Neurobiology of aging in the bat

蝙蝠衰老的神经生物学

• 批准号: 10527777
• 负责人: Rena Orman
• 金额: $ 16.15万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527777
• 关键词: 1 year old; 10 year old; 5 year old; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Basal Ganglia; Biological Assay; Biological Models; Birth; Brain; Brain region; Buffers; Calcium; Calcium-Binding Proteins; Calpain; Cells; Chiroptera; Claustral structure; DNA Methylation; Data; Disease; Disinhibition; Equilibrium; Excision; Family; Foundations; Fruit; Generations; Goals; Grant; Hippocampal Formation; Immunohistochemistry; Impairment; Individual; Interneurons; Lead; Link; Longevity; Modeling; Mus; Nerve Degeneration; Neuroanatomy; Neurobiology; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parvalbumins; Pattern; Peptide Hydrolases; Physiologic pulse; Physiology; Pilot Projects; Primates; Proteins; Regulation; Rodent; Sampling; Slice; Structure; Tail; Testing; Tissues; Western Blotting; age group; age related; aging brain; brain dysfunction; calbindin; calretinin; cell type; human model; inhibitory neuron; insight; m-calpain; member; mu-calpain; multi-electrode arrays; neuron loss; normal aging; protein expression; regional difference; sensor; targeted treatment

ABSTRACT Calcium dysregulation is a critical contributor to neuronal loss in normal aging and neurodegenerative diseases. An important cause of calcium dysregulation is the loss of calcium binding proteins such as parvalbumin, calbindin and calretinin. They serve as calcium buffers/sensors in many cells, especially inhibitory neurons. An important consequence of calcium dysregulation is calpain activation, which is postulated to cause brain aging and neurodegeneration. We hypothesize that there is (1) a progressive loss of inhibitory neurons expressing calcium binding proteins, (2) disinhibition in affected brain regions, and (3) increased calpain activation due to disinhibition as a function of age. Calpain activity will thus drive neurodegeneration due to aging. To address this, we propose to use an attractive, but understudied model of aging: Carollia perspicillata, the short-tailed fruit bat. Carollia has a lifespan >10 years and their neuroanatomy is closer to that of primates than rodents are. We will determine age-dependent changes in claustrum, hippocampal formation, and basal ganglia. Specifically, we will evaluate the expression of calcium binding proteins (parvalbumin, calbindin, calretinin) and the expression and activity of calpains 1 and 2 and relate these changes to inhibitory control of neuronal networks. The data obtained from this pilot grant will serve as a foundation for detailed mechanistic studies of neurodegeneration caused by aging and disease.

摘要 钙调节失调是正常衰老和神经退行性变中神经元丢失的关键因素 疾病。钙调节失调的一个重要原因是钙结合蛋白的丢失，如 小白蛋白、钙结合蛋白和钙视黄素。它们在许多细胞中充当钙缓冲器/传感器，尤其是 抑制性神经元。钙调节失调的一个重要后果是钙蛋白激活，这是 推测会导致大脑老化和神经退化。我们假设有(1)累进亏损 表达钙结合蛋白的抑制神经元，(2)在受影响的大脑区域解除抑制，以及(3) 随着年龄的增长，由于去抑制而增加了钙蛋白酶的活性。因此，钙蛋白酶的活动将推动 由于衰老而导致的神经退化。为了解决这个问题，我们建议使用一个有吸引力但未得到充分研究的模型。 衰老：短尾果蝠Carollia perspicillata。卡罗利亚有10年的寿命，他们的 神经解剖学比啮齿动物更接近灵长类动物。我们将确定与年龄相关的变化 屏状核、海马结构和基底节。具体地说，我们将评估 钙结合蛋白(小白蛋白、钙结合蛋白、钙视黄素)与钙蛋白酶1的表达和活性 和2，并将这些变化与神经网络的抑制控制联系起来。从这位飞行员那里获得的数据 格兰特将作为详细的机制研究的基础，神经变性引起的老化和 疾病。