"How Neurons' Innate Immunity Strengthens Memory Retention"
Memory, a fundamental aspect of human consciousness, has been a subject of fascination for centuries. From surrealist paintings to cutting-edge neuroscience, the mystery of how memories persist has captivated minds and inspired art. Now, a groundbreaking study published in Nature has uncovered a population of neurons that engages mechanisms of the innate immune system during memory formation, revealing that inflammatory signalling might pave the way for long-term memory.
The hippocampus, a seahorse-shaped region of the brain associated with memory and learning, has long been a focus for researchers. Decades ago, a patient known as H.M. underwent surgery to treat epilepsy, resulting in the removal of parts of his temporal lobes, including the hippocampus. While the surgery was successful in controlling his seizures, H.M. was left with a devastating side effect: he could no longer form new memories. This case led scientists to hone in on the hippocampus as a hub for many types of memory, sparking a flurry of research into the mechanisms that underlie memory formation and persistence.
In the new study, scientists investigated neurons in the hippocampus of mice following memory acquisition. They discovered a distinct population of neurons that showed an inflammatory response to DNA damage, persisting for days after memory acquisition. This inflammatory response was mediated by a protein of the innate immune system called TLR9 (Toll-like receptor 9), which detects extra-nuclear fragments of DNA that have been incorporated into cellular compartments called endolysosomes.
The researchers demonstrated that disrupting these mechanisms, specifically removing Tlr9 from hippocampal neurons, prevented mice from recalling long-term memories. This suggests that the sensing of double-strand DNA breaks by TLR9 is a versatile molecular process that is active in both memory and innate immunity.
The authors of the study also showed that removing a protein called RELA, which connects TLR9 activation to DNA repair by 53BP1, interferes with the accumulation of the centrosomal DNA-damage response complex. This is a key finding, as the accumulation of centrosomal DNA-damage response complexes is crucial for maintaining genome integrity.
These findings have significant implications for our understanding of memory formation and the role of the innate immune system in the brain. They also provide a molecular link between the acquisition of a memory and the ability to store it reliably for an extended period.
Despite these substantial insights, pertinent questions remain. For example, what properties of memory are conferred by these neurons, and how do they interact with engram neurons, which are known to be required for memory formation? The authors speculate that inflammatory neurons could have a key role in the stability and flexibility of memories, but that engram neurons could enable the recall of memories. Perhaps the engram neurons produce the initial memory signal, and the inflammatory neurons identified in this work support and sculpt the memory, enabling its persistence.
However, the activity or functional properties of these neurons during the acquisition, consolidation, or retrieval of memories remain undefined. Recordings of electrical activity and selective manipulation of inflammatory neurons throughout the memory process will be needed to better understand the cells' contributions to memory persistence.
This study raises pressing questions regarding the relationship between DNA damage, inflammation, and memory. Activation of TLR9, a key player in the immune response, is known to contribute to neurodegeneration, predominantly through microglia, the immune cells of the central nervous system. How is it that, in neurons, activation of TLR9 is crucial for memory formation, whereas, in microglia, it produces neurodegeneration, the antithesis of memory? What separates detrimental DNA damage and inflammation from that which is essential for memory? And how are these mechanisms disrupted in the context of aging and neurodegenerative disorders?
The discovery of the role of inflammatory neurons in memory formation provides a fascinating new avenue for understanding the complexity of the brain and memory. As researchers continue to unravel the intricate network of interactions between neurons and the immune system, we can look forward to a deeper understanding of how memories are formed, maintained, and retrieved.
Source:
Jovasevic, V., et al. (2024). Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature, <https://doi.org/10.1038/s41586-024-07220-7>
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