Regulation of fear expression by activity-dependent BDNF in direct hippocampal-to-prelimbic projections

在人类中，海马体前额叶功能的异常与恐惧调节的损害有关， 老鼠，还有老鼠。尽管这些大脑区域的功能与恐惧表达之间存在已知的联系， 对于这个回路中的功能障碍如何导致表达缺陷，我们的理解存在一个根本性的差距。 这种差距的持续存在是一个重要的问题，因为彻底了解 导致恐惧的解剖学定义的神经回路可能对开发治疗癌症至关重要 以恐惧表达失调为特征的疾病。长期目标是更好地了解如何改变 解剖连接的神经元群体中的分子和细胞功能与恐惧有关 神经精神障碍的调节失调，并利用这一信息开发新的治疗策略 通过选择性地针对这些人群中与临床相关的分子来治疗这些疾病。整体而言 这项建议的目标，也是迈向长期目标的第一步，是在两者之间建立因果联系 这种分子、脑源性神经营养因子(BDNF)、恐惧表达和一种解剖学上相关的 神经回路，由腹侧海马(VHC)神经元组成，直接投射到大脑皮层 (PRL)或VHC-PRL投影仪。我们的中心假设是BDNF信号影响VHC-PRL的能力 投影仪可以双向调节恐惧表情。提出这项研究的理由是，一旦 海马前额叶功能、脑源性神经营养因子和恐惧表达之间的因果联系已经建立，选择性 操纵海马体-前额叶通路中的脑源性神经营养因子将导致治疗恐惧的方法 仅针对受影响的神经回路的调节失调。该提案的核心假设将得到检验 通过追求三个特定的目标：1)研究改变的活性依赖的BDNF信号如何影响 VHC-PRL投影仪的结构和功能，2)VHC-PRL是否存在BDNF的过度表达 投影仪逆转受损小鼠PRL中与恐惧相关的行为和分子表型 海马-前额叶功能，以及3)研究异常的脑源性神经营养因子依赖性可塑性如何影响 恐惧表达时大脑皮层的群体动态。这种方法是创新的，因为它 用迄今不可能的解剖学研究了选择性神经回路在恐惧表达中的作用 特异性；此外，它建议使用尖端技术将BDNF与这一功能因果联系起来 在恐惧表达和与恐惧相关的人群动态过程中的循环，这是以前从未做过的。这个 提出的研究具有重要意义，因为这些结果有望从纵向上促进我们对 恐惧表达背后的神经回路，以及为解剖定位的潜在途径 以恐惧为特征的调节失调障碍的治疗靶向。很可能这种选择性的神经靶向 这些障碍中的回路将有效地减轻这些障碍的症状和副作用。 与目前的药物治疗相关的影响，这些治疗在大脑中发挥非特异性作用。

Abnormalities in hippocampal-prefrontal function are associated with impairments in fear regulation in humans, rats, and mice. Despite the known associations between function in these brain regions and fear expression, there is a fundamental gap in our understanding of how dysfunction in this circuit leads to expression deficits. Continued existence of this gap represents an important problem because a thorough understanding of how anatomically-defined neural circuits contribute to fear will likely be critical for the development of treatments for disorders featuring dysregulation of fear expression. The long-term goal is to better understand how altered molecular and cellular function in anatomically-connected populations of neurons contributes to fear dysregulation in neuropsychiatric disorders, and to use this information to develop novel treatment strategies for these disorders by selectively targeting clinically-relevant molecules within these populations. The overall objective of this proposal, and the first step toward our long-term goal, is to establish a causal link between one such molecule, brain-derived neurotrophic factor (BDNF), fear expression, and an anatomically-connected neural circuit, comprised of ventral hippocampal (vHC) neurons with direct projections to the prelimbic cortex (PrL), or vHC-PrL projectors. Our central hypothesis is that BDNF signaling impacts the ability of vHC-PrL projectors to bi-directionally regulate fear expression. The rationale for the proposed research is that, once causal links between hippocampal-prefrontal function, Bdnf, and fear expression are established, the selective manipulation of Bdnf in the hippocampal-prefrontal pathway will lead to therapeutic approaches to fear dysregulation that target only the affected neural circuitry. The central hypothesis of the proposal will be tested by pursuing three Specific Aims: 1) Examine how altered activity-dependent BDNF signaling impacts the structure and function of vHC-PrL projectors, 2) determine whether over-expression of BDNF in vHC-PrL projectors reverses fear-related behavioral and molecular phenotypes in the PrL of mice with impaired hippocampal-prefrontal function, and 3) investigate how aberrant BDNF-dependent plasticity impacts population dynamics in the prelimbic cortex during fear expression. The approach is innovative because it investigates the role of a selective neural circuit in fear expression with heretofore impossible anatomical specificity; furthermore, it proposes the use of cutting edge techniques to causally link Bdnf with function of this circuit during fear expression and fear-related population dynamics, which has never before been done. The proposed research is significant because the results are expected to vertically advance our understanding of the neural circuitry underlying fear expression, as well as provide potential avenues for anatomically-localized therapeutic targeting in disorders featuring fear dysregulation. It is likely that such selective targeting of neural circuitry in these disorders will be efficacious in reducing both the symptoms of these disorders and the side effects associated with current pharmacological treatments, which act non-specifically in the brain.