460. DIETARY CUPRIZONE AND GESTATIONAL THC EXPOSURE BOTH INDUCE LOCALIZED DEPLETION OF BRAIN COPPER
Notice bibliographique
Résumé
Abstract Background Neurobehavioural abnormalities associated with neurodevelopmental disorders are associated with a complex interplay of genetic and environmental factors. Models of these conditions commonly involve early-life environmental insult, such as chemical or drug exposure, or inflammatory events. Additionally, demyelination pathology associated with psychiatric illnesses such as schizophrenia may be modelled with dietary cuprizone administration. Despite cuprizone toxicity as a common model of demyelination, its modes of action are not known, though copper deficiency is suggested to underlie the mechanism. In the case of THC, the effects of THC exposure on brain Cu levels during early life in rats is completely unknown, although early life THC exposure is reported to impact oligodendrocyte proliferation and maturation. Aims & Objectives Our aim was to directly visualise Cu distribution at micron spatial resolution with nM detection limits to determine if brain-copper levels are disturbed in two distinct models associated with neurobehavioural abnormalities. Method For the cuprizone experiments, C57BL/6 mice (male, 8-weeks age) were fed 0.2% w/w cuprizone-containing diet or control diet for 1, 3 or 6 weeks, or 6-weeks cuprizone plus 4-weeks control diet for remyelination (n=7/group). Brain tissue was collected at the end of the designated exposure period. For the gestational THC experiments, female Sprague-Dawley rats were bred in-house and administered daily THC (3mg/kg; n=5) or vehicle (1:1:18 Kolliphor, ethanol, saline; n=3) intraperitoneally from gestational day 6-20. Following natural parturition, offspring were left undisturbed with their mother until weaning at postnatal day 21. Offspring brain tissue collection occurred at adulthood, postnatal day >90 (n=5/group). For both experiments: Immediately following humane euthanasia, tissue was rapidly dissected and frozen in liquid nitrogen-cooled isopentane without perfusion or fixation. Cryosections were air-dried onto X-ray transparent substrate for elemental mapping with X-ray fluorescence microscopy (XFM) at ANSTO-Australian Synchrotron (cuprizone) or Canadian Light Source (THC). Results For the cuprizone experiments, 2-way ANOVA of myelin density (luxol fast blue) revealed pronounced cuprizone-induced demyelination in lateral corpus callosum, medial corpus callosum, lateral striatum white matter, and medial striatum white matter. One-way ANOVA revealed significant localised reduction in copper in lateral cortex dorsal to the corpus callosum, and striatum, but not medial regions. For the gestational THC experiments, unpaired two-tailed t-test revealed significantly reduced copper in the perimeter of the corpus callosum. Discussion & Conclusions This is the first-time brain-Cu has been directly visualised in the cuprizone demyelination model and in gestational THC exposure. Notably, both environmental insults resulted in localized brain-Cu deficiency at the perimeter of the corpus callosum. Brain-copper dysregulation may occur as a common pathological feature across diverse disease models. These findings may lead to new insights into glial biology, demyelinating diseases, and neurodevelopmental disorders.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».