8388 Insulin-Like Growth Factor-1 Modulates Arcuate Kisspeptin Neuron Activity
Bibliographic record
Abstract
Abstract Disclosure: J.N. Silva: None. R. Frazao: None. The kisspeptin-producing cells located at the arcuate nucleus of the hypothalamus (ARHKisspeptin) are considered the GnRH pulse generator necessary for fertility. In addition, ARHKisspeptin cells act as a metabolic sensor to control the hypothalamic-pituitary-gonadal (HPG) axis. The insulin-like growth factor-1 (IGF-1) is considered a component contributing to puberty onset and fertility. Peripherical or intracerebroventricular IGF-1 administration is sufficient to increase hypothalamic Kiss1 expression. However, whether IGF-1 acts directly on ARHKisspeptin cells to modulate the HPG axis is not known. To determine whether IGF-1 modulates ARHKisspeptin neuron activity, we used mice expressing the green fluorescent protein “humanized renilla” under the transcriptional control of the Kiss1 gene (8-10 weeks old). Fura-2 fluorescent probe was used to evaluate the state coupled or uncoupled to calcium in the face of IGF- 1 administration (0.5 μg/ml). Furthermore, whole-cell patch-clamp was employed to determine IGF-1 effects on ARHKisspeptin neuron's resting membrane potential (RMP). FURA-2 was incorporated by 64 ARHKisspeptin neurons out of 424 cells in the ARH. IGF-1 administration to the bath led to a significant increase of the intracellular calcium levels ([Ca2+]i) in 53% of ARHKisspeptin cells evaluated in male mice (34 out of 64 cells; IGF-1, 203.0 ± 26.1 nM; baseline period, 68.8 ± 9.6 nM; P< 0.0001). Non-responsive cells (30 out of 64 ARHKisspeptin neurons) exhibited average [Ca2+]i of 53.2 ± 6.3 nM after IGF-1 application vs 46.2 ± 5.6 nM in the baseline period (P= 0.3). Of note, IGF-1 also increased [Ca2+]i in 25% of non-kisspeptin cells in the ARH (93 out of 364 cells, IGF-1, 193.8 ± 12.4 nM; vs baseline period, 73.0 ± 5.6 nM, P< 0.0001). By evaluating the IGF-1 effects on ARHKisspeptin neuron’s RMP, we observed that IGF-1 tends to depolarize the RMP of 18% of cells recorded from males (4 out of 22 cells, IGF-1, -58.0 ± 3.0 mV; baseline, -64.1 ± 4.4 mV; P= 0.05), and depolarized the RMP of 44% of cells recorded from female mice (7 out of 16 cells, IGF-1, -61.1 ± 3.3 mV; baseline, -66.3 ± 2.7 mV; P= 0.002). Importantly, IGF-1-induced depolarization of ARHKisspeptin cells RMP was blocked when the recordings were performed in the presence of tetrodotoxin and ionotropic amino acid antagonists. Therefore, IGF-1-induced effects on ARHKisspeptin cells RMP depend on action potentials mediated by synaptic transmission. Our results suggest that IGF-1 indirectly modulates the activity of a large number of ARHKisspeptin neurons. Thus, situations of metabolic stress that induce changes in growth hormone secretion and, consequently, IGF-1 circulating levels, (e.g., fasting), can modulate the HPG axis through the indirect modulation of the activity of ARHKisspeptin cells. Presentation: 6/2/2024
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| 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".