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.”

项目总结 区分“好”与“坏”的能力称为价态。 加工，价加工中的病理性扰动可以解释心理 健康障碍，从焦虑和抑郁到强迫症和躁郁症 无序。开发更有效的心理健康障碍治疗方法的关键 副作用较少的将是突触、细胞和回路机制。 这项建议不仅列出了一个非常具体的研究计划，以探索功能作用 神经肽，神经降压素(NT)，但它也展示了一个全面的，系统的 研究神经调节系统的方法。 一般的方法包括：1)识别起因果和关键作用的电路 在价处理中，2)描述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点，4)确定这一点的贡献 可塑性的神经调节信号，5)建立了可塑性的输入-输出结构 神经调节神经支配和突触后，下游靶点，6)建立 这种特殊的神经调节信号在神经活动和行为中的因果作用 与价处理相关联。 这一建议中包含的具体假设是：NT用于引导可塑性 对于适当的目标，存在具有某些局部相互作用的并行电路 在BLA中，且NT通过增加信噪比来改变编码动态 通过调制谷氨酸能传递来放大信号。 该项目的成功成果将提供一个具体的模型，说明如何 神经调节信号如NT可以解决“价分配问题”。