# DNA methylation based binary enhancers govern neuronal allocation to coding in the hippocampus

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $369,705

## Abstract

Abstract
Experiences are coded by small ensembles of recruited neurons in the hippocampus. Although multiple
neurons receive a stimulus, only a subset of them is “allocated” to encode a given memory. It has been
shown that neurons with higher levels of intrinsic excitability are preferentially recruited during context
exposure, yet the principles governing neuron recruitment are not known. Neuron allocation has medical
relevance, as it is the first step in memory formation and thus may be targeted to mitigate cognitive deficits
associated with aging and Alzheimer's disease and other neurodegenerative disorders. Here we introduce a
model that, via DNA methylation based binary enhancers may explain neuron allocation in the
hippocampus. Specifically, we identified thousands of small genomic regions that in some cells exist in
fully methylated, and in others, in fully unmethylated states, in contrast to the surrounding genome, which
is uniformly methylated or unmethylated in all neurons. Since these regions are embedded in synaptic
genes and have a DNA methylation dependent transcription-enhancing effect, they can be conceptualized
as DNA methylation based bistable enhancers regulating neuronal/synaptic activity. We propose that the
identified neuronal enhancers alternate between the “methylated” and “unmethylated” positions, and that
this provides, at any given time, a small (sparse) but sufficient population of neurons with specific
constellations of unmethylated and methylated switches that is eligible for allocation to code experiences.
The goal of this application is to test the role of the identified epigenetically bistable DNA sequences in
neuron allocation. We will 1) determine the allocation epigenetic code by sequencing the methylome of
allocated neurons, 2) test the functional link between bistable enhancers and neuron allocation, and 3)
assess if epigenetic malleability of enhancers contributes to environment-induced changes in cognitive
functioning. The premise of our model is that it provides, through epigenetic switching, a combinatorial-
molecular mechanism for the elusive process of neuron allocation and sparse/segregated population coding
of experiences. Furthermore, the sensitivity of DNA methylation based switches provides an opportunity
for their selective manipulation to improve neuron allocation and encoding in cognitive disorders.

## Key facts

- **NIH application ID:** 10191058
- **Project number:** 5R01NS106056-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Miklos Toth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,705
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191058

## Citation

> US National Institutes of Health, RePORTER application 10191058, DNA methylation based binary enhancers govern neuronal allocation to coding in the hippocampus (5R01NS106056-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10191058. Licensed CC0.

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