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Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation

有针对性地抑制应激相关途径，以提高抵抗母体免疫激活的能力

基本信息

批准号：
10358119
负责人：
Amanda Kentner
金额：
$ 38.3万
依托单位：
MCPHS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358119
关键词：
11-beta-Hydroxysteroid Dehydrogenases Adrenal Cortex Adrenal Glands Affect Animal Housing Animal Model Antigens Area Attenuated Behavioral Biological Brain Brain region Clinical Cognitive Corticosterone Corticotropin-Releasing Hormone Cytochrome P450 Data Development Discrimination Discrimination Learning Disease Effectiveness Elderly Endocrine Environment Enzymes Epigenetic Process Exposure to Female Fetus Functional disorder Genes Glucocorticoids Goals Health Housing Human Hydrocortisone Hypothalamic structure Immune Impairment Inflammatory Intervention Life Lipopolysaccharides Maternal Exposure Mediating Mediator of activation protein Mental Health Mental disorders Messenger RNA Metabolism Metyrapone Mitochondria Mixed Function Oxygenases Modeling Motivation Mus Neuraxis Neurodevelopmental Disorder Neurosecretory Systems Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Phase Pituitary Gland Placenta Plasma Poly I-C Predisposition Pregnancy Preventive treatment Proteins Rattus Regulation Research Risk Rodent Schizophrenia Signal Transduction Social Behavior Social Change Social Processes Stress Symptoms Testing Time Viral Work antagonist approach behavior attenuation autism spectrum disorder behavioral phenotyping brain circuitry cognitive function critical period early experience effective intervention environmental enrichment for laboratory animals epigenetic marker experience fetal flu immune activation improved in utero inhibitor male mouse model offspring overexpression postnatal postnatal development pregnant prenatal prevent preventive intervention programs protective effect receptor relating to nervous system resilience social social cognition tool touchscreen

项目摘要

Clinical evidence suggests that exposure to maternal immune activation (MIA) during the prenatal period (e.g., having the flu during pregnancy) increases the susceptibility for neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. These disorders are associated with the manifestation of a heterogeneous set of symptoms, including social impairments, which emerge in later life. The mechanistic underpinnings of these social disruptions and how they interact with the environment are not well understood but are a likely path for identifying factors contributing to resilience vs susceptibility against challenges to mental health functioning. Using an animal model, we aim to determine how this adverse early health experience alters the development of brain circuitry in males and females, to find preventative interventions and treatments. Our recent work shows that MIA causes an overexpression of the stress sensitive gene corticotropin releasing factor (Crh), and its associated receptor Crhr1, in areas of the brain central to social behavior and cognition. Housing pregnant dams in environmental enrichment (a translationally relevant intervention) protects the fetus by maintaining the placental 11-beta hydroxysteroid dehydrogenase (11HSD)1 and 11HSD2 metabolism of maternal corticosterone at the time of prenatal immune challenge; this housing condition also protects against Crh and Crhr1 overexpression and related social impairments associated with MIA. To confirm that excessive levels of maternal plasma corticosterone are responsible for the later life overexpression of stress sensitive genes and social impairments (Aim 1), we will employ a clinically available inhibitor of cytochrome P450 11B1, mitochondrial (11β-hydroxylase), the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex. We will use this inhibitor to attenuate the endocrine activation associated with MIA to test if this prevents these MIA-induced neural and social changes. Relatedly, we will explore protection against MIA-associated changes in Crhr1 signaling mechanisms and epigenetic machinery. In Aim 2, we will use a Crhr1 antagonist to determine if this pharmacological intervention can prevent and/or reverse the effects of MIA on social behaviors. Finally, using viral tools, we will begin studies to evaluate whether targeted deletion of Crhr1 can prevent the social consequences of MIA, and if overexpression can in turn counteract the protective effects of environmental enrichment housing. Together, these studies will help identify and confirm mechanisms by which clinically utilized environmental manipulations, such as enrichment, offer protection to the developing brain.

临床证据表明，暴露于母体免疫激活（MIA）

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial commentary on the special issue emerging psychoneuroimmunology research: Future leaders in focus.

DOI：
10.1016/j.bbih.2022.100423
发表时间：
2022-03
期刊：
Brain, behavior, & immunity - health
影响因子：
0
作者：
Kentner AC;Harden L;de Melo Soares D;Rummel C
通讯作者：
Rummel C

Regulatory Effects of Maternal Immune Activation and Environmental Enrichment on Glucocorticoid Receptor and FKBP5 Expression in Stress-sensitive Regions of the Offspring Brain.

DOI：
10.1016/j.neuroscience.2022.09.010
发表时间：
2022-11-21
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Maganga-Bakita, Ismael;Aiken, Ariel A.;Puracchio, Madeline J.;Kentner, Amanda C.;Hunter, Richard G.
通讯作者：
Hunter, Richard G.

Building a framework to optimize animal models of maternal immune activation: Like your ongoing home improvements, it's a work in progress.

建立一个框架来优化母体免疫激活的动物模型：就像您正在进行的家庭装修一样，这是一项正在进行的工作。

DOI：
10.1016/j.bbi.2018.10.011
发表时间：
2019
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
Roderick,RylandC;Kentner,AmandaC
通讯作者：
Kentner,AmandaC

Access to a high resource environment protects against accelerated maturation following early life stress: A translational animal model of high, medium and low security settings.

进入高资源环境可防止早期生活压力后加速成熟：高、中、低安全环境的转化动物模型。

DOI：
10.1016/j.yhbeh.2019.01.003
发表时间：
2019
期刊：
Hormones and behavior
影响因子：
3.5
作者：
Strzelewicz,ArielleR;OrdoñesSanchez,Evelyn;Rondón-Ortiz,AlejandroN;Raneri,Anthony;Famularo,SydneyT;Bangasser,DebraA;Kentner,AmandaC
通讯作者：
Kentner,AmandaC

Developmental Manipulation-Induced Changes in Cognitive Functioning.

发育操纵引起的认知功能变化。

DOI：
10.1007/7854_2022_389
发表时间：
2023
期刊：
Current topics in behavioral neurosciences
影响因子：
0
作者：
Kaki,Sahith;DeRosa,Holly;Timmerman,Brian;Brummelte,Susanne;Hunter,RichardG;Kentner,AmandaC
通讯作者：
Kentner,AmandaC