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Biases in sharp wave-ripple content as a transdiagnostic cognitive process

作为跨诊断认知过程的尖锐波波纹内容的偏差

基本信息

批准号：
10227162
负责人：
Matthijs van der Meer
金额：
$ 28.7万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227162
关键词：
Address Affect Affective Amphetamines Animal Behavior Animals Behavior Behavioral Belief Biological Assay Decision Making Development Dextroamphetamine Disease Dopamine Dopaminergic Agents Equilibrium Event Failure Future Generalized Anxiety Disorder Generations Hippocampus (Brain)Human Individual Laboratory Animals Learning Link Major Depressive Disorder Mammals Mediating Memory Mental disorders Mood Disorders Moods Motivation Mus Outcome Pharmaceutical Preparations Pharmacological Treatment Pharmacology Post-Traumatic Stress Disorders Process Retrieval Rewards Rodent Schizophrenia Side Signal Transduction Syndrome System Testing Translating Validation Ventral Striatum Work clinical translation cognitive process comorbidity expectation experience experimental study fictional works information processing memory retrieval neural circuit pramipexol pre-clinical relating to nervous system response success theories

项目摘要

PROJECT SUMMARY Comorbidities between different mood disorders, as well as those with other syndromes such as schizophrenia, PTSD, and OCD suggest the possibility of shared underlying mechanisms that could inform development of new treatments. However, a rate-limiting step in uncovering such mechanisms continues to be the difficulty of studying these disorders in laboratory animals: it may never be possible to look at the behavior of an animal and know that it is experiencing a mood disorder. To side-step this fundamental challenge, we take a different approach: we will establish a neural assay of negatively biased thought. Many mood disorders are characterized by biased information processing, including recall biases for negative past events (in major depression) and biases towards generating negative future scenarios (in generalized anxiety disorder). Cognitive process theories of learning, memory and decision-making indicate that such biased thought may not only be a signature of mood disorders, but in fact causally contribute to it. This work will develop a neural assay of negatively biased thought in mice by focusing on sharp wave-ripples (SWRs): bursts of internally generated, synchronous neural activity in the hippocampus that can depict past or upcoming experiences. SWRs are an attractive preclinical target because (1) SWRs are highly conserved across mammals including rodents and humans, making it likely that results will translate, and (2) SWR activity can be decoded to reveal their content, such as retrieval of specific prior experiences. This implies that we can establish an objective neural assay for negatively biased thought: given a positive and a negative experience, are both experiences retrieved equally often, equally effective downstream, or is there a bias? Aim 1 will optimize a behavioral task and neural assay to provide positive and negative experiences that can be neurally distinguished, yielding for individual subjects and individual recording sessions a SWR content bias for negative compared to positive events. Next, Aim 2 will administer drugs known to generate affectively biased information processing in rodents in humans (amphetamine and pramipexole) and determine their effects on SWR bias and behavior. Finally, we will probe the mechanisms that link SWR content to motivational/affective systems at the neural circuit level through their interaction with dopamine in Aim 3. Taken together, the proposed work is expected to establish SWR content as a candidate transdiagnostic process that is of broad relevance to a number of mental health disorders.

项目总结