Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA

食欲素和瘦素对 VTA 中进食和成瘾行为的调节

• 批准号: 8434870
• 负责人: Michael Scott
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2014-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434870
• 关键词: Addictive Behavior; Address; Adult; Alleles; Behavior; Behavioral; Biological Assay; Brain; Cocaine; Complex; Consumption; Cues; Data; Development; Diet; Drug Addiction; Drug usage; Eating; Employee Strikes; Environment; Fatty acid glycerol esters; Feeding behaviors; Food; Food Intake Regulation; Genetic Models; Homeostasis; Hyperphagia; Incidence; Individual; Instruction; Intake; Knockout Mice; Leptin; Mammals; Mediating; Metabolic; Modeling; Mus; Nature; Neurons; Nucleus Accumbens; Nutrient; Obesity; Pharmaceutical Preparations; Phenotype; Predisposition; Prefrontal Cortex; Property; Prosencephalon; Public Health; Regulation; Relative (related person); Rewards; Signal Transduction; Signaling Protein; Structure; System; Testing; Ventral Tegmental Area; design; dopaminergic neuron; drug abuse prevention; drug of abuse; drug reward; feeding; hypocretin; leptin receptor; motivated behavior; mouse model; mutant; neural circuit; neurotransmission; novel; obesity in children; obesity treatment; orexin 1 receptor; preference; psychostimulant; receptor; receptor expression; research study; response; restoration; therapeutic development; treatment strategy

Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. Recent evidence suggests the brains of obese individuals resemble those of people addicted to drugs of abuse, with alterations in dopaminergic neurotransmission, arguing that cessation of over eating may be as difficult as abstaining from drug use. Consequently, elucidating the neural circuits that are involved in both the drive to consume high calorie foods and drugs of abuse is extremely important in the development of therapeutic strategies in the treatment of obesity and drug addiction. The proposed experiments examine, using mouse genetic models, the direct action of two potent metabolic signaling proteins, leptin and orexin, on neurons of the ventral tegmental area (VTA) and their control of energy homeostasis and modulation of the reinforcing properties of food and cocaine. VTA dopaminergic neurons, projecting to forebrain structures such as the nucleus accumbens and prefr-ontal cortex, are involved in mediating many of the behavioral responses to drugs of abuse. Interestingly, evidence suggests that VTA dopamine neurons are excited by orexin and inhibited by leptin. Thus, these metabolic signals may act in the VTA to modulate energy homeostasis along with the seeking of both drug and natural food rewards. In Aim 1, lepr will be deleted from mouse VTA neurons, using the Cre-lox system, to test the necessity of lepr signalling while in aim 2, a lepr allele that can be selectively reactivated on a null lepr background in the VTA will be used to test the sufficiency of VTA leptin signalling in regulating energy homeostasis and the reinforcing properties of food and cocaine. In Aim 3, mice carrying a mutant orexin 1 receptor allele that can be reactivated in the VTA on an orexin 1 receptor null background, similar to the leptin reactivatable receptor model, will be used to test the sufficency of orexin action in the VTA in modulating both energy homeostasis and the reinforcing properties of food and cocaine. In summary, the proposed studies will comprehensively test the action of orexin and leptin in the VTA and their subsequent effect on the development of obesity and the drive to consume both food and the psychostimulant cocaine.

肥胖已成为本世纪最紧迫的公共健康问题之一。不幸的是，解决

项目成果

Central regulation of food intake, body weight, energy expenditure, and glucose homeostasis.

• DOI: 10.3389/fnins.2014.00384
• 发表时间: 2014
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Scott MM;Xu Y;Elias CF;Williams KW
• 通讯作者: Williams KW

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

• DOI: 10.1101/gad.232470.113
• 发表时间: 2014-02-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Lim CS;Hoang ET;Viar KE;Stornetta RL;Scott MM;Zhu JJ
• 通讯作者: Zhu JJ

Characterization of excitatory and inhibitory neuron activation in the mouse medial prefrontal cortex following palatable food ingestion and food driven exploratory behavior.

• DOI: 10.3389/fnana.2014.00060
• 发表时间: 2014
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Gaykema RP;Nguyen XM;Boehret JM;Lambeth PS;Joy-Gaba J;Warthen DM;Scott MM
• 通讯作者: Scott MM

Activation of Pyramidal Neurons in Mouse Medial Prefrontal Cortex Enhances Food-Seeking Behavior While Reducing Impulsivity in the Absence of an Effect on Food Intake.

• DOI: 10.3389/fnbeh.2016.00063
• 发表时间: 2016
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Warthen DM;Lambeth PS;Ottolini M;Shi Y;Barker BS;Gaykema RP;Newmyer BA;Joy-Gaba J;Ohmura Y;Perez-Reyes E;Güler AD;Patel MK;Scott MM
• 通讯作者: Scott MM