Summary: A new study reveals that the epigenetic state of neurons determines their role in memory formation. Neurons with open chromatin states are more likely to be recruited into memory traces, showing higher electrical activity during learning.
Researchers demonstrated that manipulating these epigenetic states in mice can enhance or impair learning. This discovery shifts the focus from synaptic plasticity to nuclear processes, offering potential new avenues for treating cognitive disorders.
Key Facts:
- Neurons with open chromatin states are more likely to be involved in memory formation.
- Manipulating the epigenetic state of neurons in mice can enhance or impair learning.
- This research shifts the focus from synaptic plasticity to nuclear processes in learning.
Source: EPFL
When we form a new memory, the brain undergoes physical and functional changes known collectively as a “memory trace”. A memory trace represents the specific patterns of activity and structural modifications of neurons that occur when a memory is formed and later recalled.
But how does the brain “decide” which neurons will be involved in a memory trace? Studies have suggested that the inherent excitability of neurons plays a role, but the currently accepted view of learning has neglected to look inside the command center of the neuron itself, its nucleus. In the nucleus, there seems to be another dimension altogether that has gone unexplored: epigenetics.
Inside every cell of a given living organism, the genetic material encoded by the DNA is the same, yet the various cells types that make up the body, like skin cells, kidney cells, or nerve cells each express a different set of genes. Epigenetics is the mechanism of how cells control such gene activity without changing the DNA sequence.
Now, scientists at EPFL led by neuroscientist Johannes Gräff have explored whether epigenetics might affect the likelihood of neurons to be selected for memory formation.
Their research on mice, now published in Science, shows that the epigenetic state of a neuron is key to its role in memory encoding.
“We are shedding light on the earliest step of memory formation from a DNA-centric level”, says Gräff.
Gräff and his team wondered if epigenetic factors could influence the “mnemonic” function of a neuron. A neuron can be epigenetically open when the DNA inside its nucleus is unraveled or relaxed; and closed when the DNA is compact and tight.
They found that it is the open ones that are more likely to be recruited into the “memory trace”, the sparse set of neurons in the brain that shows electrical activity when learning something new. Indeed, the neurons that were in a more open chromatin state were also the ones demonstrating higher electrical activity.
The EPFL scientists then used a virus to deliver epigenetic enzymes to artificially induce openness of the neurons. They found that the corresponding mice learnt much better. When the scientists used the opposite approach to close the neurons’ DNA, the mice’s ability to learn was cancelled.
The findings open up new ways to understand learning that encompass the neuron’s nucleus, and may even lead one day to medication for improving learning. As Gräff explains: “They move away from the dominant neuroscientific view on learning and memory that focuses on the importance of synaptic plasticity, and newly place emphasis on what happens inside the nucleus of a neuron, on its DNA.
“This is especially important, as many cognitive disorders such as Alzheimer’s disease and post-traumatic stress disorder are characterized by epigenetic mechanisms gone wrong.”
About this memory and epigenetics research news
Author: Nik Papageorgiou
Source: EPFL
Contact: Nik Papageorgiou – EPFL
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Chromatin plasticity predetermines neuronal eligibility for memory trace formation” by Johannes Gräff et al. Science
Abstract
Chromatin plasticity predetermines neuronal eligibility for memory trace formation
INTRODUCTION
During development, epigenetic heterogeneity gives rise to different cell types with different functions. By stably instructing the activation and deactivation of genomic loci to catalyze specific signaling cascades, epigenetic mechanisms play a pivotal role in lineage commitment and cellular differentiation. What remains elusive, however, is whether chromatin plasticity plays an equally important role in the development of dynamic functions in fully differentiated cells, such as adult neurons.
One of the most intriguing features of neurons is their capacity for information encoding. Notably, for each new piece of information memorized the brain deploys only a subset of its neurons, implying that even within the same developmentally defined cell type, not all neurons are equally fit for information encoding at any given time.
RATIONALE
The dependence of memory formation on neuronal selection made us ask whether chromatin architecture might be heterogenous enough, among otherwise seemingly homogeneous cellular identities, to drive information encoding. And specifically, whether enhanced chromatin plasticity could be a catalyst force to prime neurons to be preferentially selected for memory formation.
RESULTS
Focusing on the mouse lateral amygdala, a key brain region responsible for the encoding of associative forms of memory, we discovered that its excitatory neurons indeed exhibit heterogeneous chromatin plasticity, and further, that those preferentially recruited into learning-activated neurons were enriched for hyperacetylated histones, an abundant epigenetic modification in the brain.
To functionally test this correlation between chromatin plasticity and information encoding, we subsequently manipulated histone acetylation levels by either increasing or decreasing histone acetyltransferases (HATs) in these neurons. We found that a gain-of-function of histone acetylation-mediated epigenetic plasticity facilitated neuronal recruitment into the memory trace whereas a loss-of-function thereof prevented memory allocation.
Interested in the molecular mechanisms underlying this selection, we next performed single nucleus multiome sequencing for the simultaneous assessment of chromatin accessibility and gene expression changes occurring in the epigenetically modified neurons.
These results revealed gained chromatin accessibility or increased expression at genomic locations closely related to structural and synaptic plasticity, as well as to neuronal excitability, which has been identified as an important physiological process for information encoding. Accordingly, we found that increasing chromatin plasticity also led to an increase in intrinsic neuronal excitability and promoted structural and functional synaptic remodeling.
For a process to be truly qualified as influencing memory allocation, it should also support memory retention. To this end we tested the HAT-injected mice on Pavlovian fear conditioning, an associative type of memory, and found that they displayed a significantly stronger fear memory—an effect that lasted for up to eight days. Notably, optogenetic silencing of the epigenetically altered neurons prevented fear memory recall, suggesting a cell-autonomous relationship between chromatin plasticity and memory trace formation.
Lastly, by combining Förster resonance energy transfer (FRET) tools and calcium imaging in single neurons, we revealed that the nexus between chromatin plasticity and intrinsic neuronal excitability occurs endogenously, cell-autonomously, and in real time.
CONCLUSION
Our findings show that a neuron’s eligibility to be recruited into the memory trace depends on its epigenetic state prior to learning, and thereby identify chromatin plasticity as a novel form of plasticity important for information encoding. A neuron’s epigenetic landscape might therefore represent an adaptable template so as to register and integrate environmental signals in a dynamic, yet long-lasting manner.
