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: 10540772
• 负责人: ALEX DRANOVSKY
• 金额: $ 58.02万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540772
• 关键词: Ablation; 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; 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; Predisposition; 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; 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; neural; neurogenesis; neuropsychiatric disorder; optogenetics; periadolescent; postnatal; postnatal development; 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.

海马体作为压力传感器和调节器与压力生物学有关 的应激反应。它表现出大脑中最高浓度的糖皮质激素和盐皮质激素 受体，以及响应慢性压力暴露的广泛结构和生理可塑性7。 海马体还参与编码情境、学习和记忆，并且已被反复研究过。 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，它是不 令人惊讶的是，海马病理学已被归因于多种精神疾病，例如 精神分裂症、抑郁症、焦虑症和阿尔茨海默病。 在海马体内，出生后的神经干细胞系统对环境极其敏感 变化包括压力和丰富的经历。暴露于慢性压力会减少神经发生 并增加干细胞的增殖，同时暴露于丰富的环境、锻炼和 抗抑郁药可增加神经发生而不影响干细胞。虽然海马神经发生是 对环境操作高度敏感，由此产生的神经元被认为对所有的 上述海马功能包括压力调节。因此，支持多样化的神经元 功能在出生后发育过程中不断诞生，并且神经发生的过程是 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的细胞逻辑 齿状回。该提案中概述的研究旨在识别齿状回内的细胞 海马体对海马体的每项功能都很重要。我们将使用一系列最先进的 针对离散的齿状回神经元群体的遗传方法，因为它们会受到压力 在发育过程中，然后检查每个细胞群如何对正常海马体做出贡献 功能和电路。完成拟议的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确定相同或不同的细胞是否支持其他细胞 海马体功能。

项目成果

RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss.

• DOI: 10.1016/j.celrep.2018.09.077
• 发表时间: 2018-10-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Kosmidis S;Polyzos A;Harvey L;Youssef M;Denny CA;Dranovsky A;Kandel ER
• 通讯作者: Kandel ER

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis.

• DOI: 10.1002/hipo.22962
• 发表时间: 2018-08
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Youssef M;Krish VS;Kirshenbaum GS;Atsak P;Lass TJ;Lieberman SR;Leonardo ED;Dranovsky A
• 通讯作者: Dranovsky A

Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood.

• DOI: 10.1038/s41598-023-29175-x
• 发表时间: 2023-02-22
• 期刊: Scientific reports
• 影响因子: 4.6