With the constant inflow of information, one can assume that neurons, the fundamental units of information storage, are constantly writing and editing their personal diaries of memories. Scientifically speaking, every time an extra piece of data is taken in by the host, the neurons adapt, structurally as well on a molecular level, and sort themselves more and more into specific clusters, with each cluster roughly representing a particular sort of memory. This again is a far cry given how stochastic and turbulent this process is and that a particular memory cannot be isolated in this dense yet insanely organized information jungle. Recently new progress has been made by Jovasevic and colleagues in discerning how the immune system might have a crucial role in helping to create stable, context-based memories.
To this end they decided to go along with the easiest to induce fear sourced memory. They put mice in a container with cameras watching them and gave them tiny electric zaps preceded by an alarm/sound which acts as the context. If the mouse successfully registers a fear memory, then every time the alarm blares before the zap, the mouse literally freezes in fear(I would probably hightail it but hey every mammal for itself). Therefore, the duration of this frozen response is proportional to the quality of the memory that induces it.
The brain’s memory manager, the hippocampus, is known to be occupied by 50,000 to about 100,000 neurons. These neurons are in turn split up into four types, CA1, CA2, CA3 and CA4, with each population coordinating and uniquely contributing to making memories.
To see how the mouse’s neurons were able to learn from experience and orchestrate such a response, they decided to study the CA1-type neurons. These neurons are vested with the function of integrating information from the other neurons in the hippocampus, helping develop spatial memory, contemplate patterns, and of course, create context-based memories, making them prime targets of this study.
When it came down to studying the molecular events in these neurons during memory creation, the group saw something really weird happening . Usually, memory-making involves switching on a bunch of genes and creating some changes in gene expression and voila! A memory gets created. But here, the CA1 neurons were using a more violent approach to forge memories.
Using fluorescence-inducing genes and the right promoters, the group demonstrated that the neurons were undergoing DNA damage in their non-coding regions during the memory-making process. Following DNA damage, the nuclear membrane was ruptured, leading to DNA leakage into the perinuclear space, which was observed a few days after the experiment. These DNA fragments were then subsequently detected by the immune sensor, Toll-like receptors 9 or TLR9, in the endoplasmic reticulum of these neurons. TLR9s are pretty common in the world of immunology, serving as useful receptors for innate immune cells. Beyond that, they are also available in other cells like epithelial – where they play a role in their proliferation – and cancer. As immune sensors, they are normally on the lookout for exogenous DNA, an indication of a probable viral invasion, or mitochondrial DNA which indicates cellular stress and perhaps even apoptosis.
So, in these neurons when the leaked-out DNA is recognized by TLR9, it triggers an inflammatory state, while also very conveniently initiating DNA damage repair parallelly. Once the damages are fixed successfully, the researchers observed that a stable memory was created in the mice.
Given the role of TLR9 in this whole memory-making business, it becomes obvious that inhibiting or abrogating it can lead to some serious consequences. Imagine a situation where the neuron keeps breaking its DNA and nobody’s around to fix the damage and restore homeostasis. Not only does the neuron fail at making the memory but it also ends up slowly creeping towards genomic instability and eventual death. It’s like breaking down a house for renovation and fixing but then forgetting the part where you actually fix it. This could lead to neurodegeneration, accelerated senescence, psychiatric disorders, and loss of cognition. Hence the authors warrant a caution against the use of TLR9 antagonist therapies when dealing with neuroimmune conditions such as multiple sclerosis, where TLR9s play an active role in its pathogenesis and inhibiting its activity can be therapeutic. But given this research, the patients being treated using the antagonists might as well be trading one problem for another.
Personally I find it intriguing how something so risky as this could have developed into a well regulated and controlled mechanism of memory generation over the course of evolution and what could have possibly evoked its need. Since DNA damage is usually associated with bad stuff in our bodies, this discovery gives a nice shift to our perspective, adding another entry to the list of destructive things in our body that can have constructive outcomes, here, a strong, stable, memory.
Source:
Jovasevic V, Wood EM, Cicvaric A, Zhang H, Petrovic Z, Carboncino A, Parker KK, Bassett TE, Moltesen M, Yamawaki N, Login H, Kalucka J, Sananbenesi F, Zhang X, Fischer A, Radulovic J. Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature. 2024 Apr;628(8006):145-153. doi: 10.1038/s41586-024-07220-7. Epub 2024 Mar 27. PMID: 38538785; PMCID: PMC10990941.
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