Forgetting is traditionally viewed as a failure of memory. However, recent perspectives suggest it can be an adaptive process that modulates learning and memory updating. This study explores how retroactive interference, where new information disrupts the memory of previously encoded information, affects memory engrams, the physical trace of memory in the brain. By investigating the behavior of memory engram cells during interference, the study aims to uncover how these cells contribute to adaptive forgetting and memory updating.
Methods
Experimental Design
- Object-Context Recognition Paradigm: Mice were trained to associate objects with specific contexts and later tested to recognize displaced objects.
- Activity-Dependent Cell Labeling: Engram cells were labeled using doxycycline (DOX)-dependent methods to track their activation and behavior.
- Optogenetic Stimulation: Engram cells were artificially reactivated using optogenetic techniques to assess their role in memory retrieval.
Behavioral Protocol
Mice underwent habituation to two contexts over four days. On the fifth day, they were exposed to an identical pair of objects in one context (A) and a different pair in another context (B). After 24 hours, they were tested for object recognition. A control group did not receive interference, while another group was tested in context B to assess retroactivity.
Cell Labeling and Imaging
Engram cells were labeled in the hippocampus’s dentate gyrus (DG) and imaged using confocal microscopy. The overlap of labeled cells (mCherry) with activated cells (c-Fos) was assessed to determine engram reactivation.
Results
Memory Impairment by Retroactive Interference
Retroactive interference led to impaired memory recall. Mice exposed to interference could not distinguish between the displaced and non-displaced objects, unlike the control group. This was confirmed by the memory index, which showed significant differences between groups.
Engram Reactivation and Memory Recall
Engram reactivation was crucial for memory recall. Engram cells in the DG were labeled during initial exposure to contexts and later assessed. Mice without interference showed higher reactivation of the original engram during recall, while interference led to the activation of a competing engram.
Rescue of Memory by Reexposure
Memory impairment by interference could be rescued by reexposing mice to the initial object-context pair before the test. Mice reexposed to the original pair showed improved memory performance, indicating the persistence and reactivation of the original engram. Moreover, reexposure to misleading cues led to the formation of an updated memory, highlighting the malleability of forgotten engrams.
Optogenetic Reactivation
Artificial reactivation of engram cells in the DG using optogenetics successfully restored memory performance in mice following interference. Mice with optogenetic stimulation of the contextual engram explored the displaced object more, similar to the control group. This demonstrates that engram activity is sufficient for memory retrieval.
Engram Activity and Forgetting
Engram activity was necessary for forgetting. Inhibiting engram cells during the interference phase prevented forgetting, as shown by the memory performance of the light-inhibited group. This suggests that engram cell activation is crucial for interference-induced forgetting.
Interference and Memory Updating
Retroactive interference allows for memory updating. When mice were reexposed to the initial memory trace with new information, the original engram was modified to incorporate the new details. This adaptive mechanism supports the idea that forgetting facilitates memory updating and adaptation to new information.
Discussion
Adaptive Forgetting
The study supports the view that forgetting is an adaptive process involving active modulation of memory engrams. Interference between competing engrams results in selective forgetting, which can be reversed or updated through reexposure and artificial stimulation. This mechanism allows the brain to prioritize relevant information and adapt to changing environments.
Implications for Neurodegenerative Diseases
Understanding the mechanisms of adaptive forgetting has implications for neurodegenerative diseases like Alzheimer’s. Targeting engram reactivation and interference processes could offer new therapeutic approaches for memory impairment and cognitive decline.
Future Research Directions
- Investigate the molecular pathways involved in engram modulation during forgetting and reactivation.
- Explore the role of other brain regions in adaptive forgetting and memory updating.
- Examine the long-term effects of interference and engram reactivation on memory stability and plasticity.
Conclusion
This study demonstrates that retroactive interference is a form of adaptive forgetting mediated by competing memory engrams. Engram reactivation is essential for memory retrieval and can be modulated by natural and artificial cues. These findings highlight the dynamic nature of memory and the brain’s ability to adapt and update stored information.
References
For further details, you can access the full study here.
