Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits
Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits
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DOI：
10.1016/j.nbd.2013.01.010
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发表时间：
2013-06-01
影响因子：
6.1
通讯作者：
Marighetto, Aline
中科院分区：
文献类型：
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作者：
Brayda-Bruno, Laurent;Mons, Nicole;Marighetto, Aline
在衰老和阿尔茨海默病 (AD) 中，间隔海马胆碱能 (SHC) 变性与海马依赖性陈述性记忆 (DM) 退化的功能相关性仍然不明确。具体来说，选择性 SHC 损伤通常无法在动物模型中引起明显的记忆障碍。然而，尽管表现明显正常，相关大脑结构内的神经元活动可能会因 SHC 破坏而改变。我们假设部分 SHC 退化可能导致 DM 衰退前衰老过程中记忆回路的功能改变。在年轻的成年小鼠中，我们研究了行为无效（肥皂草素诱导的）SHC 损伤（其程度与老年动物中观察到的程度相似）对三个主要神经记忆系统（分别维持陈述性记忆、程序性记忆和情绪性记忆的隔海马系统、纹状体和杏仁核）之间的活动模式和功能连接的影响。动物在放射状迷宫程序中接受训练，分离动物中关系/DM 和非 R/DM 表达的人类等效物。测试诱导的 Fos 激活模式表明，尽管不存在明显的行为缺陷，但部分 SHC 损伤显着改变了大脑的功能活动和连接性（共激活模式）。具体来说，海马 CA3 过度活跃和异常的隔膜-海马-杏仁核相互连接类似于在衰老和前驱 AD 中观察到的情况。因此，SHC 神经元根据特定的记忆需求与海马外结构关键地协调海马功能。尽管部分 SHC 退化本身不足以影响 DM 表现，但当由于额外的与年龄相关的损伤，大脑无法再补偿胆碱能损失引起的整体失衡时，连接性变化可能会导致随后出现 DM 损失。 (c) 2013 Elsevier Inc. 保留所有权利。
The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions - similar in extent to that seen in aged animals - on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss. (c) 2013 Elsevier Inc. All rights reserved.