Deconstructing the cellular control of hippocampal functions related to mental health: a role for birth order.

解构与心理健康相关的海马功能的细胞控制：出生顺序的作用。

• 批准号: 10322677
• 负责人: ALEX DRANOVSKY
• 金额: $ 58.03万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322677
• 关键词: Adolescent; Adrenal Glands; Adult; Alzheimer' s Disease; American; Anesthesia procedures; Animals; Antidepressive Agents; Anxiety; Behavior; Behavioral; Biology; Birth; Birth Order; Brain; Cell Lineage; Cell physiology; Cells; Chronic stress; Complex; Date of birth; Development; Disease; Distal; Dorsal; Environmental Exposure; Exercise; Exhibits; Exposure to; Functional disorder; Genetic; Glial Fibrillary Acidic Protein; Glucocorticoid Receptor; Glucocorticoids; Hilar; Hippocampus (Brain); Hormones; Human; Hypoxemia; Infection; Injury; Learning; Life; Link; Logic; Memory; Mental Depression; Mental Health; Mental disorders; Mineralocorticoid Receptor; Modeling; Mus; Mutation; Neonatal; Neurons; Outcome; Parahippocampal Gyrus; Pathology; Performance; Pharmacogenetics; Phenotype; Physiological; Physiology; Population; Process; Psychosocial Stress; Rabies virus; Regulation; Research Personnel; Rodent; Role; Schizophrenia; Series; Slice; Stress; Structure; Supporting Cell; Synapses; System; Techniques; Testing; Thinking; Toxicant exposure; Trauma; Work; acute stress; adult neurogenesis; adult stem cell; base; behavioral response; biological adaptation to stress; cellular targeting; cohort; dentate gyrus; depressive behavior; design; drug of abuse; environmental change; environmental enrichment for laboratory animals; experience; experimental study; genetic approach; hormone regulation; improved; interest; nerve stem cell; neurogenesis; neuropsychiatric disorder; optogenetics; periadolescent; postnatal; postnatal development; relating to nervous system; resilience; response; sensor; spatial memory; stem cell proliferation; stem cells; stress resilience

The hippocampus has been implicated in the biology of stress as both a stress sensor and a regulator of the stress response. It exhibits the brain's highest concentration of glucocorticoid and mineralocorticoid receptors, as well as extensive structural and physiological plasticity in response to chronic stress exposure7. The hippocampus is also involved in encoding context, learning and memory, and has been repeatedly implicated in performance on depression and anxiety-related tasks in rodents and humans. Hence, it is no surprise that hippocampal pathology has been attributed to a wide range of psychiatric diseases like Schizophrenia, depression, anxiety, and Alzheimer's disease. Within the hippocampus, a postnatal neural stem cell system is exquisitely sensitive to environmental changes including stressful and enriching experiences. Exposure to chronic stress decreases neurogenesis and increases the proliferation of stem cells, while exposure to environmental enrichment, exercise, and antidepressants increases neurogenesis without impacting stem cells. While hippocampal neurogenesis is highly sensitive to environmental manipulations, the resulting neurons are thought to contribute to all of the hippocampal functions described above including stress regulation. Thus, neurons that support diverse functions are born continuously throughout postnatal development and this process of neurogenesis is sensitive to stress and to other environmental changes. We are interested in unraveling the cellular logic supporting the functional repertoire of the hippocampal dentate gyrus. Studies outlined in this proposal aim to identify cells within the dentate gyrus of the hippocampus that are important for each of the hippocampal functions. We will use a series of state of the art genetic approaches for targeting discrete populations of dentate gyrus neurons as they would be by stress during development and then examine how each population of cells contributes to normal hippocampal functioning and circuitry. Completing the proposed studies will help decipher which hippocampal neurons contribute to encoding stress responses and determine whether the same or different cells support other hippocampal functions.

海马体在压力生物学中既作为压力传感器又作为调节器 的压力反应。它展示了大脑中糖皮质激素和盐皮质激素的最高浓度 受体，以及广泛的结构和生理可塑性，以应对慢性应激反应7。 海马体还参与编码上下文、学习和记忆，并且已经被反复地 与啮齿动物和人类的抑郁和焦虑相关任务的表现有关。因此，它不是 令人惊讶是，海马病理学被归因于广泛的精神疾病， 精神分裂症，抑郁症，焦虑症，和老年痴呆症。 在海马体内，出生后的神经干细胞系统对环境非常敏感， 变化，包括压力和丰富的经验。暴露于慢性应激会降低神经发生 并增加干细胞的增殖，而暴露于环境富集，运动， 抗抑郁药增加神经发生而不影响干细胞。虽然海马神经发生是 对环境的操纵高度敏感，由此产生的神经元被认为有助于所有的 上述海马功能包括应激调节。因此，神经元支持不同的 在整个出生后发育过程中，神经功能不断产生， 对压力和其他环境变化敏感。 我们感兴趣的是解开支持海马神经元功能的细胞逻辑， 齿状回在这项建议中概述的研究旨在识别齿状回内的细胞， 对海马的每一个功能都很重要。我们将使用一系列最先进的 遗传学方法用于靶向离散群体的齿状回神经元，因为它们将受到压力 然后研究每个细胞群如何对正常海马 功能和电路。完成这项研究将有助于破译哪些海马神经元 有助于编码应激反应，并决定是否相同或不同的细胞支持其他细胞。 海马功能