SUN-240 Female Mice Lacking Brain Insulin Production Exhibit Learning Deficits, Anxiety, and Reduced Hippocampal Cyclin D1 Expression
Bibliographic record
Abstract
Abstract Insulin dysregulation independently underlies diabetes and Alzheimer’s Disease (AD) pathology. However, the former has also been shown to be a risk factor for the latter. The ancestral insulin gene (Ins2), but not the pancreas-specific Ins1gene, is transcribed locally within the brain in mice. We confirmed that neuronal expression of Ins2 is most prominent within the hippocampus, a brain region with established roles in learning and memory, and that it was reduced by a diet known to promote neuronal dysfunction. It is not yet clear, however, how insulin produced locally within the brain influences hippocampal function, learning and memory. To eliminate brain-derived insulin, we used young and old mice with germline Ins2knockout (Ins2-/-) and their normal complement of wildtype Ins1 alleles, which had equivalent pancreatic insulin and normal glucose homeostasis. Using the Morris water maze, we found that learning and memory performance of female Ins2-/-mice was significantly impaired relative to wild-type mice, whereas the performance of male Ins2-/-and wild-type mice did not differ. During acquisition training, the swim-speed in female Ins2-/-was faster than wild-type mice, suggesting increased stress reactivity and motivation to escape from water. Indeed, anxiety-like behavior was increased in female mice as assessed by the open-field test. Using RNA sequencing to profile isolated hippocampi, we found that femaleIns2-/-mice had a significant reduction in Cyclin D1 (Ccnd1) compared with littermate controls. This observation points to a possible defect in hippocampal neurogenesis, a physiological hallmark of impaired memory and emotionality implicated in both, diabetes and AD. Together these data suggest that Ins2plays sex- and brain region-specific roles in neuronal function and perhaps adult neurogenesis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".