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Chronic Activation of Negative Memory Engrams Induces Lasting Behavioral and Cellular Abnormalities in Mice


핵심 개념
Repeated activation of negative memory engrams in the ventral hippocampus of mice induces lasting anxiety-like behaviors, impairs spatial working memory, and disrupts fear extinction and generalization, alongside cellular changes in microglia, astrocytes, and GABAergic signaling.
요약
The study investigated the impact of chronically activating negative memory engrams in the ventral hippocampus of young (6-month-old) and aged (14-month-old) mice. The researchers first characterized the transcriptional profiles of positive and negative memory engrams, finding that negative engrams upregulated genes associated with pro-inflammatory responses. To examine the behavioral and cellular consequences of chronic negative engram activation, the researchers used a chemogenetic approach to repeatedly stimulate negative engrams in the ventral hippocampus of young and aged mice over 3 months. This chronic negative engram activation led to several key findings: Increased anxiety-like behaviors in both young and aged mice, as measured by reduced time spent in the center of an open field and open arms of a zero maze. Impaired spatial working memory in aged, but not young, mice, as assessed by reduced spontaneous alternation in a Y-maze task. Disrupted fear extinction in young mice and enhanced fear generalization in both age groups, as measured during contextual fear conditioning and recall. Cellular changes in the hippocampus, including increased microglia and astrocyte activation, as well as reduced GABAergic fluorescence, suggesting alterations in inhibitory signaling. Together, these results demonstrate that chronic activation of negative memory engrams is sufficient to induce lasting behavioral and cellular abnormalities that recapitulate aspects of stress-related neuropsychiatric disorders. The findings provide insights into how rumination and persistent negative memories may contribute to the development of mood and cognitive disturbances.
통계
Negative engram cells upregulated genes linked to pro-inflammatory responses compared to positive engram cells. Chronic activation of negative engrams in young (6-month-old) and aged (14-month-old) mice increased anxiety-like behaviors. Chronic negative engram activation impaired spatial working memory in aged, but not young, mice. Chronic negative engram activation disrupted fear extinction in young mice and enhanced fear generalization in both age groups. Chronic negative engram activation induced changes in microglia and astrocyte morphology, as well as reduced GABAergic fluorescence, in the hippocampus.
인용문
"Repeated negative rumination can parallel the effects of chronic stress. These effects include hippocampal hyperactivity and accelerating the onset of mild cognitive impairment and dementias." "Stimulation of negative engram cells has been shown to modulate social avoidance behavior and enhance fear responses, but whether chronic stimulation of fearful memories produces enduring effects on brain activity and behavior remains unknown." "Our data suggest that negative memory engrams are a potent means by which to induce cellular and behavioral changes that model pathological states."

심층적인 질문

How might the findings from this study inform the development of novel therapeutic interventions for stress-related neuropsychiatric disorders

The findings from this study provide valuable insights into the potential development of novel therapeutic interventions for stress-related neuropsychiatric disorders. By demonstrating that chronic activation of negative memory engrams induces lasting cellular and behavioral abnormalities in mice, the study highlights the importance of targeting specific neural circuits and molecular pathways involved in negative memory processing. This suggests that interventions aimed at modulating these pathways could potentially mitigate the detrimental effects of persistent negative rumination. For instance, strategies that focus on inhibiting the activation of pro-inflammatory genes associated with negative engrams or enhancing the expression of anti-inflammatory genes linked to positive engrams could offer promising therapeutic approaches. Additionally, the observed behavioral changes, such as increased anxiety and impaired memory, provide valuable endpoints for assessing the efficacy of novel interventions in preclinical studies.

What are the potential mechanisms by which chronic negative memory engram activation leads to the observed cellular changes in microglia, astrocytes, and GABAergic signaling

The observed cellular changes in microglia, astrocytes, and GABAergic signaling following chronic negative memory engram activation may be mediated through several potential mechanisms. Firstly, chronic activation of negative engrams could lead to sustained release of pro-inflammatory cytokines by microglia, contributing to neuroinflammation and synaptic dysfunction. This chronic inflammatory response may also impact astrocyte morphology and function, leading to alterations in synaptic plasticity and neurotransmitter regulation. Furthermore, dysregulation of GABAergic signaling in the hippocampus, as evidenced by reduced GABA fluorescence, could disrupt the balance between excitation and inhibition, contributing to anxiety-related behaviors and memory impairments. Overall, these cellular changes suggest a complex interplay between neuroinflammation, glial activation, and altered inhibitory signaling in response to chronic negative memory activation.

Could targeting specific molecular pathways or neural circuits involved in the processing of negative memories offer a promising approach for preventing or reversing the detrimental effects of persistent negative rumination

Targeting specific molecular pathways or neural circuits involved in the processing of negative memories holds promise as a potential approach for preventing or reversing the detrimental effects of persistent negative rumination. For example, interventions that selectively modulate the expression of genes associated with neuroinflammation or synaptic plasticity in negative engram cells could help restore normal cellular function and behavior. Additionally, targeting specific neural circuits connecting the ventral hippocampus to other brain regions involved in emotional processing, such as the amygdala and prefrontal cortex, may offer a more targeted approach to regulating anxiety and fear responses. By identifying key molecular targets and neural circuits involved in negative memory processing, researchers can develop novel therapeutic strategies that aim to restore homeostasis and promote resilience in individuals with stress-related neuropsychiatric disorders.
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