Correction of obesity by optogenetic manipulation of striatal neurons

通过纹状体神经元的光遗传学操作纠正肥胖

基本信息

批准号：
8444948
负责人：
Elizabeth Katherine Schwartz
金额：
$ 1.81万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2013-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444948
关键词：
20 year old Ablation Addictive Behavior Address Adult Animal Model Attenuated Body Weight decreased Brain-Derived Neurotrophic Factor Clinical Consumption Corpus striatum structure Data Development Diet Dopamine Dopamine Agonists Dopamine Antagonists Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Drug Addiction Eating Energy Intake Equilibrium Face Fatty acid glycerol esters Feeding behaviors Food Glucose Goals Health Hyperphagia Hypothalamic structure Individual Intervention Knowledge Laboratories Lead Link Mediating Metabolic Metabolic syndrome Modeling Motor output Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nucleus Accumbens Obesity Oral Overweight Pharmaceutical Preparations Phenotype Play Population Positioning Attribute Property Public Health Regulation Rewards Risk Factors Role Signal Transduction Synapses System Technology Testing Therapeutic Intervention Ventral Striatum Weight Weight Gain base detection of nutrient feeding improved increased appetite innovation mouse model novel therapeutic intervention optogenetics prevent psychologic reward circuitry social

项目摘要

It is becoming increasingly recognized that alterations in the mesolimbic dopaminergic circuitry may underlie the development of obesity, and that obesity has more in common with drug addiction than previously thought. Specifically, alterations in the balance of activity of D1 and D2 dopamine receptor expressing medium spiny neurons of the nucleus accumbens (NAc) have been implicated. How exactly this alteration plays out in terms of the activity of the relevant circuitry, however, is still unknown. Observations made in the clinical as well as the laboratory over the past few decades have shown that dopamine agonists often cause weight loss and decreased food reward, whereas dopamine antagonists often lead to weight gain (and often the metabolic syndrome), and increased food reward. The proposed studies are in particular based on the observation that D2 and D1 expressing neurons in the striatum are antagonistic in their roles in mediating downstream motor outputs, as well as the recent observation by our colleagues that optogenetic activation of NAc D2 expressing neurons reduces reward whereas optogenetic activation of NAc D1 expressing neurons enhances reward. Furthermore, BDNF TrkB signaling has also been shown to attenuate both D1 and D2 expressing medium spiny neurons excitability. We hypothesize that optogenetic activation of D2 expressing NAc medium spiny neurons will cause decreased energy intake and decreased food reward, leading to reversal of obesity in a high-fat diet induced model of obesity. We hypothesize that TrkB deletion in these same neurons will cause a similar phenotype. Conversely, we hypothesize that optogenetic activation of D1 expressing NAc medium spiny neurons will increase feeding behavior and feeding-induced reward, and will lead to hyperphagia and weight gain. We also hypothesize that TrkB ablation specific to D1 expressing NAc medium spiny neurons will also mirror this phenotype. If successful, these studies will lead to novel therapeutic interventions for those who struggle with obesity. Additionally, further clarification of the regulation of reward by the balance of activation of these two neuronal subtypes of the nucleus accumbens can lead to development of new treatments for addictive behaviors.

越来越认识到，中唇多巴胺能回路的改变可能是肥胖发展的基础，并且肥胖症与药物成瘾的共同点比以前想象的更多。具体而言，已涉及伏隔核（NAC）表达培养基神经元D1和D2多巴胺受体的平衡的改变。然而，这种变化在相关电路的活性方面的确尚不清楚。在过去的几十年中，在临床和实验室中进行的观察结果表明，多巴胺激动剂通常会导致体重减轻和减少食物奖励，而多巴胺拮抗剂通常会导致体重增加（通常是代谢综合征），而食物奖励则增加。拟议的研究尤其是基于这样的观察结果，即纹状体中表达神经元的D2和D1在介导下游运动输出以及我们的同事最近观察到的NAC D2的光学激活中，表达神经元的光学激活减少了奖励的作用是拮抗作用。表达神经元的NAC D1的光遗传激活增强了奖励。此外，BDNF TRKB信号传导也已显示出表达培养基神经元兴奋性的D1和D2。我们假设表达NAC培养基神经元的D2的光遗传学激活会导致能量摄入减少并减少食物奖励，从而导致高脂饮食诱导的肥胖模型中肥胖的逆转。我们假设这些相同神经元中的TRKB缺失会引起相似的表型。相反，我们假设表达NAC培养基神经元的D1的光遗传学激活将增加进食行为和喂养引起的奖励，并导致多晶状体和体重增加。我们还假设，表达NAC培养基神经元的D1特异性的TRKB消融也会反映出该表型。如果成功，这些研究将为与肥胖症斗争的人提供新的治疗干预措施。此外，通过平衡伏隔核的这两种神经元亚型的激活来进一步阐明奖励的调节，这可能会导致成瘾行为的新处理。