summary: A new study reveals that the epigenetic state of neurons determines their role in memory formation: neurons with open chromatin are more likely to be incorporated into memory traces and exhibit higher electrical activity during learning.
The researchers demonstrated that by manipulating these epigenetic states in mice, they could enhance or impair learning ability, a discovery that shifts the focus from synaptic plasticity to nuclear processes and opens up new possibilities for treating cognitive disorders.
Key Facts:
- Neurons with an open chromatin state are more likely to be involved in memory formation.
- By manipulating the epigenetic state of neurons in mice, learning can be promoted or inhibited.
- This study shifts the focus from synaptic plasticity to nuclear processes in learning.
sauce: EPFL
When a new memory is formed, the brain undergoes physical and functional changes collectively known as the “memory engraftment,” which describes the specific neuronal activity patterns and structural changes that occur when a memory is formed and later recalled.
But how does the brain “decide” which neurons are responsible for a memory trace? Research suggests that the intrinsic excitability of neurons plays a role, but the currently accepted view of learning doesn’t look inside the neuron’s own command center, the neuron’s nucleus, where there appears to be another dimension that has not been explored at all: epigenetics.
Within the cells of a particular organism, the genetic material encoded by DNA is the same, but the different types of cells that make up the body, such as skin cells, kidney cells, and nerve cells, each express a different set of genes. Epigenetics is the mechanism by which cells control this genetic activity without changing the DNA sequence.
Now, scientists at EPFL, led by neuroscientist Johannes Graef, are investigating whether epigenetics influences the likelihood of neurons being selected for memory formation.
Their research on mice is currently ScienceThis suggests that the epigenetic state of neurons plays a key role in memory encoding.
“We are uncovering the earliest steps of memory formation from a DNA-centric level,” says Gref.
Gref and his team wondered whether epigenetic factors might influence the “memory” function of neurons: neurons can be epigenetically open when the DNA in their nuclei is uncoiled or loose, or closed when the DNA is compact and tightly packed.
The researchers found that open chromatin was more likely to be recruited into “memory engraftments” — sparse collections of neurons in the brain that show electrical activity when you learn something new. Indeed, the neurons with a more open chromatin state were also the ones that showed higher electrical activity.
The EPFL scientists then used a virus to deliver an epigenetic enzyme to artificially induce the neurons to open up, and found that this significantly improved the mice’s ability to learn. When the scientists used the opposite approach, closing off the neurons’ DNA, the mice lost their ability to learn.
The discovery opens up new ways of understanding learning that encompass the nucleus of neurons and may even lead to the development of drugs to improve learning in the future. Gref explains: “This discovery moves away from the dominant neuroscience view of learning and memory, which focuses on the importance of synaptic plasticity, and places a new emphasis on what is happening inside the nucleus of neurons – in their DNA.”
“This is particularly important because many cognitive disorders, such as Alzheimer’s disease and post-traumatic stress disorder, are characterized by abnormalities in epigenetic mechanisms.”
About this Memory and Epigenetics Research News
author: Nick Papageorgiou
sauce: EPFL
contact: Nick Papageorgiou – EPFL
image: Image courtesy of Neuroscience News
Original Research: The access is closed.
“Chromatin plasticity predetermines neuronal competence for memory trace formation” Johannes Graef et al. Science
Abstract
Chromatin plasticity predetermines neuronal competence for memory trace formation
introduction
During development, epigenetic heterogeneity gives rise to distinct cell types with distinct functions. Epigenetic mechanisms play pivotal roles in lineage determination and cell differentiation by stably directing the activation and inactivation of genomic loci and catalyzing specific signaling cascades. However, whether chromatin plasticity plays an equally important role in the development of dynamic functions in fully differentiated cells such as adult neurons remains to be elucidated.
One of the most intriguing features of neurons is their ability to encode information. In particular, for each new piece of information stored, the brain deploys only a subset of neurons. This means that even within the same developmentally defined cell type, not all neurons at a given time are equally suited to encoding information.
basis
The reliance of memory formation on neuronal selection raised the question of whether chromatin structure, within a seemingly homogenous cellular identity, is sufficiently heterogeneous to drive information encoding: specifically, whether enhanced chromatin plasticity could be a catalytic force that primes neurons for preferential selection for memory formation.
result
Focusing on the mouse lateral amygdala, a key brain region responsible for encoding associative memories, we found that its excitatory neurons indeed exhibit heterogeneous chromatin plasticity and, moreover, that neurons preferentially recruited to learning-activated neurons are enriched in highly acetylated histones, an epigenetic modification that is abundant in the brain.
To functionally test the correlation between chromatin plasticity and information encoding, we manipulated histone acetylation levels by increasing or decreasing histone acetyltransferases (HATs) in these neurons. We found that gain-of-function of histone acetylation-mediated epigenetic plasticity promoted recruitment of neurons to memory traces, whereas its loss-of-function prevented memory allocation.
Intrigued by the molecular mechanisms underlying this selection, we next performed single-nucleus multi-ohmic sequencing to simultaneously assess the changes in chromatin accessibility and gene expression that occur in epigenetically modified neurons.
These results reveal increased chromatin accessibility or expression at genomic locations that are closely associated with structural and synaptic plasticity, as well as neuronal excitability, which have been identified as key physiological processes for information encoding. Thus, increased chromatin plasticity also leads to increased intrinsic neuronal excitability, promoting structural and functional synaptic remodeling.
For a process to be considered truly influencing memory allocation, it must also support memory retention. To this end, we tested HAT-injected mice in Pavlovian fear conditioning (a type of associative memory) and found that their fear memory was significantly stronger, an effect that lasted for up to 8 days. Notably, optogenetic silencing of epigenetically altered neurons prevented fear memory recall, suggesting a cell-autonomous relationship between chromatin plasticity and memory trace formation.
Finally, by combining Förster resonance energy transfer (FRET) tools with calcium imaging in single neurons, we reveal that the connection between chromatin plasticity and intrinsic neuronal excitability occurs intrinsically, cell-autonomously and in real time.
Conclusion
Our findings show that the eligibility of neurons to be incorporated into memory traces depends on their epigenetic state before learning, thereby identifying chromatin plasticity as a novel form of plasticity important for information encoding. Thus, the epigenetic landscape of neurons may represent an adaptive template for recording and integrating environmental signals dynamically and over time.
