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Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

Nociception is an important type of perception that has major influence on daily human life. There are some descending pathways related to pain management and modulation, which are collectively known as the descending antinociceptive system (DAS). Noradrenalin (NA) in the locus coeruleus (LC) and serotonin (5-HT) in the rostral ventromedial medulla (RVM) are components of the DAS. Most 5-HT neurons in the dorsal raphe (DR) have ascending projections rather than descending projections, and they project to the thalamus that modulates nociception. Both the DAS and the DR are believed to be involved in pain-emotion symptoms. In this study, we utilized a fiber photometry system to specifically examine the activity of LC NA neurons and RVM/DR 5-HT neurons using mice carrying tetracycline-controlled transactivator transgene (tTA) under the control of either a dopamine β-hydroxylase promoter or a tryptophan hydroxylase-2 promoter and site-specific infection of an adeno-associated virus carrying a TetO G-CaMP6 gene. After confirmation of specific expression of G-CaMP6 in the target populations, changes in green fluorescent signal intensity were recorded in awake mice upon exposure to acute nociceptive stimulation consisting of a pinch and application of heat (55 °C) to the tail. Both stimuli resulted in rapid and transient (<15 s) increases in the activity of LC NA neurons and RVM/DR 5-HT neurons while the control stimuli did not induce any changes. The present results clearly indicate that acute nociceptive stimuli increase the activity of LC NA neurons and RVM/DR 5 H T neurons and suggest a possible therapeutic target for pain treatment.

The perifornical area of the hypothalamus has been known as the center for the defense response, or fight-or-flight response, which is characterized by a concomitant rise in arterial blood pressure, heart rate, and respiratory frequency. It is well established that orexin neurons, which are located in this region, play a critical role in this response. In this study, we further examined this role by recording orexin neuronal activity and heart rate in freely moving mice using an original dual-channel fiber photometry system in vivo. Analysis of orexin neuron activity in relation to autonomic responses to aversive stimuli revealed a rapid increase in neuronal activity just prior to changes in heart rate. In addition, we examined whether orexin neurons would be activated by a conditioned neutral sound that was previously associated with aversive stimulus. We show that the memory of the aversive stimulus activated orexin neurons and increased heart rate. Our data suggest that orexin neurons are a key component linking aversive emotions to autonomic defense response. Our data also suggest that targeting orexin neurons may enable treatment of psychiatric disorders associated with chronic stress and traumatic memories.