title: 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.
abstract: 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 microg/animal. Treatment with higher doses of 4CIN (25 or 50 microg) 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 microg 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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of Health Sciences, University of Louisiana, Monroe, LA 71209, USA. briski@ulm.edu
authors.forename: Karen P
authors.initials: KP
authors.lastname: Briski
authors.forename: Gopal D
authors.initials: GD
authors.lastname: Patil
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D031608:Area Postrema / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003373:Coumaric Acids / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors*; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017552:Solitary Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014018:Tissue Distribution; D015533:Transcriptional Activation
chemical_list: D003373:Coumaric Acids; D027501:Monocarboxylic Acid Transporters; D016760:Proto-Oncogene Proteins c-fos; C007175:alpha-cyano-4-hydroxycinnamate