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Activating positive memory engrams suppresses depression-like behaviour.

Steve Ramirez1, Xu Liu, Christopher J MacDonald1

  • 1RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

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Artificial reactivation of positive memories in the brain can suppress stress-induced depression-like behaviors. This study highlights dentate gyrus engram cells as potential therapeutic targets for mood disorders.

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Area of Science:

  • Neuroscience
  • Behavioral Science
  • Molecular Biology

Background:

  • Chronic stress is a significant environmental risk factor for behavioral abnormalities like anxiety and mood disorders.
  • Stress can lead to quantifiable behavioral impairments in animal models, including deficits in motivation and anhedonia.
  • The hippocampus plays a role in regulating the stress response and cognitive aspects of stress-induced impairments, but its neuronal mechanisms for behavioral improvement are unclear.

Purpose of the Study:

  • To investigate the potential of optogenetically reactivating specific hippocampal cells to rescue stress-induced depression-related behaviors.
  • To identify the neural circuits involved in the acute rescue of stress-induced behavioral deficits.
  • To determine if chronic reactivation of memory-associated hippocampal cells can lead to long-term behavioral improvements and neurogenesis.

Main Methods:

  • Optogenetic reactivation of dentate gyrus cells active during positive experiences in mice.
  • Brain-wide histological analysis.
  • Pharmacological and projection-specific optogenetic blockade experiments.
  • Chronic optogenetic stimulation of hippocampal cells linked to positive memories.

Main Results:

  • Acute optogenetic reactivation of previously active dentate gyrus cells successfully rescued stress-induced depression-related behaviors in mice.
  • The hippocampus-amygdala-nucleus accumbens pathway, specifically glutamatergic activity, was identified as a key circuit for the acute rescue.
  • Chronic reactivation of hippocampal cells associated with positive memories resulted in the rescue of stress-induced behavioral impairments and promoted neurogenesis, even after stimulation cessation.

Conclusions:

  • Artificial activation of positive memories is sufficient to suppress depression-like behaviors.
  • Dentate gyrus engram cells represent promising therapeutic targets for intervening in maladaptive behavioral states induced by stress.
  • Targeting specific memory engrams offers a potential strategy for treating stress-related mood disorders.