Peptidergic neuromodulation of microcircuits that control chemosensation-induced behaviors

项目摘要 神经肽在调节处理嗅觉和味觉信息的神经回路中起重要作用。 mation。这种调节通常用于调整动物的内部状态（例如，性唤起的程度，或者食物 状态）与对感官刺激的行为反应（例如，信息素或与食物相关的气味剂）。虽然 已经描述了特定感觉神经元的神经肽能调节， 神经肽影响中枢化学感受回路的机制尚不清楚。长期目标是 通过解构这种生理学上的化学感受回路， 过程为明确定义的、行为相关的分子和神经元事件。重要的是，改变 人类的化学感觉通常与某些类型的精神障碍有关，其特征在于 在分子水平上，化学感受的神经肽能调节是向低水平化学感受迈出的基本的第一步， 支持和改善这些疾病的治疗方法。果蝇模型系统提供了一个很好的平台- 这些研究的形式，因为神经肽能系统可以被精确地操纵， 介导化学感觉诱导的行为，如雄性攻击行为， 是可以测量的。最初的实验将集中在神经肽速激肽上，其中心假设是， 神经肽局部作用以影响特定的神经元群体来调节化学感觉信息释放， 对雄性争斗行为的反应。三个具体目标，每一个基于初步的成功，是：1）charac- 2）描述了调节信息素诱导的雄性激动行为的神经肽能回路， 神经肽和共同释放的神经递质之间的协同作用，和3）阐明了细胞基础， 三种神经肽（速激肽、神经肽F和FMRF酰胺）之间的相互作用， 竞争行为（化学感觉引导的行为）。在目的1中，表达速激肽受体的神经元 （Takr 86 C）将在形态学上表征，并且那些接收来自攻击促进的突触输入的细胞将在形态学上表征，并且那些接受来自攻击促进的突触输入的细胞将在形态学上表征。 将通过光活化GFP辅助的神经元示踪和体内校准鉴定速激肽能神经元。 cium显像在目的2中，速激肽和共表达的神经递质乙酰胆碱之间的相互作用 将被定性。肽或递质释放将在相关细胞中被独立阻断， 对下游神经元活动和行为的影响。在目标3中，解剖学和生理学关系- 表达速激肽、神经肽F或FMRFamide的神经元之间将建立联系， 为了更好地理解这三种神经肽如何协同影响信息素加工神经元， Ral电路总之，这里提出的研究将揭示遗传和细胞机制， 神经肽在生理上影响化学感觉回路以调节行为。这些知识将提供 基本了解嗅觉和味觉是如何中枢控制的，以及嗅觉和味觉的功能障碍是如何发生的。 这个过程可能导致对环境线索的非适应性反应。

PROJECT SUMMARY Neuropeptides play important roles in modulating neural circuits that process olfactory and gustatory infor- mation. This modulation generally functions to align an animal's internal state (e.g., levels of arousal, or food status) with behavioral responses to sensory stimuli (e.g., pheromones or food-associated odorants). Although the neuropeptidergic modulation of specific sensory neurons has been described, the molecular and cellular mechanisms by which neuropeptides affect central chemosensory circuits are unknown. The long-term goal is to characterize the neuropeptidergic modulation of chemosensory circuits by deconstructing this physiological process into clearly defined, behaviorally relevant molecular and neuronal events. Importantly, altered chemosensation in humans is often associated with certain types of mental disorders, and characterizing at a molecular level the neuropeptidergic modulation of chemosensation is a fundamental first step toward under- standing and improving treatments for these disorders. The Drosophila model system offers an excellent plat- form for these studies, because neuropeptidergic systems can be precisely manipulated and the effects on well-characterized circuits mediating chemosensation-induced behaviors, such as male aggressive behavior, can be measured. Initial experiments will focus on the neuropeptide tachykinin, with the central hypothesis that neuropeptides act locally to affect a specific population of neurons to modulate chemosensory information rele- vant to male agonistic behavior. The three specific aims, each based on preliminary success, are to: 1) charac- terize the neuropeptidergic circuit that modulates pheromone-induced male agonistic behavior, 2) characterize synergies between neuropeptides and co-released neurotransmitters, and 3) elucidate the cellular basis of in- teractions among three neuropeptide (tachykinin, neuropeptide F and FMRFamide) that each modulate male agonistic behavior (a chemosensation-guided behavior). In Aim 1, neurons expressing the tachykinin receptor (Takr86C) will be morphologically characterized, and those receiving synaptic input from aggression-promoting tachykininergic neurons will be identified via photo-activatable GFP-assisted neuronal tracing and in vivo cal- cium imaging. In Aim 2, interactions between tachykinin and the co-expressed neurotransmitter acetylcholine will be characterized. Peptide or transmitter release will be independently blocked in relevant cells, and effects on downstream neuronal activity and behavior will be analyzed. In Aim 3, anatomical and physiological rela- tionships between neurons expressing tachykinin, neuropeptide F, or FMRFamide will be established, leading to a better understanding of how these three neuropeptides synergistically affect a pheromone-processing neu- ral circuit. Together, the research proposed here will uncover the genetic and cellular mechanisms by which neuropeptides physiologically affect chemosensory circuits to modulate behavior. Such knowledge will provide a fundamental understanding of how smell and taste perception is centrally controlled, and how dysfunction of this process may lead to non-adaptive responses to environmental cues.