Summary: A new study shows that the epigenetic state of neurons determines their role in memory formation. Neurons with an open chromatin state are more likely to be recruited into a memory trace, showing higher electrical activity during learning.
The researchers demonstrated that manipulating these epigenetic states in mice can enhance or impair learning ability. This finding shifts the focus from synaptic plasticity to nuclear processes, opening potential new avenues for treating cognitive disorders.
Important facts:
- Neurons with an open chromatin state are more likely to be involved in memory formation.
- Manipulating the epigenetic state of neurons in mice can increase or decrease learning ability.
- This research shifts the focus from synaptic plasticity to nuclear processes in learning.
Source: EPFL
When we form a new memory, physical and functional changes occur in the brain that are collectively known as the “memory trace.” The memory trace reflects the distinctive pattern 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 underlying excitability of neurons plays a role, but the currently accepted view of learning has neglected to look inside the neuron’s command center, its nucleus. In the nucleus, it seems there is another dimension that has remained completely unexplored: epigenetics.
Inside every cell of any living organism, the genetic material encoded by DNA is the same, yet the different cells that make up the body, such as skin cells, kidney cells or nerve cells, each express a different set of genes. Epigenetics is the mechanism that explains how cells control such gene activity without changing the DNA sequence.
Now, EPFL scientists led by neuroscientist Johannes Graefe have explored whether epigenetics can influence the likelihood of neurons being selected for memory formation.
Their research on mice has now been published. Sciencedemonstrates that the epigenetic state of a neuron is critical for its role in memory encoding.
“We are shedding light on the earliest stages of memory formation from a DNA-centric level,” says Graff.
Graff and his team wondered whether epigenetic factors might influence a neuron’s “memory-related” function. A neuron might be epigenetically open when the DNA inside its nucleus is open or loose; and closed when the DNA is dense and tight.
They found that open neurons were more likely to be recruited into a “memory trace,” a sparse group of neurons in the brain that shows electrical activity when learning something new. In fact, neurons that were in a more open chromatin state were also the ones that showed higher electrical activity.
The EPFL scientists then used a virus to deliver epigenetic enzymes to artificially induce the openness of neurons. They found that the corresponding mice learned much better. When the scientists used the opposite approach to close the neurons’ DNA, the mice’s learning ability was canceled out.
These findings open up new ways of understanding learning involving the nucleus of the neuron, and may one day even lead to drugs to improve learning. As Graff explains: “They move away from the dominant neuroscience view on learning and memory that focuses on the importance of synaptic plasticity, and place a renewed emphasis on what happens inside the nucleus of the neuron, on its DNA.
“This is particularly important, as many cognitive disorders, such as Alzheimer’s disease and post-traumatic stress disorder, are characterized by disturbances in epigenetic mechanisms.”
About this memory and epigenetics research news
Author: Nick Papageorgiou
Source: EPFL
contact: Nick Papageorgiou – EPFL
image: Image credit: Neuroscience News
Original Research: Closed access.
,Chromatin plasticity predetermines neuronal competence for memory trace formation” by Johannes Graff et al. Science
abstract
Chromatin plasticity predetermines neuronal competence for memory trace formation
Introduction
During development, epigenetic heterogeneity gives rise to diverse cell types with distinct functions. By stably directing the activation and inactivation of genomic loci to catalyze specific signaling cascades, epigenetic mechanisms play a crucial role in lineage commitment and cellular differentiation. However, it is still unclear 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 interesting features of neurons is their capacity for encoding information. Remarkably, for each new piece of information remembered the brain deploys only a subset of its neurons, meaning that even within a well-defined cell type, not all neurons are equally fit for encoding information at any given time.
Justification
The dependence of memory formation on neuronal selection forced us to ask whether chromatin structure, among otherwise homogeneous cellular identities, could be sufficiently heterogeneous to drive information encoding. And in particular, whether increased chromatin plasticity could be the catalytic force to induce neurons to be preferentially selected for memory formation.
Result
Focusing on the lateral amygdala of the mouse, a key brain region responsible for encoding associative forms of memory, we found that its excitatory neurons indeed display asymmetric chromatin plasticity, and furthermore, those that were preferentially recruited to 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 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 facilitated neuronal recruitment to the memory trace whereas loss of its function inhibited memory allocation.
Interested in the molecular mechanisms underlying this selection, we performed single nucleus multiome sequencing to simultaneously assess chromatin accessibility and gene expression changes that occur in epigenetically modified neurons.
These results showed that increased chromatin accessibility or expression at genomic locations is closely related to structural and synaptic plasticity as well as neuronal excitability, which has been recognized as a critical physiological process for information encoding. Accordingly, we found that increased chromatin plasticity also increased intrinsic neuronal excitability and promoted structural and functional synaptic remodeling.
For a process to be truly qualified as influencing memory allocation, it must also support memory retention. To this end we tested HAT-injected mice on Pavlovian fear conditioning, an associative type of memory, and found that they displayed significantly stronger fear memory – an effect that lasted for up to eight days. Notably, optogenetic silencing of epigenetically altered neurons prevented fear memory recall, suggesting a cell-autonomous relationship between chromatin plasticity and memory trace formation.
In conclusion, by combining Förster resonance energy transfer (FRET) instrumentation and calcium imaging in single neurons, we show that the link between chromatin plasticity and intrinsic neuronal excitability occurs endogenously, cell-autonomously, and in real time.
conclusion
Our findings suggest that the eligibility of a neuron to be recruited to a memory trace depends on its epigenetic state prior to learning, and thus identify chromatin plasticity as a novel form of plasticity critical for information encoding. The epigenetic landscape of a neuron may therefore represent an adaptable template to register and integrate environmental signals in a dynamic, yet long-lasting manner.
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