Solving the Valence Assignment Problem

解决化合价分配问题

• 批准号: 10388233
• 负责人: Kay Maxine Tye
• 金额: $ 93.8万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388233
• 关键词: Affect; Amygdaloid structure; Animals; Anxiety; Architecture; Attenuated; Behavior; Behavioral; Bipolar Disorder; Brain; Cell surface; Cells; Chemosensitization; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Cues; Data; Discrimination; Electrophysiology (science); Fright; Fruit; Funding; G-Protein-Coupled Receptors; Genes; Geniculate body structure; Glutamates; Goals; Hippocampus (Brain); Impairment; Learning; Long-Term Potentiation; Maintenance; Medial; Mediating; Mental Depression; Mental disorders; Modeling; Mus; Negative Valence; Neuromodulator; Neurons; Neuropeptides; Neurotensin; Neurotensin Receptors; Noise; Outcome; Output; Pathologic; Pharmacology; Play; Positioning Attribute; Positive Valence; Prevalence; Property; Punishment; Research; Rewards; Role; Schizophrenia; Signal Transduction; Site; Source; Stimulus; Surface; Synapses; System; Testing; Textbooks; Thalamic structure; Time; Vision; Work; addiction; antagonist; classical conditioning; differential expression; druggable target; effective therapy; glutamatergic signaling; in vivo; knock-down; memory retrieval; nerve supply; neural circuit; neuroregulation; novel; novel strategies; novel therapeutics; optogenetics; parallel processing; postsynaptic; receptor; relating to nervous system; response; self-directed learning; side effect; therapeutic development; transcriptome; transmission process

PROJECT SUMMARY The ability to discriminate between what is “good” and “bad” is termed valence processing, and pathological perturbations in valence processing can explain mental health disorders ranging from anxiety and depression to compulsivity and bipolar disorder. The key to developing more effective treatments for mental health disorders with fewer side-effects will be in the synaptic, cellular, and circuit mechanisms. This proposal not only lays out a very specific research plan to probe the functional role of a neuropeptide, neurotensin (NT), but it also lays out a comprehensive, systematic approach to investigating neuromodulatory systems. The general approach includes: 1) Identify a circuit that plays a causal and critical role in valence processing, 2) Profile the transcriptome of this circuit component, 3) Select for surface receptors or other druggable targets, 4) Determine the contribution of this neuromodulatory signal on plasticity, 5) Establish the input-output architecture of the neuromodulatory innervation and postsynaptic, downstream targets, and 6) Establish a causal role for this particular neuromodulatory signal in neural activity and behavior associated with valence processing. The specific hypotheses included in this proposal are: that NT serves to guide plasticity to the appropriate target, that there are parallel circuits that have some local interaction in the BLA, and that NT alters the coding dynamics by increasing signal-to-noise ratio by amplifying signal by modulation of glutamatergic transmission. A successful outcome of this project will provide a specific model for how a neuromodulatory signal such as NT can solve the “valence assignment problem.”

项目概要 区分“好”和“坏”的能力称为价 处理和价处理中的病理扰动可以解释心理 健康障碍，从焦虑和抑郁到强迫症和双相情感障碍 开发更有效的精神健康障碍治疗方法的关键。 在突触、细胞和电路机制中副作用较少。 该提案不仅提出了一个非常具体的研究计划来探讨功能作用 神经降压素 (NT) 是一种神经肽，但它也提出了全面、系统的 研究神经调节系统的方法。 一般方法包括： 1) 识别起因果和关键作用的回路 在化合价处理中，2) 分析该电路组件的转录组，3) 选择 对于表面受体或其他可药物靶标，4) 确定此的贡献 可塑性的神经调节信号，5）建立输入输出架构 神经调节神经支配和突触后、下游目标，以及 6) 建立 这种特定的神经调节信号在神经活动和行为中的因果作用 与价处理相关。 该提案中包含的具体假设是： NT 起到引导可塑性的作用 到适当的目标，存在具有一些局部相互作用的并行电路 在 BLA 中，NT 通过增加信噪比来改变编码动态 通过调节谷氨酸能传输来放大信号。 该项目的成功成果将为如何 NT 等神经调节信号可以解决“价态分配问题”。