Orbitofrontal cortical coordination of action-consequence decision making

行动后果决策的眶额皮质协调

• 批准号: 9753363
• 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/9753363
• 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.

糖皮质激素的升高，特别是在特定的发育时期，会导致长期的偏见， 习惯性行为与抑郁症、肥胖症和其他适应不良的成年后果有关。 神经生物学机制仍不清楚。整合素受体是与细胞粘附因子相关的细胞粘附因子。 应激反应系统与神经发育疾病遗传风险由一个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，整合素应答细胞外基质 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 在从青春期到成年期的过渡中，信号传导稳定了细胞结构，这样， β1亚基在皮质和海马中高度表达，导致树突棘从10岁开始缺失。 青春期在人类中，ITGB 1编码β1-整联蛋白，在以下基因组关联研究中被鉴定： 抑郁症和精神分裂症，这些疾病的特征是PFC依赖性计划和行动的缺陷。 尽管与神经发育疾病有关，β1-整合素参与PFC依赖性作用 选择保持不透明。我们将检验β1-整联蛋白-β 2/Arg-皮质蛋白-ROCK 2信号转导通路是否与细胞凋亡有关的假设。 轴坐标目标导向的行动选择，因此，是一个明智的目标，为阻止习惯，由于 糖皮质激素和应激源暴露。与RDoC定义的正效价域一致，具体目标是： 目标1。为了确定β1-整合素-精氨酸-皮质素-ROCK 2信号轴如何影响oPFC- 依赖动作选择我们将使用病毒介导的基因沉默和药理学相结合的方法， 操作以检验β1-整联蛋白-Arg-皮质素-ROCK 2在oPFC坐标中相互作用的假设 目标导向的反应选择，对抗不灵活的习惯。接下来，我们将检验β1-整合素- 依赖性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，我们将 测试位点选择性Itgb 1沉默在结构上模仿糖皮质激素暴露的假设， 消除前额叶皮层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。接下来我们就 验证精氨酸和皮质激素的刺激将阻断树突棘密度的习惯和变化的假设 和形态发育皮质酮或暴露于社会孤立。这一目标将揭示 在逆境中纠正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（trk B）的功能相互作用。β1-整合素的激活- 抑制ROCK 2的介导的信号传导事件刺激BDNF，BDNF结合其高亲和力受体trkB。 ROCK 2抑制还改变PFC中全长/截短trkB的比例，有利于活性全长trkB的表达。 同种型，它在多种情况下增强行动结果记忆。我们的最终目标是检验假设， 通过ROCK 2抑制的行为结果决策（阻断习惯）的富集是trkB依赖性的。