L#1 - Involuntary and Regulatory Systems Regulatory What...

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Unformatted text preview: Involuntary and Regulatory Systems Regulatory What systems are regulated? regulated? PLASTICITY CONVERGENCE CONVERGENCE MODULATORS TRANSMITTER S PEPTIDES CORTEX CORTEX HYPOTHALAMUS NTS LIMBIC SYSTEM AFFECT REWARD EFFERENTS SOMATIC VISCERAL (ANS) HPA B BB INTEGRATION INTEGRATION REDUNDANCY HIPPOCAMPUS MEMORY LEARNING AFFERENTS SOMATIC VISCERAL HORMONAL METABOLIC Some Neurally Regulated Systems Systems • • • • • • • • • • • Temperature Fluid & electrolytes Energy homeostasis Glucose homeostasis Cardiovascular Cardiovascular Respiratory Respiratory Immune Hematological Bone & mineral Biorhythms (ultradian, diurnal, seasonal) Stress Some Neurally Regulated Systems Some What Temperature Fluid & electrolytes Energy homeostasis Glucose homeostasis Cardiovascular Biorhythms (ultradian, diurnal, Biorhythms seasonal) seasonal) Stress Where AHN/PHN SFO/SON/PVNm ARC/VMN/DMN/PVNp/NTS PVNp/VMN/PHN/NTS/R.P/O ARC/VMN/DMN/PVN/PHN /NTS/ PHN RVLM/CVLM SCN/DMN PVN/DMN/Amyg/Hippocamp/PV Thal/LC/DRa, MRa Overriding and/or modulatory factors modulatory • • • • • Motivation, reward & learning (non-homeostatic) Environmental inputs Biorhythms Genetics Gender How are they regulated? How Set-point Signals External & Internal Internal Stimuli Stimuli Error Error Signals + Set-point Controlling Controlling Elements Controlled System System - - Feedback Detectors/ Effectors Adapted from Kandel e t al Set-point Signals External Internal Internal Factors Factors Nutrients/Environmental Temperature/Day length Temperature/Day Genes/Perinatal Genes/Perinatal Environment Environment Error Error Signals + Set-point Metabolic Sensors Hindbrain Hypothalamus SN/VTA Hippocampus Endocrine Behavioral Food intake Autonomic Thermogensis Substrate Substrate mobilization mobilization Adipose Stores Peripheral Peripheral Organs Organs (Lipostatic factor (Lipostatic Hormones Nutrients Neural Leptin (Insulin) of Kennedy) of - Adapted from Kandel et al ENERGY BALANCE STORAGE= INTAKE - EXPENDITURE Energy Homeostasis is Critical for Many Functions Many • • • • • • • • • • • Neural development Reproduction Lactation Secondary sex characteristics Hibernation Cognitive function Hematopoiesis Immunity Stress Bone growth Linear growth Body Weight Defense after Chronic Overand Underfeeding Rats by Gavage and Bernstein et al, 1975 Decreased Energy Expenditure after Short-term Weight Decreased Loss in Obese and Lean Humans Loss Total Energy Expenditure (kcal/day) 6000 Total Energy Expenditure (kcal/day) Initial weight 10% gain 6000 Initial weight 10% loss 20% loss 5000 5000 4000 4000 3000 3000 2000 2000 1000 25 45 65 85 1000 25 45 65 85 Fat-free Mass (kg) Fat-free Mass (kg) Leibel et al, 1995 The System is Biased Towards Preserving Existing and Replenishing Lost Energy Stores and 900 800 Obese Obese Rats Rats Weight (g) 700 600 500 400 300 200 0 4 8 12 16 20 24 28 Time in Time weight maintenance maintenance Initial gain 0 wks 8 wks 16 wks (~12 human years) 32 36 40 Weeks MacLean et al, Am. J. Physiol. 287: R1306,2004. Brain Lesions Alter the Brain Defended Body Weight Defended 400 VMH Lesion VMH Ad lib Ad Control LH Lesion Body Weight (g) 350 300 250 200 150 100 50 50 LH Lesion 12 345 Restricted Feeding 678 VMH Lesion Overfeed Ad lib 9 10 11 12 13 14 15 16 17 18 19 20 21 Adapted from Keesey et al Weeks Dual Center Hypothesis of Food Intake Regulation Intake PVN LHA “Feeding Center” DMN VMH “Satiety Center” VMN ARC ANS OUTFLOW Stellar, Psychol. Rev. 5: 5, 1954 Energy Homeostasis Anabolic CNS Catabolic – + + Food Intake – – Energy Expendi ture + • Metabolic – Physical ARate • ctivity Adiposity Signals Leptin + Insulin + – Fat Stores Energy Balance + Neuroendocrine Projections Neuroendocrine of the Hypothalamus of PVN DMN VMN LH LH ARC PIT. Neurohumoral BRAIN STEM ANS OUTFLOW US AG V ORGANS SNS SPINAL CORD SNS OUTFLOW Afferent Inputs to the Hypothalamus and Hindbrain Hypothalamus PVN DMN VMN ARC Hormone Metabolic PIT. NE/E/NPY 5-HT/GLP-1/2 Brainstem NTS ANS Outflow US AG V ORGANS SNS Spinal Cord SNS Outflow A Few of the Many Central Neuropeptides and Few Transmitters Involved in Energy Homeostasis Transmitters ANABOLIC • • • • • • • • Norepinephrine NPY AgRP Orexin MCH Dynorphin Galanin Cannabinoids CATABOLIC • • • • • • • Serotonin α -MSH CART CRF Urocortin GLP- 1 / 2 Bombesin Homeostatic (Need) and Non-homeostatic (Desire) Homeostatic (Need) (Desire) Components of Energy Homeostasis Components Homeostatic Homeostatic NPY,MC,CRH NPY,MC,CRH Orexin, MCH Orexin, DMN DMN VMN NPY Hypothalamus AgRP ARC PVN Hormones/Metabolites Adipose Liver Pancreas Muscle Peripheral Sensors Liver GI Tract Carotid Body POMC Brain Stem Amygdala BNST CeA,ABL LHA VTA VTA Cognition Cognition Memory Cerebral Cortex Hippocampus Amygdala MPFCtx NAc Non-homeostatic Non-homeostatic Opioid,DA,GABA,Glut,CB Opioid,DA,GABA,Glut,CB Extended Amygdala Homeostatic Components of Energy Homeostasis Homeostatic Homeostatic NPY,MC,CRH NPY,MC,CRH Orexin, MCH Orexin, DMN DMN VMN NPY Hypothalamus AgRP ARC PVN Hormones/Metabolites Adipose Liver Pancreas Muscle Peripheral Sensors Liver GI Tract Carotid Body POMC Brain Stem Homeostatic Components of the Control of Energy Balance Energy PVN LHA LHA MCH OREXIN CRF/Oxytoncin CRF/Oxytoncin -MSH) -MSH) P OMC ( α P OMC (α P NPY AgRP NPY AgR DMN VMN ARC Brainstem/Spinal Cord Autonomic Outflow Leptin as an adiposity signal ob/ob mouse Insulin and Leptin Receptors are Located In the ARC, VMN & DMN the CA1 Dentate Dentate DMN VMN 125 125 ARC ARC 125 125 DMN VMN ARC I Leptin binding Leptin I Insulin binding Irani et al , Endocrinol. 148:310, 2006 Food Intake Thermogenesis - + + + Hypothalamus - Food Intake Thermogenesis Free Feeding + 24 h Fast 0.48 + 0.03 0.48 0.66 + 0.03 * 0.66 Leptin and the Defended Body Weight Body weight Gain (g) 500 400 DIO DIO Restrict Chow Leptin 30 ng/ml Leptin 30 ng/ml 300 Leptin 5 ng/ml Leptin 20 ng/ml 200 100 31% Fat Diet 4 8 12 16 5% Fat 20 24 Weeks Non-Homeostatic Controls Motivational (Reward) Components of Energy Homeostasis Energy BNST CeA,ABL MPFCtx Amyg LH NAc VTA VTA Extended Amygdala Opioids Endorphins Dopamine GABA Glutamate Cannabinoids? Leptin Insulin Ghrelin Glucose Changes in Body Image During DietChanges induced Weight Loss After Diet Before Diet Homeostatic vs. Non-Homeostatic Control of Body Weight in DIO Rats of 500 Body Weight (g) 400 Non-homeostatic Leptin (ng/ml) 5% Fat 300 Ensure 200 b 100 5% Fat Ensure 31% Fat 19.3+2.7b 18.6+2.0 Homeostatic 0 5 10 15 20 25 30 Weeks Homeostatic (Need) and Non-homeostatic (Desire) Homeostatic (Need) (Desire) Components of Energy Homeostasis Components Homeostatic Homeostatic NPY,MC,CRH NPY,MC,CRH Orexin, MCH Orexin, DMN DMN VMN NPY Hypothalamus AgRP ARC PVN Hormones/Metabolites Adipose Liver Pancreas Muscle Peripheral Sensors Liver GI Tract Carotid Body POMC Brain Stem Amygdala BNST CeA,ABL LHA VTA VTA Cognition Cognition Memory Cerebral Cortex Hippocampus Amygdala MPFCtx NAc Non-homeostatic Non-homeostatic Opioid,DA,GABA,Glut,CB Opioid,DA,GABA,Glut,CB Extended Amygdala SET-POINT?? SET-POINT?? Set-point Questions? Set-point • Is there really a set-point for the Is regulation of energy homeostasis? For salt appetite? For BP? For For • Where is the set-point? • What contributes to the set-point? • Why is it moveable? Regulation of glucose homeostasis homeostasis Potential Regulatory Roles for Potential Glucosensing Neurons Glucosensing • Food intake (J. Mayer- Glucostatic J. Hypothesis) Hypothesis • Glucose metabolism • Hypoglycemic Counterregulation • Thermogenesis • ANS function • Memory and learning Memory • Neurotransmitter release CNS us Glycogen ag agon S/V luc SN d/G Me s/SNS Ad agu Liver Liver V Glycogen Amino Acids Glucose Glucose Muscle e cos Glu G lu co se Insulin Pancreas Pancreas Fa Ac tty id s Adipose Tissue Adipose Energy Homeostasis Energy Intake = Expenditure + Storage Expenditure Storage Systemic 2DG-induced feeding Systemic 3 hr Food Intake (g) 7.5 * 5.0 2.5 0.0 Saline 2DG Smith & Epstein, Am. J. Physiol. 217: 1083, 1969 Oral Glucose Alters Brain Blood Oral Flow by fMRI in Humans Increase Decrease Matsuda et al, 1999 Relationship of Blood Glucose to Meal Initiation Meal MEAL Campfield, Brandon & Smith, Br.Res.Bull, 14:605, 1985 Plasma vs. Brain Glucose Levels Plasma and Responses to Hypoglycemia and 3.0 EC Brain Glucose (mM) 2.5 2.0 1.5 1.0 0.5 0.0 Meal Fasting Epi, NE, glucagon, Epi, Cort, GH Cort, “Hunger” Impaired cognition 0 1 2 3 4 5 6 7 8 Plasma Glucose (mM) Silver and Erecinska, J Neurosci. 14:5068, 1994/ Mitrakou et al, AJP 260:E67, 1991 Silver Feeding in Relationship to Simultaneous Blood and VMH Glucose Levels Blood Food Intake (g) 10 9 8 7 6 5 4 3 2 1 0 -1 0.05 4.0 1.7 0.1 0.1 1.4 3.1 2.5 Blood Glucose (mM) VMH Glucose (mM) 2.0 1.5 1.0 0.5 0.0 0 1 2 3 4 5 6 Lights Out Hours Insulin Dunn-Meynell et al, J. Neurosci 29:7015, 2009 Energy Homeostasis Energy Intake = Expenditure + Storage Expenditure Storage Hypoglycemia and Intracarotid Glucose Activate the Hypoglycemia SAS System and PVN and ARC Neurons SAS Systemic Hypoglycemia Epinephrine (pg/ml) 9000 6000 3000 0 0 Tkacs et al, Diabetes 49:820,2000 Intracarotid Glucose Norepinephrine (pg/ml) 600 Minutes 30 60 500 400 300 200 ARC Minutes Levin et al, Brain Res. 748:100, 1997 10 20 30 40 50 60 IIIRD III Types of Glucosensing Neurons Types Anand, Am J Physiol 207:1146, 1964 Oomura, Science 143:484, 1964 GE- Glucose Excited Glucose Increased firing with Increased increased glucose levels increased GI- Glucose Inhibited Glucose Decreased firing with Decreased increased glucose levels increased Location of GE and GI Neurons GE GI LHA MCH M PVN LHA DMN Orexin POMC (α -MSH) POMC VMN ARC NPY/ AgRP AgRP Hindbrain Extended Amygdala Energy Intake Arousal Hunger Foraging Reward Satiety Striatum Energy Storage & Energy Assimilation Assimilation Direct (pancreas) Indirect (centralANS) Energy Expenditure Thermogenesis Counterregulatory Response Hypothalamus PVN LHA DMN VMN ARC TA /V SN Inf. Petrosal Inf. Ganglion Ganglion Carotid Body LC AP NTS NTS n. ’s ng er i H Nodose Nodose Ganglion Ganglion CVLM DVC RPa/Ob RVLM s s Vagu Vagu Medulla Dorsal Root Ganglion te cta ines La ok t Cy Muscle Leptin Ke to ne s Cytokines White Adipose Sympath e tic Affere nts Spinal Cord Insulin Pancreas Portal Vein Small Intestines Focal Brainstem Glucoprivation (5TG) Stimulates Food Intake and a Counterregulatory Response 3 hr Food Intake (g) 6 5 4 3 2 1 0 Blood Glucose (mg/dl) 5TG Saline * 250 200 150 100 50 0 0 30 60 90 120 5TG Saline Time (min) Ritter et al, 2000 Ritter Recordings from LH GI Neurons Recordings GI PVN LH DMN VMN ARC ANS OUTFLOW ANS Blood-brain Glucose Levels and LH Blood-brain GI Neuron Firing Rates GI Silver and Erecinska, 1998 Glucose-inhibited VMN (GI) Neuron (Whole Cell Recording) Action Potential 2.5 mM Glucose Membrane Potential Input Resistance 0.1 mM Glucose 2.5 mM Glucose pA pA 2.5 mM Glucose 0.1 mM Glucose Cl - mV Song & Routh Recordings from VMH GE Neurons Recordings GE PVN LHA LHA DMN VMN ARC ANS OUTFLOW ANS Blood-brain Glucose Levels and VMH GE Neuron Firing Rates GE Silver and Erecinska, 1998 Silver Glucose-excited VMN (GE) Neuron 2.5 mM Glucose 0.1 mM Glucose pA pA 0.1 mM Glucose + 200 mM Tolbutamide 2.5 mM Glucose 0.1 mM Glucose mV K + Song , Levin et al, Diabetes 50:2673, 2001 Capillary Glut 3 Glutamate KATP GK Gl u ta m ate Glucose 5mM 5mM ATP ADP Glut1/2 Glut1/2 Glycogen Glut1 Glucose Pyruvate Glucose (0.5-2mM) Ca+2 3 G lu t Ca+2 K GKATP ATP ADP Lactate T MC HKI Pyruvate H LD Astrocyte Astrocyte (0.7-1.2mM) ATP Lactate T T MC MC GE Neuron Combined [Ca2+]i Imaging of GE Neuron and Single Cell real-time RT-PCR Cell 2.5mM G 300 250 200 0.5mM G 2.5mM G 0.5mM G 200uM Tol 0.5mM G [Ca+] i 150 100 50 2+ 0 0 10 20 GE Neuron Neuron A-G-C-U 30 40 Time (minute) 50 60 70 A-G-C-T rt-PCR Kang et al, Diabetes 53:549, 2004 Insulin Transiently Excites a VMN GE Neuron GE in 0.1 mM Glucose in 2.5 mM Glucose 2.5 0.1 mM Glucose 0.1 mM Glucose 0.1 + 100 nM Insulin 100 Wang et al, Diabetes 53:1959, 2004 Leptin Excites a VMN GE Neuron at Leptin GE Low (0.5mM) Glucose Levels Low 2.5G 1 fM leptin 1 pM leptin 20 nM glutamate 1800 1600 Ratio 1400 1200 1000 800 600 0 600 10 Lepr-b Minutes Ins-R GAD 20 30 GLUT 3 40 Actin Glucokinase + + + + + + Kang et al, Diabetes 53:549, 2004 Oleic Acid Excited Neurons in the Oleic Rostral ARC In Vivo In ARC Saline Saline Intracarotid Oleic acid Migrenne et al, Diabetes 55, Suppl 2:S139, 2006 Migrenne Some Long Chain Fatty Acids Have a Biphasic Effect on VMN GE Neurons GE 2.5 Gluc 400 0.5 Gluc 2.5 Gluc Oleic Acid 2nM 2.5 Gluc 20nM 200µ M Intracellular Calcium (nM) 360 320 280 240 200 160 120 80 80 0 10 20 30 40 50 60 70 Minutes Glucokinase etFAT/CD36 297: R655, CPT1 Le Foll al, AJP Actin 2009GLUT 3 Kang & Levin, Unpublished + + + + + Metabolic Sensing Neuron METABOLIC SIGNALS METABOLIC Leptin Insulin LCFACoA, Lactate, Ketones CoA, PERIPHERAL AFFERENTS Taste Smell Sight Taste Liver Gut CB Liver GLUCOSE GLUCOSE METABOLIC SENSOR METABOLIC Ingestion Ingestion Energy Expenditure Autonomic Autonomic Metabolic Metabolic INTRINSIC SIGNALS INTRINSIC Peptides Transmitters Peptides Memory Memory Affect Affect Motivation ENERGY BALANCE STORAGE= INTAKE - EXPENDITURE PLASTICITY CONVERGENCE CONVERGENCE MODULATORS TRANSMITTER S PEPTIDES CORTEX HYPOTHALAMUS NTS LIMBIC SYSTEM AFFECT EFFERENTS SOMATIC VISCERAL (ANS) HPA B BB INTEGRATION INTEGRATION REDUNDANCY HIPPOCAMPUS MEMORY MEMORY AFFERENTS SOMATIC VISCERAL HORMONAL METABOLIC ...
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This note was uploaded on 02/23/2011 for the course NEURO 501 taught by Professor Dr.servatius during the Spring '11 term at University of Medicine and Dentistry of New Jersey.

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