Regulation of Feeding Behavior by Brain-based Nutrient Sensors

描述(申请人提供)：评估营养食品含量对于调节大多数动物的能量代谢和摄食行为是必不可少的。到目前为止，模型系统果蝇、黑腹果蝇和哺乳动物共享许多已被描述的营养感知途径。例如，果蝇和哺乳动物对食物的消耗，特别是碳水化合物的消耗，会释放胰岛素或胰岛素样肽。同样，它们可以感知食物中的氨基酸和蛋白质，它们有共同的能力来抑制对氨基酸混合物或缺乏一种或多种必需氨基酸的蛋白质的摄食。营养物质主要由胃肠系统感知，但也由大脑感知。例如，许多哺乳动物下丘脑神经元可以感知外部葡萄糖浓度的变化，但对它们在调节摄食和新陈代谢中的功能知之甚少。我们研究的长期目标是以果蝇为模型系统，识别和表征感知大脑中营养物质的分子和神经解剖学成分，并传播这些事件以调节摄食和能量代谢。我们最近发现味觉受体43a(Gr43a)是果蝇大脑中一种新的生电营养感受器。Gr43a与糖和果糖的关系很窄。当摄入碳水化合物时，血淋巴中的果糖浓度增加数倍，从而导致少量表达Gr43a的脑神经元的激活。行为学实验表明，Gr43a以一种饱足依赖的方式调节取食行为：在饥饿的果蝇中，它促进取食，而在饱足的果蝇中，它抑制取食。这些观察结果导致我们提出，果糖刺激Gr43a激活了一条神经通路，该通路受到依赖饱和的信号的调节，从而产生不同的摄食行为。为了阐明Gr43a激活的相反行为结果的机制，有必要确定 在大脑中发挥Gr43a下游的作用，并识别Gr43a脑神经元与之通信的神经元靶点。根据初步数据，我们认为Gr43a脑神经元的活动是通过神经肽Corazin传递的，Corazin是哺乳动物促性腺激素释放激素的功能同源。此外，我们还确定了Gr43a活性的其他几个候选效应子和调节子，并将使用分子遗传学方法来确定它们在促进和抑制摄食方面的具体作用。最后，我们将通过描述crzR表达的神经元并识别其靶点来扩展由Gr43a脑感觉神经元激活的神经回路。这些研究将为一种新型的生电营养传感器的分子和细胞逻辑提供一个框架，该传感器可以被饱腹感信号调制以产生相反的行为输出。

DESCRIPTION (provided by applicant): Evaluation of nutrient food content is essential for the regulation of energy metabolism and feeding behavior in most animals. The model system Drosophila melanogaster and mammals share many of the nutrient sensing pathways that have been characterized thus far. For example, Drosophila and mammals release insulin or insulin-like peptides in response to the consumption of food, especially carbohydrates. Likewise, they can sense amino acids and proteins in food, and they share an ability to suppress feeding on amino acid mixtures or proteins that lack one or more essential amino acids. Nutrients are sensed mostly by the gastrointestinal system, but also by the brain. For example, numerous mammalian hypothalamic neurons can sense changes in external glucose concentration, but their function in the regulation of feeding and metabolism are poorly understood. The long-term objective of our research is to identify and characterize the molecular and neuroanatomical components that sense nutrients in the brain and propagate these events to regulate feeding and energy metabolism, using Drosophila as a model system. We recently identified the Gustatory receptor 43a (Gr43a) as a novel, electrogenic nutrient sensor in the Drosophila brain. Gr43a is narrowly tuned to the sugar fructose. Upon carbohydrate feeding, fructose concentration in the hemolymph increases several fold, which then leads to the activation of a small number of Gr43a expressing brain neurons. Behavioral experiments showed that Gr43a regulates feeding behavior in a satiation dependent manner: in hungry flies, it promotes feeding, while in satiated flies, it suppresses it. These observations lead us to propose that Gr43a stimulation by fructose activates a neural pathway, which is modulated by a satiation-dependent signal to generate distinct feeding behaviors. To elucidate the mechanism of the opposing behavioral outcomes of Gr43a activation, it will be essential to identify the signaling events that act downstream of Gr43a in the brain, and to identify the neuronal targets with which the Gr43a brain neurons communicate. Based on preliminary data, we propose that Gr43a brain neurons transmit their activity via the neuropeptide corazonin, the functional ortholog of mammalian gonadotropin releasing hormone. In addition, we have identified several other candidate effectors and modulators of Gr43a activity, and we shall use molecular genetic approaches to determine their specific roles in feeding promotion and suppression. Finally, we shall expand the neural circuitry activated by the Gr43a brain sensory neurons by characterizing crzR expressing neurons and identifying their targets. These studies will provide a framework for the molecular and cellular logic of a novel electrogenic nutrient sensor, which can be modulated by satiety signals to generate opposing behavioral outputs.