Orbitofrontal cortical coordination of action-consequence decision making

行动后果决策的眶额皮质协调

• 批准号: 9923734
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923734
• 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/antagonist; knock-down; learning outcome; neurobiological mechanism; neurotrophic factor; response; social; 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，特别是在特定的发育时期，会导致长期的偏向 基于习惯的行为与成年后的抑郁、肥胖和其他适应不良结果有关。 神经生物学机制在很大程度上仍不清楚。整合素受体是细胞黏附因子，与 应激反应系统与神经发育疾病的遗传风险。由负责的α亚单位组成 对于配体结合和激活细胞内信号的β亚单位，整合素对细胞外基质做出反应 蛋白质，通过下游细胞骨架信号因子影响细胞结构。整合素介导的 信号在从青春期到成年期的转变中稳定细胞结构，从而使基因消融 β1亚单位在皮质和海马区高表达，导致树突棘从 青春期。在人类中，编码β1-整合素的ITGB1是在全基因组关联研究中发现的 抑郁症和精神分裂症是以依赖PFC的计划和行动缺陷为特征的疾病。 尽管与神经发育疾病有关，β1-整合素参与了pFC依赖的作用 所选内容保持不透明。我们将检验一个β1-整合素-ABL2/精氨酸-皮质酮-ROCK2信号 Axis协调目标导向的动作选择，因此是阻挡习惯的合理目标，因为 糖皮质激素和应激源暴露。与RDoC定义的正价域保持一致，具体目标是： 目的1.确定β1-整合素-精氨酸-皮质酮-ROCK2信号轴对PFC-2的影响。 从属操作选择。我们将使用病毒介导的基因沉默和药物作用的组合 β1-整合素-精氨酸-皮质酮-ROCK2在OPFC坐标下相互作用的实验研究 目标导向的应对选择，抵制僵化的习惯。接下来，我们将检验β1-整合素- 依赖的OPFC与基底外侧杏仁核的相互作用支持目标导向的反应选择。最后，我们会 测试位置选择性沉默Itgb1在结构上表现为表观反应会导致糖皮质激素暴露的假设， 消除OPFC内兴奋性神经元上的树突棘。 目的2.减轻oPFC的应激源相关习性和树突棘异常。接下来，我们将 测试刺激Arg和Cortactin将阻止树突棘密度改变和习性的假设 以及发育中的皮质酮或暴露于社会孤立后的形态。这一目标将揭示 纠正逆境后细胞结构变化和习惯偏见的策略。 目的3.揭示与酪氨酸受体激酶B(TrkB)的功能相互作用。激活β-1-整合素- 抑制ROCK2的中介信号事件刺激BDNF，BDNF与其高亲和力受体TrkB结合。 ROCK2抑制也改变了PFC中全长/截断TrkB的比率，有利于激活的全长 异构体，它增强了在多个背景下的行动-结果记忆。我们的最终目标将检验这一假设 通过抑制ROCK2来丰富行动-结果决策(阻止习惯)是TrkB依赖的。