10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology BEVEZETÉS A FUNKCIONÁLIS NEUROBIOLÓGIÁBA INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY STEROID FEEDBACK TO THE BRAIN www.itk.ppke.hu (Szteroid visszacsatolás az agyhoz) ZSOLT LIPOSITS INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu COMMUNICATION SYNAPTIC NON-SYNAPTIC HUMORAL INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu THYROID GLAND ADRENAL GLAND GONADS MRI FEEDBACK INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu SYNTHESIS Progesterone 17OH-pregnenolone Androstene-3,17-dione Dehydroepiandrosterone 17OH-progesterone 11-deoxycorticosterone 11-deoxycortisol Cortisol Corticosterone Aldosterone Pregnenolone INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothebrain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu Picture1.png INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY Steroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu Mineralocorticoid receptor mRNA Glucocorticoid receptor mRNA Corticosterone: 1 ligand, 2 receptors in vivo in situ autoradiographyhybridization 3H-DEX 0 50 100 Receptor saturation (%) Nadir Zenith Stress Corticosterone 3H-ALDO MR GR Courtesy of Dr. O. Almeida INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY Steroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu 77 FM EM hipc HIPPOCAMPUS GD A D X INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu Receptor: ligand dependent transcription factor Nuclear receptor superfamily R DNA mRNA Export L coregulator -/+ chaperone R INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu E S T R O G E N S SERM 1. 2. 3. 4. 5. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu va11 Gametogenesis Sexual phenotype Ovarian cycle Sexual behavior Bone metabolism Cardiovascular system Cognitive functions Synaptic plasticity Cell proliferation in breast and uterus T E2 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu Picture2.emf INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu Transactivation N C A/B C D E F Modulator DNA-binding Ligand-binding AF1 AF2 Transcription Dimerization Hsp Functional structure of steroid receptors INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 www.itk.ppke.hu Characteristics of estrogen receptor knock out (ERKO) female mice Gametogenesis Estrogen level Breast Ovary Uterus suppressed elevated agenesis abnormal follicles infantile Lubahn, DB et al., PNAS, 90:11162-11166, 1993 ERKO 3H-E2 Responses in the brain of estrogen receptor disrupted mice. Shughrue, PL et al., Proc. Natl. Acad. Sci. USA: Vol. 94, 1997 pq2071411002 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 15 www.itk.ppke.hu Proc. Natl. Acad. Sci. USA:Vol.93,No.12,5925 5930,June11, 1996 Cloning of a Novel Estrogen Receptor Expressed in Rat Prostate and Ovary GGJMKuiper, EEnmark, MPelto-Huikko, SNilsson, and JGustafsson A/B C D E F 25 95 30 20 60 . ß DNA LBD INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 16 www.itk.ppke.hu g a ER-ßLBD crystal structure genistein raloxifen ER actions 1 2 3 4 Forrás: Nillson, S., Physiol. Rev., 81:1535, 2001 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 17 www.itk.ppke.hu . ß .ß HOMODIMER HETERODIMER ER.andER ßdistribution in brain Forrás:Shughrue, P. et al.,J. Comp. Neurology 388:507-525, 1997 ERA-BmRNAs ER. ER ß INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 18 www.itk.ppke.hu Picture3.png INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 19 www.itk.ppke.hu 29 OCH OCH VASOPRESSIN ERß OCH VASERB VASOPRESSIN-ERß INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 20 www.itk.ppke.hu ERBOXY OXY-ir ERß-mRNA Hrabovszky et al, Endocrinology, 1998 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 21 www.itk.ppke.hu LHRHrendszsem Projections of LHRH neurons HYPOPHYSIS INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 22 www.itk.ppke.hu Picture4.png E2 P INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 23 www.itk.ppke.hu 0 X LHRH E2 ? HYPOTHALAMUS OVULATION OVARY HYPOPHYSIS INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothebrain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 24 www.itk.ppke.hu Image1 INDIRECT REGULATION TM HISTAMINE INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 25 www.itk.ppke.hu figv2 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 26 www.itk.ppke.hu histlhrh RAT Human Ethical permit: No. 372 Fekete et al, Endocrinology, 1999 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 27 www.itk.ppke.hu H1 H2 Effects of H receptor antagonistson LH release MEPYRAMINE RANITIDINE INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 28 www.itk.ppke.hu LHRHcells E2 KÖZVETLEN? ER-.mRNA LHRH mRNA Double ISH Hrabovszky et al., Endocrinology, 2000 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 29 www.itk.ppke.hu Picture5.png Hrabovszky et al, Endocrinology, 2000 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 30 www.itk.ppke.hu ER-ßmRNS EXPRESSZIÓLHRH SEJTEKBEN % y ERßprotein expression in LHRH neurons Hrabovszky et al., Endocrinology, 2001 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbacktothe brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 31 www.itk.ppke.hu GABA Histamine E2 ERß ER. LHRH neuron ERß Indirect, trans-synaptic effect Direct, genomic effect Fast, membrane effect INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYSteroidfeedbackto the brain 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 32 www.itk.ppke.hu BIOLOGY PHARMACOLOGY CHEMISTRY NEUROSCIENCE MULTIDISCIPLINARY RESEARCH