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，特别是在特定的发育时期，会导致长期偏向 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。 神经生物学机制仍不清楚。整合素受体是与整合素相关的细胞粘附因子。 应激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。 对于配体结合和激活细胞内信号传导的 β 亚基，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。 信号传导在从青春期到成年的过渡过程中稳定细胞结构，从而使基因消除 β1 亚基在皮质和海马中高度表达，导致树突棘损失，始于 在人类青春期，编码 β1-整合素的 ITGB1 在全基因组关联研究中被鉴定出来。 抑郁症和精神分裂症，这些疾病的特征是依赖 PFC 的计划和行动存在缺陷。 尽管与神经发育疾病有关，β1-整合素参与 PFC 依赖性作用 选择仍然不透明，我们将测试 β1-整合素-Abl2/Arg-cortactin-ROCK2 信号传导的假设。 轴协调目标导向的动作选择，因此是阻止习惯的明智目标，因为 糖皮质激素和应激源暴露与 RDoC 定义的正价域一致，具体目标是： 目标 1. 确定 β1-integrin-Arg-cortactin-ROCK2 信号轴如何影响 oPFC- 我们将结合使用病毒介导的基因沉默和药理学。 操作来检验 oPFC 坐标中 β1-整合素-Arg-cortactin-ROCK2 相互作用的假设 目标导向的反应选择，对抗僵化的习惯 接下来，我们将检验β1-整合素-的假设。 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。 测试位点选择性 Itgb1 沉默结构表型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。 目标 2. 减轻 oPFC 中与压力相关的习惯和树突棘异常。 检验以下假设：刺激 Arg 和 cortactin 会阻止树突棘密度的习惯和变化 这一目标将揭示发育皮质酮或暴露于社会隔离后的形态。 纠正逆境后细胞结构变化和习惯偏差的策略。 目标 3. 揭示与酪氨酸受体激酶 B (trkB) 激活的功能相互作用。 抑制 ROCK2 介导的信号事件会刺激 BDNF，使其与其高亲和力受体 trkB 结合。 ROCK2 抑制还改变 PFC 中全长/截短 trkB 的比率，有利于活性全长 同工型，它可以增强多种情况下的行动结果记忆。我们的最终目标将检验以下假设： 通过 ROCK2 抑制来丰富行动结果决策（阻止习惯）是 trkB 依赖性的。