Omics · study · 2026
One-Carbon Cycle and Methylation Potential Regulat Behavioral Alcohol Responses via Glutamatergic Neurons
Listed in NCBI GEO
Despite the enormous harms of alcohol use disorder (AUD), many mechanisms, as well as effective prevention or treatment strategies, remain elusive.
Description
Genetic factors dictate much of AUD risk, which can manifest as increased naïve resistance to alcohol’s intoxicating effects or increased functional tolerance, i.e., brain-mediated increases in resistance upon repeat exposure. The underlying neurobiology of how AUD-associated genes alter these endophenotypes remains poorly understood.
Genes implicated in AUDs include ones encoding epigenetic modifiers, such as histone demethylase Kdm3. We previously showed that whole-body and neuronal loss of Kdm3 affect ethanol resistance and tolerance in Drosophila. Here, we investigate the mechanisms of these effects.
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RNA-seq and pathway analysis on Kdm3KO flies revealed disproportionate upregulation of genes involved in amino acid metabolism, including the 1-carbon pathway. We show that acute amino acid feeding modulates behavioral alcohol responses in a Kdm3-dependent manner. Global manipulation of 1-carbon genes also alters alcohol responses.
These phenotypic changes are likely mediated by glycine levels (a substrate of these enzymes) rather than by 1-carbon input. Conversely, neuron-specific manipulations of the methionine cycle change alcohol responses in a pattern that suggests a mechanism via S-adenosyl methionine (SAM), a 1-carbon metabolite that is the universal methyl donor required for epigenetic methylation. Increasing SAM production specifically in glutamatergic neurons decreases alcohol resistance and increases tolerance.
Together, these findings reveal distinct mechanisms affecting alcohol responses globally (via glycine) versus neuronally (via SAM), thus revealing a complex but important role of neuronal 1-carbon metabolism in mediating behavior.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331104 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331104 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1466906 ncbi.nlm.nih.gov/bioproject/PRJNA1466906 ↗
project · from NCBI GEO
Topics
- Stated by source
- Drosophila melanogaster · Expression profiling by high throughput sequencing
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 65%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE331104 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:7227 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |