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NROC61 - Sutcliffe article notes

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University of Toronto Scarborough
Le Boutillier

Sutcliffe neuropeptide system centered in dorsolateral hypothalamus that regulates arousal states influencesfeeding and plays a role in sleep disorder narcolepsyhypocretin aka orexin system also influences hormone secretion and autonomic homeostasismost human narcolepsies result from autoimmune attack against hypocretinproducing neuronsdiscovery of a neuropeptide system that regulates arousal states and energy metabolism hypocretins aka orexins are 2 carboxyterminally amidated neuropeptides of related sequence theyre produced from a common precursor which is expressed only in a few thousand neurons of rat dorsolateral hypothalamus2 G protein coupled receptors GPCRs for hypocretins have been idd they have diff distrubution wi CNSand diff affinities for the 2 hypocretins hypocretins H detected in secretory vesicles at synapses of fibers that project to areas wi posterior hypothalamus that are implicated in feeding behaviourshormone secretion H fibers project to diverse targets in brain and spinal cord incl areas implicated in cardiovascularfunction and sleepwake regulationpeptides are excitatory when applied directly in vivo and to cultures neuronsslices in vitro also evidence for some inhibitory signallingadmin of H stimulates food intake affects blood pressure hormone secretion and locomotor activity andinc wakefulness while suppressing REM sleepinactivating mutations in gene for H receptor 2 Hcrtr2 in dogsnarcolepsymice w inactivated preprohypocretin Hcrt genenarcolepsylike phenotype humans w narcolepsy have greatly reduced levels of H peptides in their CSF and almost no H neurons in theirhypothalamiautoimmune attack against H neurons one aspect of H activity is direct excitation of cholinergic forebrain neurons and brainstem monoaminergic REMoff neurons in locus coeruleus dorsal raphe nucleus and tuberomammillary nucleus TMN which togethersuppress SWSH modulate activity of cholinergic REMon neurons in brainstem which gate REM entrydominant activities of H system are maintenace of waking state and suppression of REM entryDiscovery and properties of H 1st glimpse of H came from opensystem search for undiscovered homeostatic regulatory peptides OPENSYSTEM ANALYSISAnalysis of all the mRNAs that are expressed by a tissue without regard to whether the mRNAs have previously been identified The contrasting approach is to measure the expression of known mRNAs as is done incDNA array chip studiessystematic subtractive hybridization survey to id mRNA species expressed only in discrete nuclei wi rathypothalamus
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