Astrocyte neuronal metabolic coupling in the anterior cingulate cortex of mice with inflammatory pain
Bibliographic record
Abstract
• Female and male mice display similar pain hypersensitivity, but female mice show glutamatergic related changes before male mice. • Male mice show sustained increases in lactate levels and enhanced expression of proteins involved in ANLS in the ACC. • Disruption of ANLS in the ACC using antisense-mediated knockdown reduces pain hypersensitivity in female and male mice exposed to the CFA model. • Disruption of ANLS in the ACC reduces pain sensation in a temporary inflammatory pain model in male but not female mice. • A transgenic mouse model of spontaneous osteoarthritis (OA), shows sex-specific enhancement of ANLS in the ACC. Chronic pain is a major global concern, with at least 1 in 5 people suffering from chronic pain worldwide. Mounting evidence indicates that neuroplasticity of the anterior cingulate cortex (ACC) is a critical step in the development of chronic pain. Previously, we found that chronic pain and fear learning are both associated with enhanced neuronal excitability and cause similar neuroplasticity-related gene expression changes in the ACC of male mice. However, neuroplasticity, imposes large metabolic demands. In the brain, neurons have the highest energy needs and interact with astrocytes, which extract glucose from blood, mobilize glycogen, and release lactate in response to neuronal activity. Here, we use chronic and continuous inflammatory pain models in female and male mice to investigate the involvement of astrocyte-neuronal lactate shuttling (ANLS) in the ACC of female and male mice experiencing inflammatory pain. We found that ANLS in the mouse ACC promotes the development of chronic inflammatory pain, and expresses sex specific patterns of activation. Specifically, whereas both male and female mice show similar levels of chronic pain hypersensitivity, only male mice show sustained increases in lactate levels. Accordingly, chronic pain alters the expression levels of proteins involved in lactate metabolism and shuttling in a sexually dimorphic manner. We found that disrupting astrocyte-neuronal lactate shuttling in the ACC prior to inflammatory injury prevents the development of pain hypersensitivity in female and male mice, but only reduces temporary pain in male mice. Furthermore, using a transgenic mouse model (itga1-null mice) that displays a naturally occurring form of spontaneous osteoarthritis (OA), a painful inflammatory pain condition, we found that whereas both female and male mice develop OA, only male mice show increases in mechanisms involved in astrocyte-neuronal lactate shuttling. Our findings thus indicate that there are sex differences in astrocyte-neuronal metabolic coupling in the mouse ACC during chronic pain development.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".