CART regulation of wakefulness
CART 觉醒调节
基本信息
- 批准号:8015471
- 负责人:
- 金额:$ 8.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-01-20 至 2011-12-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptive BehaviorsAntibodiesArousalAwarenessBehaviorBehavioralBrainCARTPT geneCell NucleusCerebrospinal FluidCircadian RhythmsClinicalDepressed moodDiseaseDopamineDoseEatingEndocrineExcessive Daytime SleepinessExhibitsFosteringGeneticHomeostasisHumanHypothalamic structureIdiopathic HypersomnolenceImpairmentLateralLeadLocomotionMacaca mulattaMediatingMetabolicMidbrain structureMotivationMusMyotonic DystrophyNarcolepsyNeurobiologyNeuronsNeuropeptidesOrganismParkinsonian DisordersPathway interactionsPatternPeptidesPharmaceutical PreparationsREM SleepRattusRegulationResearch PersonnelRewardsRodentRoleRye cerealSignal TransductionSleepSleep DeprivationSleep DisordersSystemWakefulnessalertnessbasebrain pathwaycholinergicclinically significantfeedinghypocretininsightnonhuman primateprogramspsychostimulantreceptor
项目摘要
CART (Cocaine and Amphetamine-Regulated Transcript) peptides appear to mediate behaviors associated
with psychostimulant drugs including: hypothalamically mediated suppression of food intake, activation of
the HPA axis, locomotion, and reward/motivation. We hypothesized that CART-containing neurons have
additional anatomical/behavioral relationships (indirect or direct) with mesolimbic dopaminergic pathways
and other nuclei involved in mediating wakefulness; i.e.,a behavioral 'state' also associated with
psychostimulants. Our preliminary studies are supportive in demonstrating that: 1) CART exhibits a diurnal
rhythm in non-human primate spinal fluid that peaks in the early morning; 2) intracerebroventricular delivery
in rats during their major sleep period produces profound, dose-dependent, increases in wake; 3)
interference with endogenous CART signaling increases rapid-eye-movement sleep in the initial major
active period of rats; and 4)and CART is depressed in non-human primates and humans afflicted with
parkinsonism and other conditions characterized by impairments in wakefulness. We propose to further
characterize the wake promoting effects of CART peptides, and explore the underlying substrates and their
potential clinical significance. S.A. #1 proposes to differentiate between CART'S role as a homeostatic vs.
circadian wake promoting signal by examining its daily oscillations, responsiveness to sleep deprivation,
and relationship to prior sleep-wake in the diurnal (wake-active) non-human primate (rhesus). S.A. #2
proposes to demonostrate that endogenous CART is necessary for normal wakefulness by central delivery
of CART antibodies to rats and characterizing sleep/wake state in Cart +/- and Cart -/- mice. S.A. #3
proposes anatomical (rat,non-human primate, and human) and behavioral (rat)determination of the
regional, cellular, and pharmacologic bases of CART'S wake promoting actions. Finally, S.A. #4 proposes
to examine spinal fluid CART in human conditions characterized by impairments in maintaining wakefulness
(e.g., narcolepsy, parkinsonism, idiopathic hypersomnia, and myotonic dystrophy). Taken together, these
findings will provide new insights into the mechanisms governing wakefulness in the context of a growing
recognition that the key cellular mechanisms also involve integration of additional, seemingly disparate
adaptive behaviors such as energy homeostatis, feeding, reward and motivation.
CART(可卡因和安非他明调节转录)肽似乎介导相关行为
项目成果
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