Our brains store immense information about our experiences, feelings, and the world around us. Networks of neurons encode these signals as memories. These networks are called engrams. Select neurons are involved in forming engrams and storing new information. How neurons are recruited into engram networks has been one of the core mysteries of learning and memory. Now, a new study from Switzerland may have uncovered the underlying processes that make neurons eligible to form engrams. Their close examination of mouse brains after learning revealed that an engram’s ability to store memory may be predetermined by how DNA is packaged within neurons.
DNA carries the genetic instructions for every cell in our body. Two long intertwined strands create its classic double-helix structure. If stretched from end to end, a single DNA molecule would span more than six feet or approximately 2 meters. Remarkably, all of our DNA can fit inside a cell’s nucleus, which is only a few micrometers long. The diameter of the nucleus is more than a million times smaller than the total length of DNA. Therefore, DNA is condensed and wrapped tightly around proteins called histones like multiple spools of thread. Different sets of instructions are organized together depending on the cell’s function.
DNA spun around these spools is referred to as chromatin. Condensing DNA into tightly packed chromatin silences gene expression. For a gene to be transcribed, chromatin must open to make DNA more accessible. This unwinding process allows necessary enzymes and proteins to bind to gene sequences and begin the transcription process. During transcription, messenger RNA molecules transcribe the gene and carry the genetic information out of the nucleus to the cytoplasm, where it can be translated into a protein. Depending on what the cell needs, only some parts of DNA are unwrapped at any time. Each cell has an arsenal of tools that control which genes are “turned off and on” without permanently altering the DNA sequence. Some of that information is modified by histone proteins that wrap around DNA. In their study, Santoni et. al speculated that these mechanisms may mediate how neurons are selected to store memories.
The team began their investigation by recruiting a group of mice to undergo a fear conditioning experiment. Fearful memories are known to recruit neurons in a specific region of the brain called the amygdala. When we experience something frightening, the amygdala signals to other brain regions involved in memory formation, such as the hippocampus. This interaction helps encode the memory of the fear-inducing event.
In this study, the mice were periodically exposed to a high-frequency tone accompanied by a small shock. The mice quickly learned to associate the tone with a shock, freezing in place every time the tone was played and shock was administered. Even when no shock was given, the mice continued to freeze in fear upon hearing the tone. This response signified that the previously neutral tone had been encoded into a fear-linked engram in the brain. Following the fear conditioning experiment, the team compared the neurons in their amygdalae.
What they found in a comparison to mice not exposed to the fear learning experiment was a difference in the accessibility of DNA. The mice that participated in the experiment had high levels of epigenetic markers on genes that control the opening and closing of chromatin. Attachment of these markers to DNA helps relax histone proteins, enabling chromatin to open. Santoni et. al concluded that since open chromatin promotes the transcription of genes, the ability for neurons to hold information may be predetermined by the accessibility of DNA.
Understanding how neurons are recruited into engrams may have significant implications for developing therapies that enhance learning and memory. Santoni et. al experimented with this idea by enhancing the prevalence of epigenetic markers in the brains of another cohort of mice. Before undergoing fear conditioning, these mice were injected with a gene editing tool that increases the activity of enzymes that place these markers on DNA. The mice developed a much greater, longer-lasting fear of the tone that correlated with enhanced marker levels throughout their amygdala.
The conclusions from this study are a step forward in understanding changes in DNA that may underlie how memories are formed and strengthened. Principal investigator and pioneering researcher in the field of engrams, argues, “We are shedding light on the earliest step of memory formation from a DNA-centric level.” Additional studies on the epigenetic mechanisms driving learning and memory may one day lay the groundwork for treating a range of cognitive disorders, such as Alzheimer’s disease and post-traumatic stress syndrome.
