Orbitofrontal cortical coordination of action-consequence decision making

行动后果决策的眶额皮质协调

• 批准号: 10401335
• 负责人: Shannon Leigh Gourley
• 金额: $ 44.19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401335
• 关键词: Ablation; Actins; Acute; Adolescence; Adolescent; Adult; Affinity; Amygdaloid structure; Award; Behavior; Binding; Brain; Brain-Derived Neurotrophic Factor; Cell Adhesion; Cellular Structures; Chronic; Cognitive; Complex; Corpus striatum structure; Corticosterone; Cytoskeleton; Decision Making; Dendritic Spines; Development; Disease; EMS1 gene; Event; Exposure to; Extracellular Matrix Proteins; F-Actin; Failure; Gene Silencing; Genetic; Genetic Risk; Glucocorticoids; Glutamates; Goals; Habits; Hippocampus (Brain); Human; Impairment; Incidence; Individual; Integrins; Intervention; Investigation; Lead; Learning; Length; Ligand Binding; Link; Long-Term Potentiation; Mediating; Memory; Mental Depression; Mental Health; Modification; Moods; Morphology; Mus; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Outcome; Pharmacology; Phenocopy; Positive Valence; Prefrontal Cortex; Protein Isoforms; Proteins; Rattus; Receptor Cell; Receptor Protein-Tyrosine Kinases; Regulatory Element; Research Domain Criteria; Rewards; Schizophrenia; Short-Term Memory; Signal Transduction; Site; Smoking; Social isolation; Stimulus; Stress; Structure; System; Testing; Vertebral column; Viral; base; behavioral response; biological adaptation to stress; combat; critical period; density; early experience; early life stress; excitatory neuron; experience; fasudil; genome wide association study; inhibitor; knock-down; learning outcome; neurobiological mechanism; neurotrophic factor; response; social adversity; stressor; synergism; two-photon

Elevated glucocorticoids, particularly during specific developmental periods, cause long-term biases towards habit-based behaviors that are linked with depression, obesity, and other maladaptive outcomes in adulthood. Neurobiological mechanisms remain largely unclear. Integrin receptors are cell adhesion factors linked with the stress response system and genetic risk for neurodevelopmental disease. Composed of an α subunit responsible for ligand binding and a β subunit that activates intracellular signaling, integrins respond to extracellular matrix proteins, influencing cell structure through downstream cytoskeletal signaling factors. Integrin-mediated signaling stabilizes cell structure in the transition from adolescence to adulthood, such that genetic ablation of the β1 subunit, highly expressed in the cortex and hippocampus, causes dendritic spine loss starting in adolescence. In humans, ITGB1, encoding β1-integrin, is identified in genome-wide association studies of depression and schizophrenia, diseases characterized by deficits in PFC-dependent planning and action. Despite connections with neurodevelopmental disease, β1-integrin involvement in PFC-dependent action selection remains opaque. We will test the hypothesis that a β1-integrin-Abl2/Arg-cortactin-ROCK2 signaling axis coordinates goal-directed action selection and thus, is a sensible target for blocking habits due to glucocorticoid and stressor exposure. Aligned with RDoC-defined positive valence domains, specific aims are: Aim 1. To identify how the β1-integrin-Arg-cortactin-ROCK2 signaling axis influences oPFC- dependent action selection. We will use a combination of viral-mediated gene silencing and pharmacological manipulations to test the hypothesis that β1-integrin-Arg-cortactin-ROCK2 interactions in the oPFC coordinate goal-directed response choice, countering inflexible habits. Next, we will test the hypothesis that β1-integrin- dependent oPFC interactions with the basolateral amygdala support goal-directed response choice. Last, we will test the hypothesis that site-selective Itgb1 silencing structurally phenocopies glucocorticoid exposure, eliminating dendritic spines on excitatory neurons within the oPFC. Aim 2. To mitigate stressor-related habits and dendritic spine abnormalities in the oPFC. Next, we will test the hypothesis that stimulation of Arg and cortactin will block habits and changes in dendritic spine densities and morphologies following developmental corticosterone or exposure to social isolation. This aim will reveal strategies by which to correct cyto-structural change and habit biases following adversity. Aim 3. To reveal functional interactions with tyrosine receptor kinase B (trkB). Activation of β1-integrin- mediated signaling events that inhibit ROCK2 stimulates BDNF, which binds to its high-affinity receptor trkB. ROCK2 inhibition also modifies the ratio of full-length/truncated trkB in the PFC, favoring the active full-length isoform, and it enhances action-outcome memory in multiple contexts. Our final aim will test the hypothesis that the enrichment of action-outcome decision making (blocking habits) via ROCK2 inhibition is trkB-dependent.

糖皮质激素升高，特别是在特定发育时期，导致长期偏见 与抑郁，肥胖和成年后的其他不良适应性结果有关的习惯行为。 神经生物学机制在很大程度上不清楚。整联蛋白受体是细胞粘附因子，与 压力反应系统和神经发育疾病的遗传风险。由负责的α亚基组成 对于激活细胞内信号传导的配体结合和β亚基，整联蛋白对细胞外基质有反应 蛋白质，通过下游细胞骨架信号传导因子影响细胞结构。整合素介导的 信号传导稳定了从青春期到成年的过渡中的细胞结构，因此 在皮质和海马中高度表达的β1亚基导致树突状脊柱损失在 青少年。在人类中，编码β1-整合蛋白的ITGB1在全基因组的关联研究中鉴定 抑郁症和精神分裂症，以PFC依赖性计划和行动定义为特征的疾病。 尽管与神经发育疾病有联系，但β1-整合素参与PFC依赖性作用 选择仍然不透明。我们将检验以下假设： 轴心协调目标指导的动作选择，因此，是阻止习惯的明智目标 糖皮质激素和胁迫暴露。与RDOC定义的正价域保持一致，具体目的是： 目的1。确定β1-整合素 - 阿尔格 - - cortactin-rock2信号轴如何影响OPFC- 依赖的动作选择。我们将结合病毒介导的基因沉默和药物 操纵以检验以下假设：OPFC坐标中的β1-整合素 - arg-cortactin-rock2相互作用 目标指导的响应选择，抵消了不灵活的习惯。接下来，我们将测试β1-整合素 - 依赖性OPFC与基本杏仁核支持目标指导的响应选择的相互作用。最后，我们会的 检验以下假设，即现场选择性ITGB1沉默在结构上表观糖皮质激素暴露， 消除OPFC中兴奋性神经元的树突状刺。 目标2。减轻OPFC中与压力相关的习惯和树突状脊柱异常。接下来，我们会的 测试刺激ARG和Cortactin将阻止习惯和树突密度变化的假设 以及在发育性皮质酮或接触社会隔离之后的形态。这个目标将揭示 广告后，通过纠正细胞结构变化和习惯偏见的策略。 目标3。揭示与酪氨酸受体激酶B（TRKB）的功能相互作用。激活β1-整合素 - 抑制Rock2的介导的信号事件刺激了BDNF，BDNF与其高亲和力受体TRKB结合。 Rock2抑制作用还改变了PFC中全长/截短的TRKB的比率，有利于主动的全长 同工型，并在多种上下文中增强动作结果记忆。我们的最终目标将检验以下假设 通过ROCK2抑制的动作结果决策（阻止习惯）的丰富依赖于TRKB。