Transcript Powerpoint
Neural control Aim Outline basic structure and function of the nervous system Outline the ways in which the nervous system controls food intake What’s in a nervous system? CNS has neurons 109 glia 3 • 109 blood vessels developmentally Fore-brain Mid-brain Hind-brain Spinal cord What is a neuron? Parts of a neuron dendrite soma axon How do we know what neurons look like? silver staining fluorescent dyes antisera Resting potential Cells are all negative contain K+ outside Na+ anions e.g. Cl have semipermeable membranes Animation of resting potential Bezanilla http://nerve.bsd.uchicago.edu/ Summary so Far Brains made of neurons and glia All cells have resting potentials Normally maintained passively by balance of diffusion and electrical forces Extracellular action potential time → Intracellular recording 50 mV zero 50 mV 0.5s 0.02s Action potential membrane becomes permeable to Na+ Na+ floods in diffusion electrical K+ still goes out Role of Na+ Two crucial properties of the Na+ current starts at a voltage threshold stops itself -30mV open 1ms Arise from Na+ channel channel is voltage sensitive and opens closes with a second mechanism closed inactivated -70mV Animation of Na channel http://nerve.bsd.uchicago.edu/testna8.html TTX kills Chemical connections release chemical transmitter respond with receptors advantages effective excite or inhibit variable gain disadvantages slower than electrical [??] Synaptic connections Examples from snail neurons Excitation Inhibition Transmitter release Uptake and drugs Transmitters recycled by transporters Vesicles filled by transporters Major pharmaceutical target Prozac – a SSRI – selective serotonin uptake inhibitor Cocaine – blocks dopamine and serotonin (++) uptake Pharmacology of receptors many kinds of transmitters and their receptors ACh, adrenaline glutamate, glycine serotonin, dopamine peptides: FMRFamide, CCK, NPY, most transmitters have multiple types of receptors separate pharmacologically Pharmacology of receptors Nicotinic ACh receptor agonist - nicotine, succinylcholine antagonist - curare, bungarotoxin Muscarinic ACh receptor agonist - muscarine antagonist - atropine Ionotropic & Metabotropic Ionotropic receptor binding opens hole ions flow through metabotropic receptor binding activates Gprotein requires second messenger 7 transmembrane format phosphorylates another protein [e.g. channel] Peptides as neurotransmitters oxytocin released from neurons in the hypothalamus milk letdown uterine contraction at birth substance P Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met transmission of painful signals cellular damage to skin spinal cord Summary - neurotransmission transmitter is stored in vesicles vesicles released by local Ca influx following action potential transporters are major drug targets multiple kinds of transmitter ACh, 5-HT, dopamine, peptides different receptors ionotropic / metabotropic How much do we need to eat for homeostasis? digestion – metabolic rate – thermoregulation role of nervous system Insulin & glucagon Ghrelin “hunger hormone” release from gut when blood sugar is low elevated in Anorexia nervosa peaks before meal enhance fat deposition prevent synthesis → leaner mice causes release of growth hormone ghrelin used to treat some cases of short stature If homeostasis fails? Human who gains 1 kg over 10 years – extra 59MJ 44 GJ normal energy intake over this time 0.1% excess Hunger varies inversely with body weight Metabolism varies directly with body weight WHO estimate 1.6 billion adults overweight, 0.4 billion obese (BMI >30kg/m2) up to 8% of health costs What stops us eating? Short term NTS stomach distension CCK (cholecystokinin) Long term hypothalamus leptin insulin CCK long term: adiposity short term: satiety Leptin obese ob/ob mice – fail to synthesize leptin perceived starvation in midst of plenty obese db/db mice have no leptin receptor How does leptin act? receptors in brainstem satiety Nucleus accumbens reward hypothalamus peptide neurotransmitters Agouti-related peptide Neuropeptide Y pro-opiomelanocortin cocaine and amphetamine related transcript α-melanocyte-stimulating hormone Badman & Flier Science 2005;307:1909-14 Ways to treat obesity? Manipulation of body weight behavioural diet, exercise surgical most effective, but high cost and high mortality risk pharmacological 1930s – increase energy expenditure (Thyroxine, Dinitrophenol) 1940s - “Rainbow Pills,” amphetamine, thyroxine, digitalis, and a diuretic 1992 – 1997 fenfluramine [+ phentermine] modulate 5HT signaling in hypothalamu all associated with serious heart disease [RPs with addiction] Current pharmacological treatments Orlistat - a lipase inhibitor with diet and exercise 2-3 kg more weight loss than placebo rimonabant – a cannabinoid-1 (CB-1) receptor antagonist 6 - 7 kg more weight loss safety concerns depression and related psychiatric problems sibutramine – a reuptake blocker of 5-HT and noradrenaline amplifies satiety signals 2.5 – 5.5 kg weight loss Summary Brains made of neurons and glia Resting potentials maintained passively by balance of diffusion and electrical forces Properties of Na and K channels determine action potential Multiplicity of transmitters each with several kinds of receptors Range of peptides control food intake & energy homeostasis No magic bullet to control obesity – many redundant pathways, development of resistance Reading … PowerPoints on VLE or at http://biolpc22.york.ac.uk/003C/ Schmidt-Nielsen, K (1997) Animal Physiology CUP Books, etc Purves, D (et al) (2008) Neuroscience Sinauer 4th ed Badman & Flier Science 2005;307:1909-14