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Orbitofrontal cortical coordination of action-consequence decision making

行动后果决策的眶额皮质协调

基本信息

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
项目类别：
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

项目摘要

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，会导致长期偏向