investigate the roles of Ca^(2+),CaMKⅡ and PKC in sleep-wake regulation in rat DRN. RESULTS Ca^(2+)in the DRN exert arousal effects by reducing the NREMs,SWS and REMs via up-regulating serotonergic functions and activating CaMK Ⅱ-PKC.However,inhibition of PKC leads to significant promotion of total sleep time especial y the NREM sleep,but there were no changes in sleep parameters after the inhibition of CaMKⅡ by its inhibitor KN-93 in DRN.CONCLUSION The molecular,pharmacological,and behavioral findings of this study demonstrate a novel wake promoting and sleep-suppressing role for the Ca^(2+)/CaMK Ⅱ/PKC signaling pathway in DRN. Abnormalities in CaMK Ⅱ are found in patients with several neurological disorders that are associated with disturbed sleep,such as schizophrenia,depression,and Alzheimer′s disease. Several psychotropic drugs modulate CaMK Ⅱ activity. In addition,PKC is a cellular target of most current mood stabilizing and anti-manic agents and involved in bipolar disorder. The data of the present study raise the question whether PKC or CaMKⅡ modulations may also be effective on the sleep disorders or the mood disorders associated with sleep disorders.
