Remodeling of projections from ventral hippocampus to prefrontal cortex in Alzheimer's mice

Emotional dysregulation often accompanies cognitive deficits in Alzheimer's disease (AD). The hippocampus, most notably damaged by AD pathology, is classified into the cognition‐bound posterior and emotion‐bound anterior hippocampi. Since the anterior hippocampus or its rodent counterpart, the ventral hippocampus (VH), sends dense afferents to the prefrontal cortex (PFC) and the basolateral amygdala (BLA), the two structures implicated in fear responses, we investigated whether these afferents are modified in 3xTg AD model mice. An anterograde dextrin tracer injected into VH revealed that axons in PFC were more ramified in 3xTg than wild‐type (WT) mice, with the synaptic density reduced. The VH projections to BLA were not affected. Intracellular accumulation of amyloid β (Aβ) or Aβ‐like immunoreactivity was found in PFC and BLA neurons alike. Behaviorally, in the 2‐way active avoidance test, the frequency of chamber change was higher, with the test performance better, in 3xTg than WT mice, suggesting a distorted contextual fear in the 3xTg group. Given the essential involvement of parts of PFC in contextual fear responses and that of BLA in fear responses in general, the observed remodeling of VH‐to‐PFC afferents and the accumulation of intracellular Aβ in BLA and PFC pyramidal cells might exercise critical influences on enhanced avoidance behavior in 3xTg mice.

在阿尔茨海默病（AD）中，情绪失调常常伴随着认知缺陷。海马体受AD病理影响最为显著，它被分为与认知相关的后部海马体和与情绪相关的前部海马体。由于前部海马体或其在啮齿动物中的对应部分——腹侧海马体（VH）向前额叶皮层（PFC）和基底外侧杏仁核（BLA）发送密集的传入纤维，而这两种结构与恐惧反应有关，我们研究了在3xTg AD模型小鼠中这些传入纤维是否发生了改变。将顺行性糊精示踪剂注入VH后发现，3xTg小鼠PFC中的轴突比野生型（WT）小鼠分支更多，且突触密度降低。VH到BLA的投射未受影响。在PFC和BLA神经元中均发现了淀粉样β蛋白（Aβ）的细胞内积聚或Aβ样免疫反应。在行为方面，在双向主动回避测试中，3xTg小鼠换室的频率更高，测试表现更好，这表明3xTg组的情境恐惧出现了扭曲。鉴于PFC的某些部分在情境恐惧反应中至关重要，而BLA在一般恐惧反应中也起着关键作用，观察到的VH到PFC传入纤维的重塑以及BLA和PFC锥体细胞中细胞内Aβ的积聚可能对3xTg小鼠增强的回避行为产生关键影响。