Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3A 2B4, Canada.
Basic Neuroscience Division, Douglas Hospital Research Centre, Montreal, Quebec H4H 1R3, Canada, and.
J Neurosci. 2019 Sep 18;39(38):7576-7590. doi: 10.1523/JNEUROSCI.1958-18.2019. Epub 2019 Aug 12.
The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor. Compared with resilient and nonstressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e., engram cells) in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD and optogenetic approaches to activate and inactivate social defeat-related CA1 engram cells enhanced and suppressed social avoidance, respectively. Increased engram cells in susceptible mice could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-related, but not neutral stimuli-related, CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. The susceptibility to chronic social defeat stress is regulated by hippocampal CA1 engrams for negative memory. Hippocampal negative memory engrams may underlie the vulnerability and expression of cognitive symptoms in depression. We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams has been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.
海马体与抑郁症状高度相关。最近的研究结果表明，抑郁症状的表达和易感性与海马体功能增强有关。我们推测，海马体记忆痕迹（代表记忆形成后活性增强的神经元集合）可能是海马体对抑郁症状产生某些影响的基础。我们使用慢性社交挫败应激模型，在易受应激影响和有应激抵抗力的小鼠中研究了与应激相关的海马体记忆痕迹。使用 LacZ 标记社交挫败相关的海马体集合。记忆痕迹细胞对应于通过相同应激重新激活的集合。与有应激抵抗力和未受应激的对照小鼠相比，易感小鼠在背侧和腹侧海马体 CA1 区显示出更高的社交挫败相关 LacZ 标记细胞（即记忆痕迹细胞）的再激活。CA1 记忆痕迹细胞的密度与社交回避的水平相关。使用 DREADD 和光遗传学方法激活和失活社交挫败相关的 CA1 记忆痕迹细胞分别增强和抑制了社交回避。易感小鼠的齿状回中找不到增加的记忆痕迹细胞。与有应激抵抗力的小鼠相比，易感小鼠的背侧海马体中与负性刺激相关的记忆痕迹细胞更多，而与中性刺激相关的记忆痕迹细胞较少。最后，慢性而非短暂和阈下的社交挫败方案是增加 CA1 记忆痕迹细胞密度所必需的。对慢性社交挫败应激的易感性受海马体 CA1 记忆痕迹的调节，用于负性记忆。海马体负性记忆痕迹可能是抑郁认知症状易感性和表达的基础。我们提供的证据表明，负性记忆海马体记忆痕迹有助于在慢性社交挫败应激后发展出与抑郁相关的行为。阳性记忆痕迹的激活已被证明可以缓解与抑郁相关的行为，而我们的发现揭示了负性记忆痕迹的病理性作用，可能导致这些行为。增加的负性记忆痕迹可能是报道的动物模型和抑郁症患者中海马体高活性的下游效应。与情感症状不同，我们对抑郁症的认知症状的细胞机制了解甚少。鉴于海马体记忆痕迹在记忆形成中的关键作用，负性记忆痕迹的增强再激活可能是抑郁症认知症状的一个重要细胞机制。
