Determining the unique and dynamic neural constellation belonging to acute and chronic stress states

确定属于急性和慢性应激状态的独特且动态的神经星座

基本信息

批准号：
10365980
负责人：
Julia C Lemos
金额：
$ 49.13万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365980
关键词：
3-Dimensional Acute Affective Anxiety Award Behavior Brain Brain region Cell Nucleus Cells Chronic stress Corpus striatum structure Corticotropin-Releasing Hormone Depressed mood Disease Environment Female Fiber Genetic Genetic Recombination Glutamates Imaging Techniques In Situ Hybridization Individual Investigation Knock-out Lead Light Link Maps Mediating Mental Depression Microscopy Mus National Institute of Mental Health Nature Negative Valence Neuroanatomy Neuromodulator Neurons Neuropeptides Neurotransmitters Pathologic Pathway interactions Pattern Peptides Peripheral Nervous System Photometry Population Positive Valence Process Regulation Reporter Research Research Personnel Research Project Grants Scientist Site Stimulus Stress System Techniques Technology Testing Therapeutic Transgenic Organisms Viral Vision Withdrawal Work acute stress anxiety-related disorders approach avoidance behavior approach behavior avoidance behavior base behavioral outcome behavioral response biobehavior biological adaptation to stress brain pathway calcium indicator cell type dopaminergic neuron dorsal raphe nucleus experience experimental study high risk hypothalamic-pituitary-adrenal axis in vivo calcium imaging innovation life history male mind control neurochemistry neuropsychiatric disorder novel optogenetics particle programs relating to nervous system release factor response stress state stressor success tool wireless

项目摘要

Project Summary: The objective of this “Biobehavioral Research Awards for Innovative New Scientists” proposal is to determine the contributions of the CRF (corticotropin releasing factor) system to encoding and responding to salient stimuli in the environment in individuals with different life histories of stressor exposure. CRF is a neuropeptide neuromodulator that is expressed in several brain regions and is released in response to both positive and negative arousing environmental stimuli. It is unclear how CRF as a brain wide neural system differentially responds to stimuli with different valences to motivate appropriate approach or avoidance behaviors. In addition, there is evidence that the CRF system is highly plastic and can undergo allostatic adaptations in response to stressor exposure. Moreover, it is thought that in pathological states of allostatic overload, these adaptations in the CRF system persist in suboptimal ways. Yet, it is unclear how the activity patterns of CRF enriched nuclei across the brain are altered in a stress-induced state of allostatic overload, nor is it understood how changes at different CRF loci combine to promote maladaptive behavioral responses. This proposal seeks to resolve these unanswered questions by testing the hypothesis that positive or negative salient environmental stimuli stimulate the activity of unique ensembles of CRF-containing nuclei to drive the appropriate affective behavioral responses. Furthermore, that chronic stress shifts CRF network responsivity toward greater activation to negative stimuli and depressed activation toward positive stimuli which leads to enhanced avoidance of these salient environment stimuli. To test this hypothesis, I propose two specific aims. Aim 1. Generate a whole brain functional map of activity patterns of CRF-containing neurons in response to acute environmental stimuli in control and chronically stressed male and female mice. This aim uses three-dimensional functional neuroanatomy and in vivo calcium imaging techniques to determine the activity patterns of CRF expressing nuclei in response to salient environmental stimuli that carry different valences. We will assess this in control and chronically stressed male and female mice. Collectively, these experiments will offer a holistic perspective on the response(s) of CRF to salient stimuli by viewing it as a whole-brain neural system rather than focusing on a single region or pathway. Aim 2. Determine the effects of site-specific suppression of CRF-containing neurons or deletion of CRF peptide on behavioral responses to acute salient stimuli presented to control and stress-exposed mice. This aim assesses the relative contributions of CRF localized to different brain nuclei in modulating approach and avoidance behavior by utilizing cutting-edge transgenic and optogenetic techniques. The purpose of the BRAINS program is to nurture innovative new investigators by promoting investigation of ambitious and important questions. This proposal answers that call and is poised to transform the way we think about CRF in the brain.

项目概要：本次“创新新科学家生物行为研究奖”的目的提案的目的是确定 CRF（促肾上腺皮质激素释放因子）系统对编码和具有不同压力源暴露生活史的个体对环境中的显着刺激做出反应。 CRF 是一种神经肽神经调节剂，在多个大脑区域表达，并根据目前还不清楚 CRF 作为全脑神经系统如何产生积极和消极的环境刺激。对不同价的刺激有不同的反应，以激发适当的接近或回避行为。此外，有证据表明 CRF 系统具有高度可塑性，可以在此外，人们认为在稳态超负荷的病理状态下，这些反应。 CRF 系统的适应以次优的方式持续存在，但尚不清楚 CRF 的活动模式如何。大脑中的富集核在应激诱导的变稳态超载状态下发生了改变，这一点目前尚不清楚该提案寻求如何结合不同 CRF 位点的变化来促进适应不良的行为反应。通过检验积极或消极的显着环境的假设来解决这些悬而未决的问题刺激物刺激含有 CRF 的核团的独特活动，以驱动适当的情感此外，慢性压力会使 CRF 网络的反应性转向更大的激活。对消极刺激的反应和对积极刺激的抑制激活，从而导致对这些刺激的回避增强为了检验这个假设，我提出了两个具体目标。目标 1. 生成包含 CRF 的神经元响应活动模式的全脑功能图这一目标使用了控制和长期应激的雄性和雌性小鼠的急性环境刺激。三维功能神经解剖学和体内钙成像技术来确定活性 CRF 表达细胞核响应不同价态的显着环境刺激的模式。这些实验将在对照小鼠和长期承受压力的雄性和雌性小鼠中评估这一点。通过将 CRF 视为全脑神经元，提供 CRF 对显着刺激的反应的整体视角系统而不是专注于单个区域或途径。目标 2. 确定对含有 CRF 的神经元进行位点特异性抑制或删除 CRF 的效果肽对对照小鼠和应激小鼠的急性显着刺激的行为反应的影响。该目的评估了位于不同脑核的 CRF 在调节方法中的相对贡献利用尖端转基因和光遗传学技术的回避行为。 BRAINS 计划的目的是通过促进对以下问题的调查来培养具有创新精神的新研究人员这项雄心勃勃且重要的问题回应了这一呼吁，并将改变我们的思维方式。关于大脑中的 CRF。