Neural Mechanisms of Inflexible Learning Caused by BDNF Deficiency

BDNF 缺乏导致学习不灵活的神经机制

• 批准号: 8935926
• 负责人: KAZUKO SAKATA
• 金额: $ 15万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8935926
• 关键词: Address; Affect; Behavior; Behavioral; Biological; Biological Markers; Biological Neural Networks; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cognitive Therapy; Development; Electroencephalography; Epigenetic Process; Extinction (Psychology); Frequencies; Fright; Functional disorder; Genetic; Genotype; Goals; Growth Factor; Head; Health; Hippocampus (Brain); Human; Knowledge; Learning; Long-Term Potentiation; Measures; Medial; Memory; Mental disorders; Modeling; Mus; Mutant Strains Mice; Neurons; Neurophysiology - biologic function; Patients; Performance; Phase; Phenotype; Prefrontal Cortex; Recovery; Research; Signal Transduction; Smell Perception; Staging; Stress; Symptoms; Synaptic plasticity; System; Taste Perception; Taste aversion; Testing; Time; Wild Type Mouse; base; behavioral response; flexibility; improved; in vivo; innovation; meetings; neuromechanism; neuronal growth; neurotransmission; novel; novel therapeutics; performance tests; postsynaptic; promoter; relating to nervous system; response; signal processing

DESCRIPTION (provided by applicant): Inflexible learning, the inability to change from one course of action to another by learning from a behavioral consequence, is a common symptom of many psychiatric disorders. Its biological mechanisms are largely unknown, but one important epigenetic cause is brain-derived neurotrophic factor (BDNF), a major neuronal growth factor in the brain. BDNF deficiency in the hippocampus (HIP) and medial prefrontal cortex (mPFC) causes inflexible learning. Stress reduces BDNF levels in these regions via epigenetic inactivation of promoter IV, a major activity-dependent BDNF promoter. Reduced BDNF levels and inactive promoter IV are observed in psychiatric patients. Extensive studies have elucidated the mechanisms underlying BDNF deficiency within specific brain regions. However, the neural mechanisms underlying BDNF deficiency between different brain regions remain unknown. In particular, we still do not know how BDNF deficiency affects signal processing between the HIP and mPFC during flexible learning. This knowledge gap may be attributable to the technical difficulties of manipulating BDNF in multiple brain regions and in measuring neural functions across brain regions. We have addressed these issues by generating mutant mice (KIV) that lack promoter IV-driven BDNF and show inflexible learning. We also have developed an in vivo electrophysiological system that allows simultaneous recording and stimulation of multiple brain regions in mice behaving in a smell-taste flexible learning test. Our long-term goal is to elucidat the neural mechanisms of inflexible learning caused by BDNF promoter IV deficiency. Meeting this goal will help to explain the pathophysiology underlying many psychiatric disorders arising from stress that inactivates promoter IV. We recently found that BDNF promoter IV deficiency reduces long-term potentiation (LTP), a cellular form of memory, in the HIP, but enhances LTP in the mPFC. How do these opposing effects of BDNF deficiency affect the signal processing between the HIP and mPFC, and how does this relate to flexible learning? From our preliminary results, we hypothesize that BDNF deficiency impairs the normal suppression of mPFC responses to input from the HIP during breaks between flexible learning tasks, which reflects inflexible behavior. To explain how this occurs, we also propose a novel model: neuronal synchrony acts as a gate to control the timing of the HIP-mPFC signals in a frequency-dependent manner; BDNF deficiency reduces neuronal synchrony and thus impairs timing controls of HIP-mPFC signals. We will test these hypotheses by determining the effects of BDNF deficiency on Aim 1) HIP-mPFC signals/LTP and Aim 2) neuronal synchrony during flexible learning, and by determining timing relations among HIP-mPFC signals, neuronal synchrony, and correct behavioral responses. Successful completion of this project will elucidate the timing-dependent neural mechanisms of inflexible learning, and will expand the understanding of learning mechanisms from synaptic plasticity within single brain regions to timing-dependent signaling across brain regions.

描述（由申请人提供）：学习不灵活，即无法通过从行为后果中学习而从一种行动方针改变为另一种行动方针，是许多精神疾病的常见症状。其生物学机制在很大程度上是未知的，但一个重要的表观遗传原因是脑源性神经营养因子（BDNF），一种主要的神经元生长因子在大脑中。海马体（HIP）和内侧前额叶皮质（mPFC）中的BDNF缺乏导致学习不灵活。应激通过启动子IV（一种主要的活性依赖性BDNF启动子）的表观遗传失活来降低这些区域的BDNF水平。在精神病患者中观察到BDNF水平降低和启动子IV失活。广泛的研究已经阐明了特定脑区BDNF缺乏的机制。然而，不同脑区之间BDNF缺乏的神经机制仍然未知。特别是，我们仍然不知道BDNF缺乏如何影响灵活学习过程中HIP和mPFC之间的信号处理。这种知识差距可能是由于在多个脑区操纵BDNF和测量跨脑区神经功能的技术困难。我们已经解决了这些问题，通过产生突变小鼠（KIV），缺乏启动子IV驱动的BDNF，并显示出灵活的学习。我们还开发了一种体内电生理系统，可以同时记录和刺激小鼠在嗅觉-味觉灵活学习测试中的多个大脑区域。我们的长期目标是阐明BDNF启动子IV缺陷引起的不灵活学习的神经机制。满足这一目标将有助于解释许多精神疾病的病理生理学引起的压力，失活启动子IV。 我们最近发现，BDNF启动子IV缺陷减少长时程增强（LTP），一种细胞形式的记忆，在HIP，但增强LTP的mPFC。BDNF缺乏的这些相反效应如何影响HIP和mPFC之间的信号处理，以及这与灵活学习有何关系？从我们的初步研究结果，我们假设，BDNF缺乏损害正常的抑制mPFC反应的输入从HIP之间的休息灵活的学习任务，这反映了不灵活的行为。为了解释这种情况是如何发生的，我们还提出了一种新的模型：神经元同步作为一个门，以频率依赖的方式控制HIP-mPFC信号的时序; BDNF缺乏减少神经元同步，从而损害HIP-mPFC信号的时序控制。我们将通过确定BDNF缺乏对灵活学习过程中Aim 1）HIP-mPFC信号/LTP和Aim 2）神经元同步性的影响，以及通过确定HIP-mPFC信号、神经元同步性和正确行为反应之间的时序关系来验证这些假设。本项目的成功完成将阐明不灵活学习的时间依赖性神经机制，并将扩大对学习机制的理解，从单个脑区域内的突触可塑性到跨脑区域的时间依赖性信号传导。