Induction of fos immunoreactivity labeling in rat forebrain metabolic loci by caudal fourth ventricular infusion of the monocarboxylate transporter inhibitor, alpha-cyano-4-hydroxycinnamic acid
Induction of fos immunoreactivity labeling in rat forebrain metabolic loci by caudal fourth ventricular infusion of the monocarboxylate transporter inhibitor, alpha-cyano-4-hydroxycinnamic acid
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DOI：
10.1159/000090785
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发表时间：
2005-01-01
影响因子：
4.1
通讯作者：
Patil, GD
中科院分区：
文献类型：
--
作者：
Briski, KP;Patil, GD
尾侧第四脑室(CV4)注入单羧酸转运蛋白抑制剂α-氰基-4-羟基肉桂酸(4CIN)，可导致高血糖，并与后脑孤束核Fos的表达一致，孤束核是代谢缺陷信号的罕见中心来源。目前的研究通过检测这种药物治疗范例对前脑结构中Fos表达模式的影响来检验这一假说，即后脑Lactoprivic信号激活调节全身糖平衡的中枢自主神经通路，前脑结构整合来自代谢传感器的感觉输入，并协调对能量短缺的运动反应。在CV4注射不同剂量的4CIN或单独注射赋形剂后2小时，成年雌性大鼠经心脏灌流处死，取端脑和间脑的代谢区进行Fos免疫反应(-ir)。下丘脑室旁核(PVH)、背内侧核(DMH)和腹内侧核(VMH)的FOS标记显著高于赋形剂对照组，以回应最低剂量的4CIN，例如10微克/只。大剂量4CIN(25或50 mg)处理后，这些结构中Fos-ir阳性神经元的数量进一步增加，并引起终纹(Bst)、视前内侧核(MPN)、弓状核(ARH)、视上核(SO)、下丘脑前核(Ahn)和下丘脑外侧区(LHA)床核的染色。在注射25和50微克4CIN的动物之间，ARH、DMH、LHA、Ahn、MPN和SO的Fos免疫标记神经元的平均数量没有差异，而VMH、BST和PVH的Fos免疫标记神经元的平均数量在高剂量组和中剂量组显著增加。目前的数据表明，药物抑制尾侧后脑摄取乳酸会导致中枢代谢回路中特定的前脑成分中剂量依赖的神经元Fos免疫表达，并且这些神经元转录激活的模式与药物对血糖水平的影响平行。这些结果表明，后脑尾侧的代谢“感觉”神经元发出的Lactoprivic信号启动了控制全身能量供应的中枢神经机制，局部的乳酸“敏感”神经元在神经解剖学上与调节血糖平衡的主要高阶自主代谢位点有关。版权所有(C)2005 S.Karger AG，巴塞尔。
Caudal fourth ventricular (CV4) infusion of the monocarboxylate transporter inhibitor, alpha-cyano-4-hydroxycinnamic acid (4CIN), causes hyperglycemia coincident with Fos expression in the hindbrain nucleus tractus solitarius, a rare central source of metabolic deficit signaling. The present studies examined the hypothesis that hindbrain lactoprivic signaling activates central autonomic pathways that regulate systemic glucostasis by examining the effects of this drug treatment paradigm on patterns of Fos expression in forebrain structures that integrate sensory input from metabolic sensors and coordinate motor responses to energy shortages. Two hours after CV4 infusion of graded doses of 4CIN or vehicle alone, adult female rats were sacrificed by transcardial perfusion and sections through the telencephalic and diencephalic metabolic loci were processed for Fos immunoreactivity (- ir). Fos labeling of the hypothalamic paraventricular (PVH), dorsomedial (DMH), and ventromedial (VMH) nuclei was significantly elevated, relative to the vehicle-treated controls, in response to the lowest dose of 4CIN, e.g. 10 mu g/animal. Treatment with higher doses of 4CIN (25 or 50 mu g) further augmented numbers of Fos-ir-positive neurons in these structures, and also elicited staining of the bed nuclei of the stria terminalis ( BST), medial preoptic (MPN), arcuate (ARH), supraoptic ( SO), and anterior hypothalamic nuclei (AHN), and lateral hypothalamic area (LHA). Mean numbers of Fos-immunolabeled neurons in the ARH, DMH, LHA, AHN, MPN, and SO were not different between animals infused with 25 versus 50 mu g 4CIN, whereas neuronal labeling in the VMH, BST, and PVH was significantly greater in the high-versus the middle-dose groups. The present data show that pharmacological inhibition of lactate uptake within the caudal hindbrain results in dose-dependent neuronal Fos immunoexpression within characterized forebrain components of the central metabolic circuitry, and that these patterns of neuronal transcriptional activation parallel observed drug effects on blood glucose levels. These results suggest that lactoprivic signaling by metabolic 'sensing' neurons in the caudal hindbrain initiates central neural mechanisms that control systemic energy availability, and that local lactate-'sensitive' neurons are connected neuroanatomically with principal higher-order autonomic metabolic loci that regulate glucostasis. Copyright (C) 2005 S. Karger AG, Basel.