Neural Mechanisms of Inflexible Learning Caused by BDNF Deficiency

描述(由申请人提供)：缺乏灵活性的学习，即不能通过从行为后果中学习来从一种行为过程改变到另一种行为过程，是许多精神障碍的常见症状。其生物学机制在很大程度上尚不清楚，但一个重要的表观遗传学原因是脑源性神经营养因子(BDNF)，它是大脑中的一种主要神经生长因子。脑源性神经营养因子在海马区(HIP)和内侧前额叶皮质(MPFC)缺乏会导致学习缺乏灵活性。应激通过表观遗传失活启动子IV来降低这些区域的BDNF水平，启动子IV是主要的活性依赖的BDNF启动子。在精神病患者中观察到脑源性神经营养因子水平降低和启动子IV失活。广泛的研究已经阐明了脑源性神经营养因子在特定脑区缺乏的机制。然而，不同脑区之间脑源性神经营养因子缺乏的神经机制仍不清楚。特别是，我们仍然不知道在灵活学习过程中，BDNF缺乏如何影响HIP和mPFC之间的信号处理。这种知识差距可能归因于在多个大脑区域操作BDNF和测量跨大脑区域的神经功能的技术困难。我们已经通过产生缺乏启动子IV驱动的BDNF的突变小鼠(KIV)来解决这些问题，并表现出僵化的学习。我们还开发了一种体内电生理系统，允许同时记录和刺激在嗅觉-味觉灵活学习测试中表现的小鼠的多个大脑区域。我们的长期目标是阐明BDNF启动子IV缺陷导致的学习僵化的神经机制。达到这一目标将有助于解释许多精神疾病的病理生理学基础，这些疾病是由应激引起的，启动子IV失活。我们最近发现，BDNF启动子IV缺陷降低了髋部的长时程增强(LTP)，但增强了mPFC中的LTP。脑源性神经营养因子缺乏的这些相反的影响如何影响HIP和mPFC之间的信号处理，以及这与灵活学习有什么关系？根据我们的初步结果，我们假设BDNF缺乏损害了在灵活学习任务之间的休息时间对来自髋部的输入的mPFC反应的正常抑制，这反映了不灵活的行为。为了解释这是如何发生的，我们还提出了一个新的模型：神经元同步性作为一个门，以一种依赖于频率的方式控制HIP-mPFC信号的时序；BDNF缺乏会降低神经元的同步性，从而损害HIP-mPFC信号的时序控制。我们将通过确定BDNF缺乏对AIM 1)HIP-mPFC信号/LTP和AIM 2)灵活学习期间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。该项目的成功完成将阐明僵化学习的时间依赖神经机制，并将扩大对学习机制的理解，从单个脑区内的突触可塑性到跨脑区域的时间依赖信号。

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.