Control of sensory habituation by an ultra-conserved calcium sensor

动物神经系统不断地感知外部环境，产生大量的感觉数据，这些数据被传输到中枢神经回路。习惯化是一个重要的神经过程，它允许动物过滤掉不相关的感觉数据，导致对重复的感觉刺激的反应不断减弱，并允许有机体主要专注于显著的刺激。这种形式的非联想记忆在后生动物(多细胞动物)物种中随处可见，并在一系列人类神经精神和神经发育障碍中受到干扰，包括精神分裂症、自闭症谱系障碍和智力残疾。因此，揭示习惯化的分子和神经回路基础有望促进我们对保守记忆机制和一些具有高度社会经济意义的高度衰弱疾病的理解。我们的目标是用果蝇作为一个模型系统来实现这一点。我们提出了两个关键的进展--一个是技术上的，另一个是数据驱动的--这将有助于我们进一步理解习惯化。首先，我们开发了一种新的技术来快速而有力地量化成年果蝇对机械刺激的习惯性。其次，我们使用这种方法发现了一种名为神经钙素的蛋白质在促进习惯性方面的新作用。Neurocalin是一类被称为神经元钙感受器的蛋白质的成员，当结合钙离子时，它移位到膜间隔并改变其结合伙伴的光谱，导致神经兴奋性、神经递质释放、突触可塑性和基因表达的改变。在初步实验中，我们已经准确地将神经钙素在习惯化中的功能定位到苍蝇脑中的一小部分神经元：蘑菇体的α‘/β’神经元。我们提出了一系列实验，以了解神经钙素和蘑菇体α/β‘神经元如何影响习惯化。Neurocalin的一个显著特征是，它在后生动物基因组中保存得非常好，果蝇Neurocalin与其来自线虫的同源物之间90%的氨基酸相同。因此，我们进一步提出了一个令人兴奋的跨物种基因替换策略，以证明不同的Neurocalin同源物可以整合到驱动习惯的细胞路径中。综上所述，上述方法有望揭示影响记忆的关键和基本形式的保守分子路径。由于人类神经钙素同系物Hippocalin的突变与智力残疾有关，我们的发现也将对理解与记忆缺陷和习惯性有关的高度衰弱和社会经济破坏性神经疾病具有重要意义。

Animal nervous systems continually sense the external environment, generating a huge volume of sensory data that is transmitted to central neural circuits. Habituation is an important neural process that allows animals to filter out irrelevant sensory data, leading to ever-diminishing responses to repeated sensory stimuli and allowing organisms to focus primarily on salient stimuli. This form of non-associative memory appears ubiquitous across Metazoan (multi-cellular animal) species and is disrupted in a range of human neuropsychiatric and neurodevelopmental disorders, including Schizophrenia, autism spectrum disorder, and intellectual disability. Uncovering the molecular and neural circuit basis of habituation therefore promises to advance our understanding of conserved memory mechanisms and a number of highly debilitating diseases of high socio-economic importance. We aim to do so using the fruit fly, Drosophila, as a model system. We present two key advances - one technical, and one data-driven - that will help further our understanding of habituation. Firstly, we have developed a new technique to rapidly and robustly quantify habituation of adult Drosophila to mechanical stimuli. Secondly, we have used this method to uncover a novel role for protein called Neurocalcin in promoting habituation. Neurocalcin is a member of a class of proteins called neuronal calcium sensors, which upon binding calcium, translocate to membrane compartments and change their spectrum of binding partners, leading to alterations in neural excitability, neurotransmitter release, synaptic plasticity, and gene expression. In preliminary experiments, we have precisely mapped the function of Neurocalcin in habituation to a small number of neurons in the fly brain: mushroom body alpha'/beta' neurons. We propose a series of experiments to understand how Neurocalcin and mushroom body alpha'/beta' neurons act to influence habituation. A notable feature of Neurocalcin is that it is incredibly well-conserved across Metazoan genomes, with >90% of amino-acids identical between Drosophila Neurocalcin and its homologue from the Cnidarian Nematostella vectensis. We therefore further propose an exciting cross-species gene replacement strategy to demonstrate that diverse Neurocalcin homologues can integrate into cellular pathways driving habituation.Collectively, the above approaches promise to shed light on conserved molecular pathways influencing a critical and fundamental form of memory. Since mutations in the human Neurocalcin homologue Hippocalcin have been linked to intellectual disability, our findings will also have important implications for the understanding of highly debilitating and socio-economically damaging neurological disorders linked to defective memory and habituation.