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.

海马已与应力传感器和调节器有关 压力反应。它表现出大脑最高浓度的糖皮质激素和矿物皮质激素 受体，以及响应慢性应激暴露的广泛结构和生理可塑性7。 海马还参与了编码，学习和记忆的编码，并且已经反复 与啮齿动物和人类的抑郁症和焦虑相关的任务的表现有关。因此，这不是 海马病理学归因于多种精神病疾病，例如 精神分裂症，抑郁，焦虑和阿尔茨海默氏病。 在海马中，产后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历。暴露于慢性应激会降低神经发生 并增加干细胞的扩散，同时暴露于环境富集，运动和 抗抑郁药增加神经发生而不会影响干细胞。海马神经发生是 对环境操纵高度敏感，所产生的神经元被认为有助于所有 上面描述的海马功能包括应力调节。因此，支持多样化的神经元 功能在整个产后发育过程中一直持续出生，这种神经发生过程是 对压力和其他环境变化敏感。 我们有兴趣解开支持海马功能库的细胞逻辑 齿状回。该提案中概述的研究旨在鉴定细胞中的细胞 海马对于每个海马功能都很重要。我们将使用一系列的最新状态 靶向齿状回神经元离散群体的遗传方法，就像压力一样 在开发过程中，然后检查每个细胞的群体如何促进正常海马 功能和电路。完成拟议的研究将有助于破译哪个海马神经元 有助于编码应力反应并确定相同还是不同的细胞支持其他 海马功能。