Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan; SLEEP Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan.
Brain Behav Immun. 2016 Oct;57:58-67. doi: 10.1016/j.bbi.2016.06.009. Epub 2016 Jun 16.
Hypocretin, also known as orexin, maintains the vigilance state and regulates various physiological processes, such as arousal, sleep, food intake, energy expenditure, and reward. Previously, we found that when wild-type mice and hypocretin/ataxin-3 littermates (which are depleted of hypothalamic hypocretin-expressing neurons postnatally) were administered lipopolysaccharide (LPS), the two genotypes exhibited significant differences in their sleep/wake cycle, including differences in the degree of increase in sleep periods and in recovery from sickness behaviour. In the present study, we examined changes in the hypothalamic vigilance system and in the hypothalamic expression of inflammatory factors in response to LPS in hypocretin/ataxin-3 mice. Peripheral immune challenge with LPS affected the hypothalamic immune response and vigilance states. This response was altered by the loss of hypocretin. Hypocretin expression was inhibited after LPS injection in both hypocretin/ataxin-3 mice and their wild-type littermates, but expression was completely abolished only in hypocretin/ataxin-3 mice. Increases in the number of histidine decarboxylase (HDC)-positive cells and in Hdc mRNA expression were found in hypocretin/ataxin-3 mice, and this increase was suppressed by LPS. Hypocretin loss did not impact the change in expression of hypothalamic inflammatory factors in response to LPS, except for interferon gamma and colony stimulating factor 3. The number of c-Fos-positive/HDC-positive cells in hypocretin/ataxin-3 mice administered LPS injections was elevated, even during the rest period, in all areas, suggesting that there is an increase in the activity of histaminergic neurons in hypocretin/ataxin-3 mice following LPS injection. Taken together, our results suggest a novel role for hypocretin in the hypothalamic response to peripheral immune challenge. Our findings contribute to the understanding of the pathophysiology of narcolepsy.
食欲肽，又称下丘脑泌素，维持警觉状态，并调节各种生理过程，如觉醒、睡眠、摄食、能量消耗和奖励。此前，我们发现当野生型小鼠和食欲肽/ataxin-3 同窝仔（出生后下丘脑食欲肽表达神经元缺失）接受脂多糖（LPS）时，两种基因型在睡眠/觉醒周期中表现出显著差异，包括睡眠期增加程度和疾病行为恢复的差异。在本研究中，我们研究了 LPS 对食欲肽/ataxin-3 小鼠下丘脑警觉系统和下丘脑炎症因子表达的影响。外周免疫挑战 LPS 影响下丘脑免疫反应和警觉状态。这种反应被食欲肽的缺失改变。LPS 注射后，食欲肽/ataxin-3 小鼠及其野生型同窝仔的食欲肽表达均受到抑制，但仅在食欲肽/ataxin-3 小鼠中完全被抑制。在食欲肽/ataxin-3 小鼠中发现组氨酸脱羧酶（HDC）阳性细胞数量和 Hdc mRNA 表达增加，并且这种增加被 LPS 抑制。食欲肽缺失对 LPS 反应中下丘脑炎症因子表达的变化没有影响，除了干扰素γ和集落刺激因子 3。给予 LPS 注射的食欲肽/ataxin-3 小鼠中 c-Fos 阳性/HDC 阳性细胞的数量增加，即使在休息期间，所有区域均增加，这表明 LPS 注射后，食欲肽/ataxin-3 小鼠中的组胺能神经元活性增加。总之，我们的结果表明，食欲肽在下丘脑对外周免疫挑战的反应中具有新的作用。我们的研究结果有助于理解发作性睡病的病理生理学。
