Summary: Enhanced reactivation of negative memory engrams may be an important cellular mechanism behind the cognitive symptoms of depression.
Physical manifestations of negative memories in the hippocampus could underlie cognitive symptoms of depression, according to research in mice published in Journal of Neuroscience. Inhibiting these manifestations could be a future treatment route.
Groups of neurons that are activated after an experience are thought to be the physical representation of memory. These so-called engrams in the hippocampus could be involved in depression, which is characterized by impaired recall of positive memories and increased recall of negative memories.
In a mouse model of depression, Tak Pan Wong and colleagues at Douglas Hospital Research Centre tagged the engrams that formed after mice experienced social stress and examined their social avoidance behavior. Even though all mice experienced the same stressor, only some displayed depression behaviors, indicating a predisposition to developing depression.
The depression-prone mice displayed higher concentrations of engram cells compared to the less susceptible mice, and the density of the cells correlated with the level of social avoidance behavior. Activating the engram cells increased social avoidance behavior while suppressing the cells decreased it, suggesting a role in the cognitive symptoms of depression.
Calli McMurray – SfN
The image is credited to Zhang et al., JNeurosci 2019.
Original Research: Closed access
“Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress”. Tian Rui Zhang, Amanda Larosa, Marie-Eve Di Raddo, Vanessa Wong, Alice S. Wong and Tak Pan Wong.
Journal of Neuroscience. doi:10.1523/JNEUROSCI.1958-18.2019
Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress
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 (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag 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 to resilient and non-stressed 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-, 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 CSDS 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 have 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.