Recent research has unveiled a significant breakthrough in understanding how long-term memories are formed and maintained in the brain. A team of international scientists has identified a molecule known as KIBRA, which acts as a “molecular glue,” crucial for the stability and persistence of memories over time. This discovery was published in the journal *Science Advances* on June 26, 2024.

Neuroscience Evidence for Memory Storage in Synapses

For those who need it, here is a list of scientific articles that support the concept that human memories are stored as changes in brain neuron synaptic connections.

Definitive Evidence for Memory Storage in Synapses

1. Long-Term Potentiation (LTP):
   • Study: Bliss, T.V.P., & Collingridge, G.L. (1993). “A synaptic model of memory: long-term potentiation in the hippocampus.” Nature.
   • Summary: LTP is a long-lasting enhancement in signal transmission between two neurons that results from their repeated stimulation. This phenomenon has been shown to be a cellular mechanism underlying learning and memory. Read more here.
2. Synaptic Plasticity and Memory:
   • Study: Malenka, R.C., & Bear, M.F. (2004). “LTP and LTD: An embarrassment of riches.” Neuron.
   • Summary: This paper discusses how synaptic modifications, specifically LTP and long-term depression (LTD), are critical for memory formation and storage. The evidence shows that changes in synaptic strength correlate with learning and memory processes. Read more here.
3. Hippocampus and Memory Encoding:
   • Study: Scoville, W.B., & Milner, B. (1957). “Loss of recent memory after bilateral hippocampal lesions.” Journal of Neurology, Neurosurgery & Psychiatry.
   • Summary: This classic study demonstrated that damage to the hippocampus impairs the ability to form new memories, providing direct evidence that synaptic changes in this area are essential for memory encoding. Read more here.
4. Synaptic Changes in Memory Formation:
   • Study: Tonegawa, S., et al. (2015). “Memory engram storage and retrieval.” Nature.
   • Summary: This research identifies specific synaptic changes associated with memory engrams and shows that manipulating these synapses can directly affect memory retrieval, providing strong evidence that memories are stored in synaptic connections. Read more here.

Key Articles on Synapses and Memory Storage

1. Synapses and Memory Storage
   • Study: “Synapses and Memory Storage”
   • Summary: This article discusses how synaptic connections can be altered by past patterns of use and modulatory neurotransmitters, which are essential for memory storage. It provides evidence of the relationship between synaptic changes and memory encoding. Read more here.
2. Is Plasticity of Synapses the Mechanism of Long-Term Memory Storage?
   • Study: “Is Plasticity of Synapses the Mechanism of Long-Term Memory Storage?”
   • Summary: This review highlights synaptic plasticity as a primary mechanism for memory retention, supported by extensive research in various model systems. It emphasizes the critical role of synaptic changes in the formation and retrieval of memories. Read more here.
3. The Power of Neighbors: Neighboring Synapses Shape Learning and Memory
   • Study: “The Power of Neighbors: Neighboring Synapses Shape Learning and Memory”
   • Summary: This study emphasizes the importance of interactions among neighboring synapses in forming stable, long-lasting memories. It demonstrates how synaptic connectivity influences learning outcomes. Read more here.
4. Upgrading Brain Storage: Quantifying How Much Information Our Synapses Can Hold
   • Study: “Upgrading Brain Storage: Quantifying How Much Information Our Synapses Can Hold”
   • Summary: This research discusses new techniques to measure synaptic strength and plasticity, enhancing understanding of learning and memory processes. It provides insights into how synaptic changes correlate with memory capacity. Read more here.

The Molecular Glue of Long-Term Memory

With that review behind us, let’s delve into an extraordinary discovery.

The Role of KIBRA in Memory Formation

KIBRA, which stands for kidney and brain expressed protein, plays a crucial role in memory retention. It acts as a “persistent synaptic tag” that binds to key molecules, particularly protein kinase Mzeta (PKMzeta), essential for strengthening synaptic connections between neurons. These connections, or synapses, form the foundation of memory storage in the brain.

Key Research Insights

Lead researchers André Fenton from New York University and Todd Sacktor from SUNY Downstate Health Sciences University noted that earlier studies on memory formation primarily focused on individual molecules. Their research emphasizes the significance of interactions among these molecules, particularly how KIBRA anchors PKMzeta at specific synapses. This ensures that robust synapses remain strengthened even as the proteins that sustain them are gradually replaced over time.

Mechanism of Action

The researchers conducted experiments with laboratory mice to observe KIBRA’s interaction with PKMzeta during memory formation. They found that KIBRA is strategically located at the synapses activated during memory formation.

Interaction Process

1. Activation: Once KIBRA is in place, PKMzeta attaches to it.
2. Synaptic Strength: This attachment helps maintain the strength of those synapses.
3. Replacement: Although PKMzeta typically degrades within a few days, KIBRA facilitates the recruitment of new PKMzeta to replace the degraded enzyme, thus preserving the memory.

Memory Manipulation Findings

Interestingly, the study revealed that disrupting the bond between KIBRA and PKMzeta could erase existing memories. This finding offers a biological basis for understanding how memories can be altered or lost, with significant implications for addressing memory-related disorders.

• Memory Erasure: Breaking the KIBRA-PKMzeta bond leads to the erasure of established memories.
• Enhancing Memories: Previous studies indicated that increasing PKMzeta levels in the brain could enhance weak or faded memories. The persistent synaptic tagging by KIBRA explains this phenomenon, as the additional PKMzeta reinforces synapses already tagged by KIBRA.

Memory Maintenance

This new research draws on philosophical concepts introduced by Francis Crick in 1984, likening the persistent synaptic tagging mechanism to the “Theseus’s Ship” paradox. Just as a ship can be maintained over generations by replacing its planks, memories can endure despite the ongoing turnover of the molecular components that support them. This analogy highlights the complexity of memory storage and the brain’s dynamic nature.

Philosophical Implications

The ability to strengthen or erase memories raises profound philosophical questions regarding personal identity, knowledge, and the essence of memory itself. Recent scientific advancements unveiling mechanisms of memory manipulation prompt exploration of several key philosophical themes.

1. Memory and Personal Identity

Memory is intricately linked to our sense of self. Philosophers like Schechtman argue that cherished memories significantly contribute to our identity and continuity over time. The capacity to erase or enhance memories could fundamentally alter an individual’s identity, raising questions about authenticity. Are we still the same person without our memories, or do we become an entirely new entity?

2. Knowledge and Justification

Philosophers assert that remembering constitutes a form of knowing, and the reliability of our memories underpins our beliefs and justifications. If memories can be manipulated, this raises concerns about the nature of knowledge itself. For example:

• If a memory is artificially enhanced, does it remain a valid source of knowledge?
• If a memory is erased, does that result in a loss of knowledge or justification for beliefs previously grounded in that memory?

These questions challenge traditional views on the relationship between memory and knowledge, suggesting a need for a reevaluation of epistemic frameworks.

3. The Ethics of Memory Manipulation

The ability to strengthen or erase memories introduces ethical considerations. For instance, should individuals have the right to alter their memories? This is particularly relevant in therapeutic contexts, such as trauma treatment. Ethical dilemmas arise regarding the implications of memory manipulation on personal autonomy and consent. If memories can be altered without an individual’s full understanding or agreement, it may lead to violations of personal integrity and authenticity.

4. Collective Memory and Social Identity

Beyond individual implications, memory manipulation can affect collective memory and social identity. Collective memories shape societal narratives and cultural identities. If groups can selectively enhance or erase shared memories, this could alter historical perceptions and cultural dynamics. Philosophers like Halbwachs emphasize the importance of collective memory in maintaining social cohesion. Thus, the ability to manipulate collective memories raises questions about the integrity of cultural identity and the ethical implications of altering shared histories.

Specific Human Memories Are Not Readable by This Knowledge

While this mechanism explains how memories can persist long-term, it doesn’t reveal the content of those memories. The specific information stored is likely encoded in the pattern of strengthened synapses across neural networks, rather than in the molecular interactions themselves. This research provides a biological explanation for how memories can last a lifetime, but it doesn’t allow us to “read” the content of memories from the KIBRA-PKMzeta interactions at individual synapses. The situation may be somewhat similar to understanding how a ROM chip stores a charge at one junction. This would not tell you anything about the actual data stored.

To recap: The KIBRA-PKMzeta mechanism is part of the molecular machinery that maintains synaptic strength. This maintenance of synaptic strength is crucial for long-term memory storage. The actual memory content is believed to be encoded in the specific pattern of strengthened and weakened connections across vast networks of neurons. Understanding this molecular mechanism gives insight into how memories persist, but not into what those memories are.

How Do Researchers Know Rat Long Term Memory Was Wiped?

Based on the search results, the researchers in this case did or could have used several methods to determine that decreasing PKMzeta activity erased long-term memories in rats:

1. Behavioral testing: After inhibiting PKMzeta, researchers observed changes in the rats’ behavior that indicated loss of previously established memories. For example: In taste aversion studies, rats that had learned to avoid saccharin would return to drinking it after PKMzeta inhibition, suggesting the aversive memory was erased[9][10]. In spatial memory tests like the active place avoidance task, rats showed impaired performance after PKMzeta inhibition, indicating loss of spatial memories[13].

2. Timing of effects: The memory loss persisted long after the PKMzeta inhibitor had cleared from the brain. Memory disruption lasted for days to weeks, much longer than the ~2 hour half-life of the agent, suggesting permanent erasure rather than temporary retrieval impairment[11].

3. Specificity of effects: – Only established memories were affected. Rats could form new memories after PKMzeta inhibition, indicating the brain regions were not damaged[11]. Memories could be erased and reformed multiple times by repeated PKMzeta inhibition and retraining[11].

4. Molecular evidence: PKMzeta inhibition led to changes in AMPA receptor trafficking at synapses, consistent with erasure of synaptic potentiation underlying memory[11][12].

5. Comparison to controls: Memory loss was observed in normal rats given PKMzeta inhibitors, but not in PKMzeta knockout mice given the same inhibitors, supporting PKMzeta’s specific role[13].

Future Directions

Understanding the mechanisms behind memory retention not only enriches our knowledge of cognitive processes but also opens pathways for therapeutic interventions for memory-related conditions, such as Alzheimer’s disease and other forms of dementia. As researchers continue to investigate KIBRA and its interactions, there is hope that these insights will lead to effective strategies for enhancing memory and addressing memory impairments in the future.

Conclusion

The discovery of KIBRA as a key player in the molecular framework of memory formation represents a significant advancement in neuroscience. This research not only clarifies how memories are formed and maintained but also sets the stage for future explorations into the treatment of memory-related disorders.

Read More
^{[1] https://www.technologynetworks.com/cell-science/news/molecular-glue-explains-how-memories-last-a-lifetime-388179
[2] https://www.nyu.edu/about/news-publications/news/2024/june/how-do-our-memories-last-a-lifetime–new-study-offers-a-biologic.html
[3] https://interestingengineering.com/science/memory-glue-revealed-study
[4] https://www.sciencedaily.com/releases/2024/06/240626152118.htm
[5] https://www.livescience.com/health/neuroscience/secret-to-lifelong-memories-sticking-is-molecular-glue
[6] https://science.slashdot.org/story/24/08/29/002223/brain-scientists-finally-discover-the-glue-that-makes-memories-stick-for-a-lifetime
[7] https://neurosciencenews.com/genetics-memory-recall-26377/
[8] https://www.reddit.com/r/tech/comments/1f3qeky/brain_scientists_finally_discover_the_glue_that/
[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564217/
[10] https://www.nih.gov/news-events/news-releases/enzyme-enhances-erases-long-term-memories-rats
[11] https://molecularbrain.biomedcentral.com/articles/10.1186/1756-6606-5-31
[12] https://www.sciencedirect.com/science/article/abs/pii/S0361923013001445
[13] https://elifesciences.org/articles/14846
[14] https://www.thetransmitter.org/memory/persistent-protein-pairing-enables-memories-to-last/
[15] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947452/
[16] https://www.degruyter.com/document/doi/10.1515/revneuro-2020-0105/html?lang=en}