Senescence, neurodegeneration, and sensory/motor decline in a social invertebrate

描述（由申请人提供）：人口老龄化带来了重大的社会和健康挑战。在衰老的分子和社会方面的研究中特别重要的是实现对作为正常衰老和疾病的一部分发生的行为和神经生物学过程的全面理解。社会无脊椎动物衰老模型的发展，蚂蚁Pheidole dentata，在老龄化的分析中呈现出多重优势。1.与人类一样，蚂蚁高度依赖社会互动，我们可以通过实验操纵蚂蚁的社会环境，以快速评估其对衰老的分子，神经和行为方面的影响。对社会生物学中的“果蝇”--齿状实蝇的研究在理解该物种的行为和神经生物学发育方面取得了重大进展; 3.工蜂在羽化后20天内经历行为发育，寿命只有4个半月，这使它们成为在加速时间框架内探索神经退行性变和认知能力下降模式的有用模型。我们新的老龄化社会模型的发展将阐明社会互动如何介导神经和行为衰退，并确定血清素是否可以挽救衰老表型，血清素在蚂蚁的行为成熟和患有神经退行性疾病的人类的认知功能中具有重要意义。拟议的研究检查了年龄相关的行为衰退是否是由神经退行性细胞死亡和/或根据社会背景的大脑血清素变化介导的。我们预测：1）老年工人的行为效能感会下降。2)在整个行为发育过程中，脑细胞凋亡将是高的，并随着年龄的增长而下降;和3）血清素水平将在衰老个体中下降，并将在剥夺社会环境的个体中更快地下降。此外，使用5-羟色胺前体和抑制剂对脑5-羟色胺进行药理学改变将决定5-羟色胺是否足以挽救行为衰退。我们的研究结果将扩大我们对年龄相关行为和衰老之间关系的理解，并研究社会性和神经调节剂如何减轻神经退行性变和衰老的感觉和运动后果。我们有三个具体目标：具体目标1：通过量化齿状突工作者的嗅觉灵敏度和运动表现来表征衰老相关的行为变化。具体目标2：电化学定位和定量神经元凋亡。具体目标3：通过HPLC分析和药物治疗，确定血清素是否可以在社会背景下挽救与年龄相关的感觉和运动功能下降。 公共卫生相关性：人类衰老受社会互动的影响。我们开发了一种新的昆虫模型系统，以研究社会行为和神经递质5-羟色胺如何调节与年龄相关的行为下降。5-羟色胺的普遍存在和昆虫和人类神经变性分子事件的巨大相似性，使我们能够通过实验操作有效地检查脑化学和社会环境对认知衰退和神经过程的影响。

DESCRIPTION (provided by applicant): The aging population poses significant social and health challenges. Of particular importance in the study of molecular and social aspects of senescence is achieving a comprehensive understanding of behavioral and neurobiological processes that occur as part of both normal aging and disease. The development of a social invertebrate model of aging, the ant Pheidole dentata, presents multiple advantages in the analysis of aging. 1. Like humans, ants are highly dependent on social interactions, and we can experimentally manipulate the social environment in ants to rapidly assess its influence on molecular, neural and behavioral aspects of aging; 2. Research on P. dentata, the "fruit fly" of sociobiology, has yielded significant progress in understanding behavioral and neurobiological development in this species; and 3. Workers undergo behavioral development within 20 days of eclosion and have a lifespan of only four and a half months, making them useful models to explore patterns of neurodegeneration and cognitive decline within an accelerated timeframe. The development of our new social model of aging will illuminate how social interactions mediate neural and behavioral decline and determine if serotonin, which is significant in behavioral maturation in ants and cognitive functioning in humans afflicted with neurodegenerative disease, can rescue aging phenotypes. The proposed research examines if age-associated behavioral decline is mediated by neurodegenerative cell death and/or changes in brain serotonin according to social context. We predict: 1) Behavioral efficacy will decline in old-age workers. 2) Brain apoptosis will be high throughout behavioral development and decline with increasing age; and 3) Serotonin levels will decrease in senescing individuals and will decline more rapidly in individuals in a deprived social environment. Furthermore, pharmacological alteration of brain serotonin using both a serotonin precursor and inhibitor will determine if serotonin is sufficient to rescue behavioral decline. Our findings will expand our understanding of the relationship between age-related behavior and senescence, and examine how sociality and neuromodulators may mitigate the sensory and motor consequences of neurodegeneration and aging. We have three specific aims: Specific Aim 1: To characterize senescence-associated behavioral changes by quantifying olfactory sensitivity and motor performance in P. dentata workers. Specific Aim 2: To immunohistochemically localize and quantify neuronal apoptosis. Specific Aim 3: To determine whether serotonin can rescue age-related decline in sensory and motor function in a social context by HPLC analysis and pharmacological treatments. PUBLIC HEALTH RELEVANCE: Human aging is influenced by social interactions. We have developed a novel insect model system to examine how social behavior and the neurotransmitter serotonin may regulate age-related declines in behavior. The common occurrence of serotonin and great similarity in molecular events of neurodegeneration in insects and humans allows us to efficiently examine the effect of brain chemistry and the social environment on cognitive decline and neural processes through experimental manipulation.