Interactive function of classical neurotransmitters and neuropeptides

经典神经递质和神经肽的相互作用功能

• 批准号: RGPIN-2017-06272
• 负责人: Chee, Melissa
• 金额: $ 2.4万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710814
• 关键词: Interactive; function; classical; neurotransmitters; neuropeptides

Neurons do not function in isolation, but rather, as part of an interconnected network. They can do so by releasing neurotransmitters like GABA and glutamate to directly transmit information to the apposing neuron. Additionally, neurons also release neuropeptides in order to regulate neurotransmission. This latter process though critical to neuronal function, is complex and not well-defined. Neuropeptides co-express with neurotransmitters in the same neuron but they are released by different mechanisms and can travel longer distances to reach their target sites. This proposal uses neurons that produce melanin-concentrating hormone (MCH) to determine the interactive functions between neurotransmitters and neuropeptides. MCH is necessary for normal energy homeostasis, reward and social behaviors, and these actions are critical for survival and are conserved across species. Importantly, MCH neurons form an instrumental model for studying the network functions of a neuropeptide because they co-release the neurotransmitter glutamate and are found only in one region of the brain thus are easily isolated for investigation. We recently showed that MCH neurons send long range projections to the lateral septum where they release glutamate and functionally innervate cells in the lateral septum. Here we will determine if 1) MCH itself is also released in the lateral septum; 2) if MCH regulates glutamatergic transmission in the lateral septum; and 3) given the unprecedented role for glutamate in the function of MCH neurons, we will determine if MCH and glutamate have overlapping or independent behavioral roles. Our research program will use a transformative optogenetic technique to enable precise control of neuronal activity, which we can capture via electrophysiological recordings, even within small defined brain regions. Since neuropeptide release may require prolonged high frequency nerve stimulations, we can deliver timed light pulses to specifically activate MCH nerve fibers to evoke MCH release. In order to study the functions of co-expressed MCH and glutamate, we will generate a novel transgenic mouse model, in which we conditionally disrupt glutamatergic transmission by MCH neurons only, then compare it to mice lacking MCH but with an intact glutamate system. In aggregate, these studies will disentangle the roles of MCH and glutamate and provide a detailed, mechanistic understanding of the neuropeptidergic processes that may underlie reward or social behaviors. These findings are significant as they contribute towards a deeper understanding of peptidergic events underlying information processing. We are assembling a team of highly-motivated students who will receive directed hands-on training on cutting-edge techniques. Together we will be at the forefront of this technology and develop translational skills and tools to conduct innovative research.

神经元的功能不是孤立的，而是作为一个相互连接的网络的一部分。他们可以通过释放GABA和谷氨酸等神经递质直接将信息传递给对方的神经元来做到这一点。此外，神经元还会释放神经肽来调节神经传递。后一个过程虽然对神经元功能至关重要，但很复杂，也没有明确的定义。神经肽与神经递质在同一个神经元中共同表达，但它们由不同的机制释放，并可以通过更长的距离到达它们的靶点。这项建议使用产生黑色素浓缩激素(MCH)的神经元来确定神经递质和神经肽之间的相互作用功能。MCH对正常的能量平衡、奖励和社会行为是必需的，这些行为对生存至关重要，并且在物种之间是保守的。重要的是，MCH神经元形成了研究神经肽网络功能的工具模型，因为它们共同释放神经递质谷氨酸，并且只在大脑的一个区域发现，因此很容易分离出来进行研究。我们最近发现，MCH神经元向外侧隔发出长距离投射，在那里它们释放谷氨酸，并对外侧隔中的细胞进行功能神经支配。在这里，我们将确定是否1)MCH本身也在外侧隔中释放；2)MCH是否调节外侧隔中的谷氨酸能传递；以及3)鉴于谷氨酸在MCH神经元功能中的前所未有的作用，我们将确定MCH和谷氨酸是否具有重叠或独立的行为作用。 我们的研究计划将使用一种变革性的光遗传学技术来实现对神经元活动的精确控制，我们可以通过电生理记录来捕获这些活动，即使是在定义的小脑区内。由于神经肽的释放可能需要长时间的高频神经刺激，我们可以提供定时光脉冲来特异性地激活MCH神经纤维来激发MCH的释放。为了研究MCH和谷氨酸共表达的功能，我们将建立一种新型的转基因小鼠模型，在该模型中，我们只通过MCH神经元条件性地阻断谷氨酸能传递，然后将其与缺乏MCH但谷氨酸系统完整的小鼠进行比较。总而言之，这些研究将解开MCH和谷氨酸的作用，并提供对可能构成奖励或社会行为基础的神经肽能过程的详细、机械的理解。这些发现具有重要意义，因为它们有助于更深入地理解信息处理背后的肽能事件。 我们正在组建一支积极进取的学生团队，他们将接受关于尖端技术的直接动手培训。我们将共同走在这项技术的前沿，开发翻译技能和工具来进行创新研究。