HSM330 article 1 summary

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Ryerson University
Health Services Management
HSM 330
Daolun Chen

Sutcliffe -neuropeptide system, centered in dorsolateral hypothalamus, that regulates arou sal states, influences feeding, and plays a role in sleep disorder narcolepsy -hypocretin aka orexin system: also influences hormone secretion and autonomic h omeostasis -most human narcolepsies result from autoimmune attack against hypocretin-produc ing neurons -discovery of a neuropeptide system that regulates arousal states and energy met abolism -hypocretins aka orexins are 2 carboxy-terminally amidated neuropeptides of rela ted sequence -they're produced from a common precursor, which is expressed only in a few thou sand neurons of rat dorsolateral hypothalamus -2 G protein coupled receptors (GPCRs) for hypocretins have been id'd, they have diff distrubution w/i CNS and diff affinities for the 2 hypocretins -hypocretins (H) detected in secretory vesicles at synapses of fibers that proje ct to areas w/i posterior hypothalamus that are implicated in feeding behaviours & hormone secretion -H fibers project to diverse targets in brain and spinal cord, incl areas implic ated in cardiovascular function and sleep-wake regulation -peptides are excitatory when applied directly in vivo, and to cultures neurons & slices in vitro, also evidence for some inhibitory signalling -admin of H stimulates food intake, affects blood pressure, hormone secretion, a nd locomotor activity, and inc wakefulness while suppressing REM sleep -inactivating mutations in gene for H receptor 2 (Hcrtr2) in dogs = narcolepsy -mice w/ inactivated preprohypocretin (Hcrt) gene = narcolepsy-like phenotype -humans w/ narcolepsy have greatly reduced levels of H peptides in their CSF, an d almost no H neurons in their hypothalami = autoimmune attack against H neurons -one aspect of H activity is direct excitation of cholinergic forebrain neurons and brainstem monoaminergic REM-off neurons in locus coeruleus, dorsal raphe nucleus and tuberomammillary nu cleus (TMN) which together suppress SWS -H modulate activity of cholinergic REM-on neurons in brainstem, which gate REM entry -dominant activities of H system are maintenace of waking state and suppression of REM entry Discovery and properties of H -1st glimpse of H came from open-system search for undiscovered homeostatic regu latory peptides OPEN-SYSTEM ANALYSIS Analysis of all the mRNAs that are expressed by a tissue without regard to wheth er the mRNAs have previously been identified. The contrasting approach is to measure the expression of known mRNAs, as is done in cDNA array (chip) studies. -systematic subtractive hybridization survey to id mRNA species expressed only i n discrete nuclei w/i rat hypothalamus -40% of mRNA species that were highly enriched in hypothalamus encoded hormones & releasing factors -among new mRNAs was a species w/ a pattern of expression (detected by in situ h ybrid.) restricted to a few thousand neurons that were bilaterally distributed w/i dorsolateral hypothalamus -the complementary DNA sequences of the rat and homologous mouse mRNAs encoded a 130-residue, putative secretory protein w/ an apparent signal sequence -features indicated that the product of this hypothalamic mRNA was a preprohormo ne for 2 carboxy-terminally amidated, secreted peptides -one was hypocretin 2 (Hcrt2), predicted to contain 28 residues -other was hypocretin 1 (Hcrt1), undefined amino-terminal extent -carboxy-terminal 19 residues of the 2 peptides shared 13 AA identities, thus th ey had related structures and functions -this region of Hcrt2 had 7 AA match w/ secretin -detection of H peptides w/i brain allowed their structures to be determined by mass spectrometry -Hcrt1 has 2 intrachain disulphide bonds -human HCRT1 is identical to the rodent peptide, whereas human HCRT2 differs fro m rodent Hcrt2 at 2 residues -genes that encode preprohypocretins in pufferfish and frogs, so gene arose earl y in chordate lineage -sequence similarities w/ members of incretin family, esp secretin = Hcrt gene f ormed from secretin gene by 3 genetic rearrangements: 1) duplication of secretin gene 2) secretin w/ amino & carboxyl termini circularly permuted 3) further duplication of permuted gene w/ modifications to form gene that encod ed 2 related peptides -portions of 3D solution structures of hypocretins and secretin are similar (det ermined by nuclear magnetic resonance) despite their primary sequence consisting of 2 adjacent alpha helices (6-7 and 9-14 AA in length) separated by 2-3 AA turn, longer helix = region of identity btwn the 2 peptides The H receptors -initial orphan GPCR, (Hcrtr1) bound Hcrt1 w/ high affinity, but Hcrt2 w/ 100-10 00 fold lower affinity -related GPCR, (Hcrtr2) had high affinity for Hcrt2 and Hcrt1 -mRNAs that encode for the 2 H receptors are enriched in brain and abundant in h ypothalamus, but had diff distribution in brain -Hcrtr1 mRNA prominent in prefrontal & intralimbic cortex, hippocampus, paravent ricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus -Hcrtr2 mRNA detected in cerebral cortex, septal nuclei, hippocampus, medial tha lamic groups, raphe nuclei, various nuclei of hypothalamus, incl TMN, dorsomedial nucleus, paraventricular n ucleus and ventral premammillary nucleus Localization of the H -hypothalamus is ancient region of mammalian brain, is a collection of distinct, autonomously active nuclei -several of these nuclei are regulatory centers for autonomic and endocrine home ostatic systems -perifornical region associated w/ nutritional homeostasis, blood pressure, ther mal regulation, neural control of endocrine secretion and arousal - these activites might be affected b y H -perifornical hypothalamus contains neurons that express melanin-concentrating h ormone (MCH), a peptide involved in feeding behaviour -MCH and H neurons are distinct but spatially intermingled -one-to-one correspondence btwn neurons in lateral hypothalamus that express the opioid receptor agonist dynorphin and the H neurons -H neurons receive direct projections from neurons in SCN which generates circad ian rhythm -antisera against H fragments show a few thousand immunoreactive neurons btwn fo rnix and mammillothalamic tracts, and projections from these cells to neurons in perifornical and posterio r hypothalamus -further projections w/ terminal fields w/i septal nuclei in basal forebrain, pr eoptic area, paraventricular nucleus of thalamus, central grey, locus coeruleus, pedunculopontine tegmental n ucleus (PPT) and spinal cord -set of projections is consistent w/ patterns of expression of 2 H GPCRs, so the re are no other receptors for these peptides - projection fields in humans similar to those in rodents H are neuroexcitatory -H immunoreactivity is associated w/ dense-core vesicles (can be seen traversing Golgi network, along myelinated axons and at presynaptic terminals apposed to dendritic shafts) -accumulation of H w/i dense-core vesicles at axons terminals = H might have int ercellular signalling activity -bath application of synthetic Hcrt2 to mature hypothalamic neurons = inc in fre q of postsynaptic currents -# responsive neurons in diff brain regions consistent w/ projection & receptor densities: 33% of hypothalamic neurons respond to Hcrt2 compared w/ 5% cerebral cortex neur ons and 15% spinal cord neurons - 80% of neurons w/i hypothalamic paraventricular nucleus are excited by Hcrt2, similar results obtained by applying Hcrt1 to locus coeruleus slices -Hcrt2 has potent effect at presynaptic & postsynaptic receptors; in presence of TTX, it inc the freq, but not the amplitude of mini postsynaptic currents (presynaptic effect) and evokes an i nc in cytoplasmic Ca by opening plama-membrane Ca channels in arcuate postsynaptic neurons (postsynaptic effect) -most synaptic activity in hypothalamic circuits due to axonal release of GABA ( gamma-aminobutyric acid) or glutamate -H, acting at axon terminals can inc release of each of these NTs (shown by whol e cell patch clamp recording) -Hcrt1&2 evoke rises in Ca in ~ 1/3 of hypothalamic neurons, by opening a Ca cha nnel -responses to H are completely blocked by the PKC-specific inhibitor bisindolylm aleide and by phospholipase C inhibitors, indicating that H operate through a family of GTP-binding proteins ( Gq) that activate PKC and mobilize intracellular Ca -Gq-activated signalling cascades result in phosphorylation of Ca channels, whic h can inc Ca conductance and neuronal excitability - non-amidated forms of the peptides are not electrophysio logically active -adrenal glands also express Hcrtr2 -treatment of human adrenal membranes from fetal/adult tissue w/ HCRT1 inc label ling of Gs and Gi in both preparations, and also of Gq in adult tissue -most H signalling is excitatory, but can be inhibitory in some cases -acting as excitatory peptides, H can enhance activities of both excitatory & in hibitory neurons H and feeding -leptin, encoded by obese gene, is a peptide hormone produced by peripheral adip ocytes -its conc in circulation is proportional to fat stores and it serves as an anore xigenic (appetite-suppressing) signal, in part by binding to leptin receptors in hypothalamus -there are leptin receptors in arcuate nucleus neurons that express neuropeptide Y (NPY) and agouti-related peptide (AgRP), and others that express pro-opiomelanocortin (POMC) and cocaine- and amphetamine regulated transcript (CART) -also leptin receptors in MCH neurons of lateral hypothalamus -NPY, AgRP, alpha melanocyte stimulating hormone (alpha-MSH, aPOMC-derived pepti de), CART, and MCH all contribute to regulation of food intake -intracerebroventricular (icv) admin of Hcrt1/Hcrt2 inc short-term food consumpt ion in rats -rats food-deprived for 48 hrs had inc concs of H mRNA and peptides in the hypot halamus -these observations lead to alternative name, orexin, for the hypocretin peptide s -feeding can be elicited by local admin of Hcrt1 to paraventricular nucleus, dor somedial nucleus, lateral hypothalamus, or perifornical area -icv admin of Hcrt2 inc food intake in sheep -central imptce of H to feeding activities is uncertain, H influences&influenced by primary nutritional homeotasis circuits but H may not be crucial players in feeding activities -H immunoreactive fibers form synapses on neurons in arcuate nucleus that contai n NPY, an impt orexigenic (appetite stimulating) peptide, and w/ POMC expressing neurons, which produce al pha-MSH, a satiety factor -H neurons express leptin receptors -preprohypocretin mRNA expression is reduced in obese (ob/ob) mice which lack le ptin -H neurons receive inputs from NPY and AgRP positive neurons in arcuate nucleus, which themselves express leptin receptors, and NPY stimulates c-FOS expression by H neurons, whereas NPY receptor antagonists block feeding effect of H -H-expressing cells respond to circulating leptin by reducing Hcrt1 concs and c- fos expression -icv injection of antibodies agaisnt Hcrt1 reduces feeding activity and attenuat es feeding response to injected NPY -icv admin of ghrelin activates c-fos expression by H neurons, ghrelin also caus es dec in core body temp -H neurons express Stat3 (signal transducer and activator of transcription 3), a transcription factor that is induced by leptin -H cells are sensitive to glucose and food deprivation, activity of H neurons & expression of H mRNA and c-fos inc during hypoglycaemia -H mRNA dec during glucopenia -c-fos inc during fasting = appetite controlling signalling molecules in arcuate & lateral hypothalamus, in which H might have a role Contrasting data from other groups: -Hcrt1-induced incs in food intake were small compared to those induced by NPY i nfusion -no effect of Hcrt2 on feeding -inc in food intake after icv infusion, but not after local intrahypothalamic in jection of Hcrtr2 -no alteration in Hcrt1 conc or H mRNA in rat hypothalamus in response to fastin g/high-fat diet -no effect on H mRNA of exp induced diabetes -but, H mRNA inc after leptin admin to fasted mice and no effect of obese mutati on on H expression -high doses of H might activate circuits other than those activated by local axo nal release of NT -H might be orexigenic only in some physiological states (in relation to circ rh ythms/stress) -H activate dopamine-mediated stereotypical behaviours -Hcrt1 conc in hypothalamus are under circadian control and are highest during t he awake, dark period in nocturnal rodents -during fasting, Hcrt1 accumulation in CSF does not exceed normal conc for awake period = some of food-uptake effect might result from arousal rather than direct feeding pressure -continuous admin of Hcrt1 for 7 days in rats does not significantly alter daily food intake, body weight, blood glucose, total cholesterol or levels of free fatty acids = many effects of H might be limited to immediate, short-term stimulation of feeding behaviour due to inc wakefulness Autonomic & Endocrine homeostasis -H neurons receive inputs from brainstem areas associated w/ cardiovascular func tion, and project to ventrolateral medulla, locus coeruleus, lateral paragigantocellular nucleus, nuc leus of solitary tract and other areas implicated in regulation of blood pressure and HR -projections to arcuate nucleus = possible role in regulation of hormone release -in ovine hypothalamus, there are H terminals on neurons that produce gonadotrop in-releasin
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