[Animal models of trauma and post-traumatic stress disorder]. / Les modèles animaux du traumatisme et du trouble de stress post-traumatique.

Initially believed to be specific to humans emerging from life-threatening events, Post-traumatic stress disorder (PTSD) has been found to occur in wild animals and can also be experimentally induced in laboratory rodents. This article aims to highlight and discuss the evolution and relevance of animal models in PTSD research. Studies by LeDoux, Davis, and McGaugh have made significant contributions to our understanding of PTSD. By focusing on fear responses in rodents and aversive Pavlovian conditioning, they suggested that PTSD could result from excessively efficient aversive learning processes, with a significant role played by amygdala. However, numerous studies have shown that this explanation fails to account for the complexity of processes involved in PTSD. Current hypotheses focus on deficits in extinction retention, perception of safety signals, or emotional regulation. This review will specifically address the animal models that closely resemble human PTSD and explore reasons for their limited utilization, as a majority of animal studies continues to employ classical Pavlovian conditioning protocols. Furthermore, this review will present cutting-edge experimental studies that tackle previously challenging questions in animal research. Specifically, we will examine the relationship between respiration and the maintenance of fear states, offering a potential explanation for the efficacy of meditation and breath control techniques in emotion regulation. We will also shed light on recent findings on decoding neural activity related to internal representations in animals, thus enabling now the exploration of rumination, a characteristic symptom of PTSD previously inaccessible to animal studies.

Title: Les modèles animaux du traumatisme et du trouble de stress post-traumatique. Abstract: Le trouble de stress post-traumatique (TSPT) est généralement associé à menace vitale et est parfois considéré comme une condition spécifiquement humaine. Cependant de nombreuses études ont montré qu'il pouvait être observé chez des animaux en milieu sauvage et pouvait être induit en laboratoire chez des rongeurs. Cet article vise à présenter et discuter l'évolution et la pertinence des modèles animaux dans l'étude du TSPT. Les études de LeDoux, Davis et McGaugh sur la peur et le conditionnement aversif pavlovien chez le rongeur ont apporté une immense contribution à la compréhension du TSPT. Initialement, il a été proposé que le TSPT résulterait d'un apprentissage aversif trop efficace, impliquant en particulier l'amygdale. Néanmoins, de nombreuses études ont révélé que cette hypothèse n'était pas suffisante pour expliquer la complexité des processus mis en jeu dans le TSPT. Les théories actuelles suggèrent plutôt des déficits dans la capacité à maintenir l'extinction, la perception des signaux de sécurité ou la régulation émotionnelle. Nous examinerons plus précisément les modèles animaux qui se rapprochent le plus du TSPT humain et nous discuterons des raisons pour lesquelles leur utilisation reste limitée. En effet, la plupart des études chez l'animal continuent de s'appuyer majoritairement sur des protocoles classiques de conditionnement pavlovien. Enfin, cette revue mettra en lumière de nouvelles études expérimentales permettant d'aborder des questions auparavant difficiles à étudier chez l'animal. Nous examinerons notamment les liens entre respiration et maintien des états de peur, offrant une explication potentielle à l'efficacité des techniques de méditation et de contrôle de la respiration dans la régulation des émotions. De plus, nous présenterons des résultats récents sur le décodage de l'activité neuronale liée aux représentations internes chez l'animal, offrant ainsi la possibilité d'étudier les ruminations, symptômes caractéristiques du TSPT qui étaient auparavant inaccessibles à l'expérimentation animale.

Zebrafish optineurin: genomic organization and transcription regulation.

Optineurin (OPTN) is involved in a variety of mechanisms, such as autophagy, vesicle trafficking, and nuclear factor kappa-B (NF-κB) signaling. Mutations in the OPTN gene have been associated with different pathologies, including glaucoma, amyotrophic lateral sclerosis, and Paget's disease of bone. Since the relationship between fish and mammalian OPTN is not well understood, the objective of the present work was to characterize the zebrafish optn gene and protein structure and to investigate its transcriptional regulation. Through a comparative in silico analysis, we observed that zebrafish optn presents genomic features similar to those of its human counterpart, including its neighboring genes and structure. A comparison of OPTN protein from different species revealed a high degree of conservation in its functional domains and three-dimensional structure. Furthermore, our in vitro transient-reporter analysis identified a functional promoter in the upstream region of the zebrafish optn gene, along with a region important for its transcription regulation. Site-directed mutagenesis revealed that the NF-κB motif is responsible for the activation of this region. In conclusion, with this study, we characterize zebrafish optn and our results indicate that zebrafish can be considered as an alternative model to study OPTN's biological role in bone-related diseases.

Free-fall landing and interval running have different effects on trabecular bone mass and microarchitecture, serum osteocalcin, biomechanical properties, SOST expression and on osteocyte-related characteristics.

The effects of treadmill interval training (IT) and free-fall exercise were evaluated on bone parameters including osteocyte related characteristics. Thirty-eight 4-month-old male Wistar rats were randomly divided into a control (C) group and exercise groups: IT, 10 free-fall impacts/day with a 10-s (FF10) or 20-s interval between drops (FF20), 5 days/week, for 9 weeks. We assessed bone mineral density (BMD); microarchitecture by µCT; mechanical strength by a 3-point bending test; density and occupancy of the osteocyte lacunae by toluidine blue staining; osteocalcin and NTx systemic levels by ELISA; and bone tissue Sost messenger RNA (mRNA) expression by RT-PCR. NTx levels were significantly lower in exercise groups as compared with the C group. In exercise groups the Sost mRNA expression was significantly lower than in C. Tb.N was significantly higher for IT and FF20 compared with the C group. Tb.Sp was significantly lower in FF10 compared with the C group. Both IT and FF20 were associated with higher tibial lacunar density as compared with FF10. compared with FF10, IT fat mass was lower, while tibial osteocyte lacunae occupancy and systemic osteocalcin level were higher. All exercise modes were efficient in reducing bone resorption. Both IT and free-fall impact with appropriate recovery periods, which may be beneficial for bone health and osteocyte-related characteristics. Novelty: Interval training is beneficial for bone mineral density. Exercises decreased both bone resorption and inhibition of bone formation (Sost mRNA). Longer interval recovery time favors osteocyte lacunae density.

ß-Cell compensation concomitant with adaptive endoplasmic reticulum stress and ß-cell neogenesis in a diet-induced type 2 diabetes model.

Insulin-secreting pancreatic ß-cells adapt to obesity-related insulin resistance via increases in insulin secretion and ß-cell mass. Failed ß-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of ß-cell compensation are not fully understood. Our previous study reported changes in ß-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other ß-cell adaptive responses, including glucose metabolism and ß-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of ß-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in ß-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative ß-cell growth as a mechanism of ß-cell mass adaptation. In contrast, decreased neogenesis and ß-cell dedifferentiation were observed in ß-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of ß-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for ß-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. ß-Cell neogenesis but not proliferation contributes to ß-cell mass adaptation.

Gene expression patterns indicate that a high-fat-high-carbohydrate diet causes mitochondrial dysfunction in fish.

Expensive and unsustainable fishmeal is increasingly being replaced with cheaper lipids and carbohydrates as sources of energy in aquaculture. Although it is known that the excess of lipids and carbohydrates has negative effects on nutrient utilization, growth, metabolic homeostasis, and health of fish, our current understanding of mechanisms behind these effects is limited. To improve the understanding of diet-induced metabolic disorders (both in fish and other vertebrates), we conducted an eight-week high-fat-high-carbohydrate diet feeding trial on blunt snout bream (Megalobrama amblycephala), and studied gene expression changes (transcriptome and qPCR) in the liver. Disproportionately large numbers of differentially expressed genes were associated with mitochondrial metabolism, neurodegenerative diseases (Alzheimer's, Huntington's, and Parkinson's), and functional categories indicative of liver dysfunction. A high-fat-high-carbohydrate diet may have caused mitochondrial dysfunction, and possibly downregulated the mitochondrial biogenesis in the liver. While the relationship between diet and neurodegenerative disorders is well-established in mammals, this is the first report of this connection in fish. We propose that fishes should be further explored as a potentially promising model to study the mechanisms of diet-associated neurodegenerative disorders in humans.

Adrenocortical development: Lessons from mouse models.

The adrenocortical gland undergoes structural and functional remodelling in the fetal and postnatal periods. After birth, the fetal zone of the gland undergoes rapid involution in favor of the definitive cortex, which reaches maturity with the emergence of the zona reticularis(zR) at the adrenarche. The mechanisms underlying the adrenarche, the process leading to pre-puberty elevation of plasma androgens in higher primates, remain unknown, largely due to lack of any experimental model. By following up fetal and definitive cortex cell lines in mice, we showed that activation of protein kinase A (PKA) signaling mainly impacts the adult cortex by stimulating centripetal regeneration, with differentiation and then conversion of the zona fasciculata into a functional zR. Animals developed Cushing syndrome associated with primary hyperaldosteronism, suggesting possible coexistence of these hypersecretions in certain patients. Remarkably, all of these traits were sex-dependent: testicular androgens promoted WNT signaling antagonism on PKA, slowing cortical renewal and delaying onset of Cushing syndrome and the establishment of the zR in male mice, this being corrected by orchidectomy. In conclusion, zR derives from centripetal conversion of the zona fasciculata under cellular renewal induced by PKA signaling, determining the size of the adult cortex. Finally, we demonstrated that this PKA-dependent mobilization of cortical progenitors is sexually dimorphic and could, if confirmed in humans, account for female preponderance in adrenocortical pathologies.

Intrauterine growth-restricted Yucatan miniature pigs experience early catch-up growth, leading to greater adiposity and impaired lipid metabolism as young adults.

Early nutrition has critical influences on cardiovascular disease risk in adulthood. The study objectives were to evaluate the impact of low birth weight on fasting and postprandial lipid metabolism and endothelium function in Yucatan miniature pigs. Intrauterine growth-restricted (IUGR) piglets (n = 6; 3 days old, 0.73 ± 0.04 kg) were paired with normal-weight (NW) same-sex littermates (n = 6; 1.11 ± 0.05 kg) and fed milk replacer ad libitum for 4 weeks. Thereafter, all pigs were fed a standard diet ad libitum for 5 h/day with growth, intakes, and blood samples collected for 8 months. At 9 months old, pigs were surgically fitted with venous catheters and an oral fat tolerance test was performed. At 10 months old, pigs were killed and endothelium-dependent and -independent vasodilations of isolated coronary arteries were measured using wire-myographs. IUGR pigs demonstrated catch-up growth (P < 0.05) in body weight and abdominal circumference prior to sexual maturity (<7 months old) and had more (P < 0.05) subcutaneous fat at 10 months old compared with NW pigs. IUGR pigs had consistently higher fasting plasma triglyceride concentrations from 5 to 10 months old and higher liver triglyceride and total cholesterol concentrations at 10 months old (P < 0.05). The fat tolerance test revealed delayed postprandial triglyceride clearance in IUGR pigs, but no differences in plaque formation or vascular reactivity. To conclude, IUGR and early postnatal catch-up growth are associated with increased overall body fat deposition and altered triglyceride metabolism in adult Yucatan miniature swine.

Combining two antifungal agents does not enhance survival of Galleria mellonella larvae infected with Madurella mycetomatis.

OBJECTIVE: To determine whether combination therapy would improve therapeutic outcome in eumycetoma caused by Madurella mycetomatis. METHODS: Survival, colony-forming units (CFU), melanisation and histopathology in M. mycetomatis-infected Galleria mellonella larvae treated with amphotericin B, itraconazole, terbinafine or combinations thereof were determined. RESULTS: Compared to larvae treated with 5% glucose, enhanced survival was obtained when M. mycetomatis-infected larvae were treated with amphotericin B, but not when they were treated with itraconazole or terbinafine. Combination therapy did not increase survival compared to 5% glucose-treated larvae, itraconazole-treated larvae or terbinafine-treated larvae. Compared to amphotericin B monotreatment, a significant decrease in survival was noted when this therapy was combined with either itraconazole or terbinafine. CFU, melanisation and histopathology did not differ between monotherapy, combination therapy or 5% glucose-treated larvae. CONCLUSIONS: Combining different classes of antifungal agents did not enhance the survival of M. mycetomatis-infected G. mellonella larvae. Instead of improving the therapeutic outcome, combining either itraconazole or terbinafine with amphotericin B resulted in significantly lower survival rates of infected larvae than amphotericin B monotherapy. This experimental study does not provide support for the use of combined amphotericin B and itraconazole, combined itraconazole and terbinafine or combined terbinafine and amphotericin B and should be confirmed in other animal models.

Sodium 4-phenylbutyrate reduces myofiber damage in a mouse model of Duchenne muscular dystrophy.

We performed a placebo-controlled pre-clinical study to determine if sodium 4-phenylbutyrate (4PB) can reduce contraction-induced myofiber damage in the mdx mouse model of Duchenne muscular dystrophy (DMD). At 72 h post-eccentric contractions, 4PB significantly increased contractile torque and reduced myofiber damage and macrophage infiltration. We conclude that 4PB, which is approved by Health Canada (Pheburane) and the United States Food and Drug Administration (Buphenyl) for urea cycle disorders, might modify disease severity in patients with DMD.

Effects of exercise and dietary epigallocatechin gallate and ß-alanine on skeletal muscle in aged mice.

Aging leads to sarcopenia and loss of physical function. We examined whether voluntary wheel running, when combined with dietary supplementation with (-)-epigallocatechin-3-gallate (EGCG) and ß-alanine (ß-ALA), could improve muscle function and alter gene expression in the gastrocnemius of aged mice. Seventeen-month-old BALB/cByJ mice were given access to a running wheel or remained sedentary for 41 days while receiving either AIN-93M (standard feed) or AIN-93M containing 1.5 mg·kg(-1) EGCG and 3.43 mg·kg(-1) ß-ALA. Mice underwent tests over 11 days from day 29 to day 39 of the study period, including muscle function testing (grip strength, treadmill exhaustive fatigue, rotarod). Following a rest day, mice were euthanized and gastrocnemii were collected for analysis of gene expression by quantitative PCR. Voluntary wheel running (VWR) improved rotarod and treadmill exhaustive fatigue performance and maintained grip strength in aged mice, while dietary intervention had no effect. VWR increased gastrocnemius expression of several genes, including those encoding interleukin-6 (Il6, p = 0.001), superoxide dismutase 1 (Sod1, p = 0.046), peroxisome proliferator-activated receptor gamma coactivator 1-α (Ppargc1a, p = 0.013), forkhead box protein O3 (Foxo3, p = 0.005), and brain-derived neurotrophic factor (Bdnf, p = 0.008), while reducing gastrocnemius levels of the lipid peroxidation marker 4-hydroxynonenal (p = 0.019). Dietary intervention alone increased gastrocnemius expression of Ppargc1a (p = 0.033) and genes encoding NAD-dependent protein deacetylase sirtuin-1 (Sirt1, p = 0.039), insulin-like growth factor I (Igf1, p = 0.003), and macrophage marker CD11b (Itgam, p = 0.016). Exercise and a diet containing ß-ALA and EGCG differentially regulated gene expression in the gastrocnemius of aged mice, while VWR but not dietary intervention improved muscle function. We found no synergistic effects between dietary intervention and VWR.

Modelos animais em psiquiatria: avanços e desafios / Animal models in psychiatry: Advances and challenges / Les modèles animaux en psychiatrie: progrès et défis / Los modelos animales en psiquiatría: avances y desafios

Objetivos: Discutir os avanços e limitações do uso dos modelos animais nos transtornos psiquiátricos. Método: Uma revisão narrativa de artigos. Resultados: Diferentes modelos animais atualmente demonstram validade adequada para características específicas de determinados transtornos mentais. Conclusão: Resguardadas as devidas limitações que impossibilitam mimetizar sintomas psicopatológicos complexos em modelos animais, estes seguem como úteis ferramentas de estudo na psiquiatria. .(AU)

Objectives: To discuss the advances and limitations of animal models in psychiatric disorders. Method: A narrative review of articles. Results: Different animal models currently demonstrate adequate validity for specific characteristics of certain mental disorders. Conclusion: Recognizing limitations that stay away from any mimicking of complex psychopathological symptoms in animal models, such models nonetheless represent useful tools in the study of psychiatry. .(AU)

Objectifs: Examiner les progrès et les limites des modèles animaux pour l'étude des troubles psychiatriques. Méthode: Révision narrative d'articles. Résultats: De différents modèles animaux possèdent actuellement une validité suffisante par rapport aux caractéristiques spécifiques de certains troubles mentaux. Conclusion: Malgré le fait des limites qui ne permettent pas de reproduire les symptômes psychopathologiques complexes dans les modèles animaux, ceux-ci restent néanmoins des outils utiles d'étude en psychiatrie. .(AU)

Objetivos: Discutir los avances y las limitaciones de los modelos animales en los trastornos psiquiátricos. Método: Una revisión narrativa de artículos. Resultados: Los diferentes modelos animales actualmente demuestran validez adecuada para las características específicas de determinados trastornos mentales. Conclusión: Guardadas las debidas limitaciones que imposibilitan mimetizar los síntomas psicopatológicos complejos en modelos animales, estes siguen siendo herramientas útiles en el estudio de la psiquiatría. .(AU)

Modelos animais em psiquiatria: avanços e desafios / Animal models in psychiatry: advances and challenges / Les modèles animaux en psychiatrie: progrès et défis / Los modelos animales en psiquiatría: avances y desafios

Objetivos: Discutir os avanços e limitações do uso dos modelos animais nos transtornos psiquiátricos. Método: Uma revisão narrativa de artigos. Resultados: Diferentes modelos animais atualmente demonstram validade adequada para características específicas de determinados transtornos mentais. Conclusão: Resguardadas as devidas limitações que impossibilitam mimetizar sintomas psicopatológicos complexos em modelos animais, estes seguem como úteis ferramentas de estudo na psiquiatria.

Objectives: To discuss the advances and limitations of animal models in psychiatric disorders. Method: A narrative review of articles. Results: Different animal models currently demonstrate adequate validity for specific characteristics of certain mental disorders. Conclusion: Recognizing limitations that stay away from any mimicking of complex psychopathological symptoms in animal models, such models nonetheless represent useful tools in the study of psychiatry.

Objectifs: Examiner les progrès et les limites des modèles animaux pour l'étude des troubles psychiatriques. Méthode: Révision narrative d'articles. Résultats: De différents modèles animaux possèdent actuellement une validité suffisante par rapport aux caractéristiques spécifiques de certains troubles mentaux. Conclusion: Malgré le fait des limites qui ne permettent pas de reproduire les symptômes psychopathologiques complexes dans les modèles animaux, ceux-ci restent néanmoins des outils utiles d'étude en psychiatrie.

Objetivos: Discutir los avances y las limitaciones de los modelos animales en los trastornos psiquiátricos. Método: Una revisión narrativa de artículos. Resultados: Los diferentes modelos animales actualmente demuestran validez adecuada para las características específicas de determinados trastornos mentales. Conclusión: Guardadas las debidas limitaciones que imposibilitan mimetizar los síntomas psicopatológicos complejos en modelos animales, estes siguen siendo herramientas útiles en el estudio de la psiquiatría.

Metabolic effects of glycerol supplementation and aerobic physical training on Wistar rats.

We evaluated the effects of oral glycerol supplementation on trained rats fed a normal diet. Wistar rats were distributed among 6 groups in a completely randomized 2 × 3 factorial design. The animals were subjected to 6 weeks of aerobic training. In the last 4 weeks, the animals' diet was supplemented with saline, glucose, or glycerol. Data were subjected to one-way analysis of variance (ANOVA) followed by a Student-Newmann-Keuls test, with values for P < 0.05 considered statistically significant. The change in body mass was lower in the trained groups, and their food and water consumption were higher. Glycerol supplementation resulted in an increase in the levels of triacylglycerol (TAG) and total cholesterol, as well as in the area and diameter of adipocytes. When associated with training, these parameters were similar to those of other trained groups. Levels of low-density lipoprotein + very-low-density lipoprotein cholesterol decreased in the trained animals that received glycerol compared with the non-trained ones. Glycerol consumption caused a reduction in food intake and increased the villous:crypt (V:C) ratio. No changes in glycemia, high density lipoproteins, or density of adipocytes were observed. Supplementation with glycerol together with aerobic physical training promoted beneficial metabolic effects. However, in non-trained rats glycerol increased the diameter and area of adipocytes, as well as the levels of TAG and total cholesterol.

[Pathophysiology of myopia: nature versus nurture]. / Physiopathologie de la myopie, entre hérédité et environnement.

Myopia is the most frequent refractive disorder in the world. It has become a real Public Health problem, due to its frequency and to high myopia-related blinding complications. Myopic progression depends on genetic and environmental factors. Genetic studies have identified more than forty candidate genes that take part in pathophysiological pathways, from retinal phototransduction to axial lengthening via scleral remodelling. Environmental factors also influence scleral remodelling by way of visual perception. In the case of predominant attention to near tasks, a physiological feedback loop leads to axial growth. This phenomenon, called active emmetropization, is particularly obvious in animal models and in some human populations. To date, research has failed to identify a molecule common to all the implicated metabolic pathways which could be a target for an effective preventive treatment against myopic progression.

Antimicrobial activity of Mentha piperita and Saturenja hortensis in a murine model of cutaneous protothecosis.

BACKGROUND: To date there is no defined pharmacologic treatment protocol available against cutaneous protothecosis, which is difficult to combat using conventional drugs. OBJECTIVES: Our experiment aimed to comparatively investigate the effect of two essential oils (Mentha piperita and Saturenja hortensis) against cutaneous protothecosis experimentally induced by Prototheca zopfii in mice. MATERIALS AND METHODS: Immunosuppressed BALB/c female mice, were divided into six experimental groups, infected with P. zopfii, and then treated for 21 days against the infection. The effectiveness of the different treatments was assessed clinically and histologically by quantifying the degree of inflammation (immunohistochemical quantification of macrophages, T lymphocytes and neutrophils) and fibrosis. RESULTS: Skin lesions in experimental protothecosis from non-treated mice were more severe as compared to the four groups of treated animals. Both M. piperita and S. hortensis have proved to be efficient in vivo in the treatment of cutaneous protothecosis by reducing the clinical signs and significantly reducing the degree of inflammation (P<0.05 for the number of macrophages, T lymphocytes and neutrophils) and fibrosis as compared to untreated animals. CONCLUSION: Interestingly, our study shows that M. piperita and S. hortensis could represent a potential source of natural antimicrobial products in the treatment of cutaneous protothecosis.

[Establishment of a keloid model by transplanting human keloid onto the backs of nude mice]. / Mise au point d'un modèle animal original de cicatrice chéloïde.

Keloid scar is a proliferative healing dysfunction formed by an excessive build-up of collagen fibers on the dermis. It is responsible of aesthetic and functional disabilities. There is no ideal treatment and recurrence occurs very often. Keloid scars occur only to human, that's why animal model needs to be made to study this pathology and new treatments. Few models have been described using human keloid scars implanted into subcutaneous tissue of nude mice or rat. To allow study of topical and laser treatment we have developed a new animal model using human keloid scar fragment with epidermal and dermal tissue implanted into back of nude mice like a full thickness skin graft. Keloid fragments from five donors have been grafted onto 40 nudes mice. Macroscopic and microscopic studies have been made at day 28, 56, 84 and 112. We observed integration of the fragments in all cases. Hyalinized collagen bundles were observed in all implant biopsies confirming the stability of the keloid architecture within 112 days. This model is easily reproducible and allows the study of topical treatment and laser due to the accessibility of the keloid.