AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors

AGRP 神经元。

• 批准号: 8668942
• 负责人: BRADFORD B LOWELL
• 金额: $ 53.82万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668942
• 关键词: Afferent Neurons; Anatomy; Animals; Anorexia; Area; Attention; Automobile Driving; Behavior; Body fat; Brain; Collaborations; Complex; Dendritic Spines; Eating; Eating Disorders; Excitatory Synapse; FOS gene; Fasting; Feeding behaviors; Food; Genes; Glutamates; Growth; Hormones; Laser Scanning Microscopy; Lateral; Leptin; Light; Maps; Mediating; Metabolism; Microscopy; Mind; Mus; N-Methyl-D-Aspartate Receptors; Nerve; Neurobiology; Neurons; Obesity; Pharmacogenetics; Play; Potassium Channel; Rabies; Regulation; Relative (related person); Role; Signal Transduction; Source; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Vertebral column; Weight; Work; awake; base; feeding; gamma-Aminobutyric Acid; ghrelin; hormone regulation; in vivo; innovation; mRNA Expression; neural circuit; neuroregulation; optogenetics; parabrachial nucleus; postsynaptic; prevent; relating to nervous system; synaptogenesis; tomography; transmission process; two-photon

DESCRIPTION (provided by applicant): The brain regulates feeding behavior and metabolism however the neurocircuitry responsible for this is largely unknown. The complexity of the brain and the need to manipulate it in awake, behaving animals, represent significant technical challenges. The application of new, innovative approaches is likely to greatly accelerate progress. Recently, we and others, using pharmacogenetic and optogenetic technology, have discovered that AgRP neurons drive intense feeding behavior. With this in mind, it is now critical to determine the afferent signals (hormones and neural inputs) controlling AgRP neuron activity as well as the effectors (GABA, NPY, AgRP, and downstream neural circuits) that bring about AgRP neuron-driven feeding. Remarkably, little attention has been paid to afferent (upstream) neural inputs regulating AgRP neurons. This is unfortunate because a) defective neural control of AgRP neurons could contribute importantly to complex eating disorders (ranging from anorexia to obesity), and b) the hormonal regulation of AgRP neurons, one example being ghrelin, likely works by modulating these inputs. Recently, in Preliminary Studies, we discovered that NMDA receptors (NMDARs), key regulators of excitatory synaptic plasticity, play a critical role in regulating AgRP neuron activity and feeding; NMDARs on POMC neurons, on the other hand, play little or no role. Consistent with this, AgRP neurons have abundant dendritic spines (postsynaptic specializations where most excitatory synapses reside and within which NMDARs operate to control plasticity); POMC neurons, in contrast, lack spines. Finally, we have found that fasting-activation of AgRP neurons require NMDARs and involves dendritic spinogenesis, and very likely increased excitatory synaptogenesis. Thus, NMDAR-mediated plasticity of excitatory input to AgRP neurons plays a key, previously unknown role in regulating AgRP neuron activity and consequently feeding behavior. The present application will pursue key implications of the above-mentioned findings. In Aim 1, using advanced 2-photon microscopy, we will mechanistically investigate "regulatory" plasticity of excitatory inputs, via NMDARs/spines, to AgRP neurons. In Aim 2, using Cre-dependent, Monosynaptic Rabies Mapping and also Channelrhodopsin-Assisted Circuit Mapping, we will identify and assess function of afferent neurons sending glutamatergic input to AgRP neurons. In Aim 3, using pharmacogenetic activation of AgRP neurons unable to signal via GABA, NPY and/or AgRP and also anatomic-selective, optogenetic activation of AgRP nerve terminals, we will identify the downstream effectors (transmitters and circuits) of AgRP neurons.

描述（由申请人提供）：大脑调节喂养行为和代谢，但是负责此的神经记录是未知的。大脑的复杂性以及在清醒，表现动物中操纵它的需求代表了重大的技术挑战。新的创新方法的应用可能会大大加速进步。最近，我们和其他使用药物遗传学和光遗传学技术的人发现，AGRP神经元驱动强烈的进食行为。考虑到这一点，现在确定控制AGRP神经元活性以及效应子（GABA，NPY，AGRP和下游神经回路）的传入信号（激素和神经输入）至关重要，从而带来了AGRP神经元驱动的进食。值得注意的是，对调节AGRP神经元的传入（上游）神经输入的关注很少。这是不幸的，因为a）A）AGRP神经元的神经控制有缺陷可以对复杂的饮食失调（从厌食症到肥胖症）以及b）AGRP神经元的激素调节，这是Ghrelin的一个例子，这是Ghrelin，这可能是通过调节这些输入来起作用的。最近，在初步研究中，我们发现NMDA受体（NMDARS）是兴奋性突触可塑性的关键调节剂，在调节AGRP神经元活性和喂养方面起着至关重要的作用。另一方面，pomc神经元上的NMDAR扮演很少或没有角色。与此相一致，AGRP神经元具有丰富的树突状刺（突触后的特殊性，其中大多数兴奋性突触都居住，而NMDARS则在其中控制可塑性）；相比之下，POMC神经元缺乏刺。最后，我们发现AGRP神经元的禁食激活需要NMDAR，并且涉及树突状旋转生成，并且很可能增加了兴奋性突触发生。因此，NMDAR介导的兴奋性输入对AGRP神经元的可塑性在调节AGRP神经元活性并因此喂养行为中起着以前未知的作用。本申请将追求上述发现的关键含义。在AIM 1中，使用先进的2光子显微镜，我们将通过NMDARS/Spine机械地研究兴奋性输入的“调节性”可塑性，以将其用于AGRP神经元。在AIM 2中，使用CRE依赖性，单突触狂犬病映射以及ChannelRhopopsin辅助电路映射，我们将识别和评估将谷氨酸能输入到AGRP神经元发送的传入神经元的功能。在AIM 3中，使用无法通过GABA，NPY和/或AGRP发出信号的AGRP神经元的药物遗传学激活，以及AGRP神经末端的解剖学选择性，光遗传学激活，我们将识别AGRP神经元的下游效应子（递质和电路）。