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.”

项目摘要 区分“好”和“坏”的能力被称为价 价处理中的病理性扰动可以解释心理 从焦虑和抑郁到强迫症和躁郁症 disorder.开发更有效的治疗精神疾病的关键 副作用较少的是突触、细胞和电路机制。 这份提案不仅提出了一个非常具体的研究计划，以探讨 神经降压素（NT），但它也提供了一个全面的，系统的 研究神经调节系统的方法。 一般的方法包括：1）确定起因果和关键作用的电路 在效价处理中，2）分析该电路组件的转录组，3）选择 对于表面受体或其他药物靶点，4）确定这种作用的贡献 5）建立神经元的输入-输出结构， 神经调节神经支配和突触后下游靶点，以及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 与化合价处理有关。 具体的假设包括在这个建议是：NT服务于指导可塑性 到适当的目标，有平行的电路，有一些局部相互作用 在BLA中，NT通过增加信噪比来改变编码动态 通过调制电磁传输来放大信号。 这一项目的成功结果将提供一个具体的模式， 神经调节信号如NT可以解决“价分配问题”。