Otlivanchik Oleg, Sanders Nicole M, Dunn-Meynell Ambrose, Levin Barry E
Graduate School of Biomedical Sciences, Rutgers University, Newark, New Jersey; Department of Neurology, New Jersey Medical School, Rutgers University, Newark, New Jersey;
Seattle Veterinary Specialists, Kirkland, Washington.
Am J Physiol Regul Integr Comp Physiol. 2016 Jan 1;310(1):R66-73. doi: 10.1152/ajpregu.00066.2015. Epub 2015 Oct 28.
While the neural control of glucoregulatory responses to insulin-induced hypoglycemia is beginning to be elucidated, brain sites responsible for behavioral responses to hypoglycemia are relatively poorly understood. To help elucidate central control mechanisms associated with hypoglycemia unawareness, we first evaluated the effect of recurrent hypoglycemia on a simple behavioral measure, the robust feeding response to hypoglycemia, in rats. First, food intake was significantly, and similarly, increased above baseline saline-induced intake (1.1 ± 0.2 g; n = 8) in rats experiencing a first (4.4 ± 0.3; n = 8) or third daily episode of recurrent insulin-induced hypoglycemia (IIH, 3.7 ± 0.3 g; n = 9; P < 0.05). Because food intake was not impaired as a result of prior IIH, we next developed an alternative animal model of hypoglycemia-induced behavioral arousal using a conditioned place preference (CPP) model. We found that hypoglycemia severely blunted previously acquired CPP in rats and that recurrent hypoglycemia prevented this blunting. Pretreatment with a brain penetrant, selective orexin receptor-1 antagonist, SB-334867A, blocked hypoglycemia-induced blunting of CPP. Recurrently hypoglycemic rats also showed decreased preproorexin expression in the perifornical hypothalamus (50%) but not in the adjacent lateral hypothalamus. Pretreatment with sertraline, previously shown to prevent hypoglycemia-associated glucoregulatory failure, did not prevent blunting of hypoglycemia-induced CPP prevention by recurrent hypoglycemia. This work describes the first behavioral model of hypoglycemia unawareness and suggests a role for orexin neurons in mediating behavioral responses to hypoglycemia.
虽然对胰岛素诱导的低血糖症的葡萄糖调节反应的神经控制开始得到阐明，但负责对低血糖症作出行为反应的脑区却相对了解较少。为了帮助阐明与低血糖无意识相关的中枢控制机制，我们首先评估了反复低血糖对大鼠一项简单行为指标——对低血糖的强烈摄食反应的影响。首先，经历首次（4.4±0.3克；n = 8）或第三次每日反复胰岛素诱导的低血糖症发作（IIH，3.7±0.3克；n = 9；P<0.05）的大鼠，其食物摄入量显著且类似地高于基线盐水诱导的摄入量（1.1±0.2克；n = 8）。由于先前的IIH并未损害食物摄入量，我们接下来使用条件性位置偏爱（CPP）模型开发了一种低血糖诱导行为觉醒的替代动物模型。我们发现低血糖严重减弱了大鼠先前获得的CPP，而反复低血糖可防止这种减弱。用一种可穿透脑的选择性食欲素受体-1拮抗剂SB-334867A预处理可阻断低血糖诱导的CPP减弱。反复低血糖的大鼠在穹窿周下丘脑的前食欲素原表达也降低了（50%），但在相邻的外侧下丘脑则未降低。先前已证明可预防与低血糖相关的葡萄糖调节功能衰竭的舍曲林预处理，并不能防止反复低血糖对低血糖诱导的CPP预防作用的减弱。这项工作描述了首个低血糖无意识行为模型，并提示食欲素神经元在介导对低血糖的行为反应中起作用。
