Biology subjects

Gontijo, J. A. R.

Publications and source records attributed to Gontijo, J. A. R..

6 recordsLinked to original sources

bioRxiv2026

EARLY-LIFE STRESS INDUCES SEXUALLY DIMORPHIC BRAIN AGING VIA MESOLIMBIC ALTERATIONS AND FRONTO-STRIATAL DYSFUNCTION

Prenatal stress influences brain development; however, its long-term, region-specific effects on brain aging in males and females remain insufficiently characterized. This study examined the impact of unpredictable mild prenatal stress on behavior, cognition, and maternal care in C57BL/6J mice at middle (12 months) and old (18 months) ages. Stressed dams showed fragmented, unpredictable maternal behaviors, creating a stressful postnatal environment without impairing caregiving capacity. Both male and female offspring were born with lower birth weights and showed rapid postnatal growth, a trajectory associated with central insulin resistance and hippocampal signaling deficits. Sex-specific behavioral differences emerged with age. Middle-aged stressed males exhibited anhedonia, which progressed to hyperactivity, stereotypy, and persistent spatial memory deficits in old age. These outcomes corresponded with accelerated fronto-striatal decline, likely mediated by insulin resistance and increased rigidity of medial prefrontal cortex structures due to diminished local estrogenic activity. In contrast, middle-aged stressed females displayed hypoactivity and reduced anxiety, later developing anhedonia in old age while maintaining hippocampus-dependent memory. In females, this pattern supports a model in which a neuroestrogen - and growth factor-dependent feedback loop transiently preserves hippocampal plasticity but compromises dopaminergic function in reward circuits. This balance may deteriorate with reproductive senescence. Both sexes retained cognitive flexibility, indicating domain-specific rather than global cognitive impairment. These findings demonstrate that excessive prenatal glucocorticoid exposure and unpredictable postnatal care produce a combined hormonal and metabolic insult, resulting in sexually divergent trajectories of brain aging. The results underscore the necessity of incorporating sex as a biological variable in fetal programming research across the lifespan.

neuroscience↗

bioRxiv2024

Enriched environmental intervention mitigates hippocampal cellularity and behavioral disorders in maternal protein-restricted male rat offspring

BackgroundGestational protein intake restriction induces long-lasting harmful outcomes in the offsprings organs and systems. AimsThis study sought to evaluate the effects of protein restriction during pregnancy and breastfeeding in 42-day-old male offspring on the structure of the hippocampus, behavior tests related to memory and emotions, and the influence of an enriched environment on these parameters. Results and DiscussionThe current study demonstrated that maternal protein restriction during neural development causes crucial morphological changes in the hippocampus, making the LP offspring vulnerable to specific neural disorders in adulthood. In addition, it supports the selfish brain theory, a paradigm that postulates the brain maintains its mass selfishly by reallocating resources from other body parts when faced with nutritional stress. However, the hippocampus cellularity pattern was profoundly altered, significantly reducing the number of neurons after the breastfeeding period. This may expand the understanding of nutritional stress affecting the brain areas constitution and its supposed effects on posterior behavioral disorders. Here, reciprocal data was observed between brain masses, changes in the hippocampus cell pattern, and decreased body mass in the LP progeny. In conclusion it was demonstrated that neuronal composition and structure profoundly modified by dietary restriction are surprisingly restored from primordial cells by exposure to the enriched environment. In addition, we must emphasize that although we have observed a significant reduction in the number of neurons after gestational and breastfeeding periods, we demonstrated for the first time a substantial reduction in the fear-reflecting behavior, which an enriched environment exposure may revert. The enriched environment also significantly modified the discrimination ratio, increasing the ability of both progenies to discriminate between novel and familiar objects in a short time associated with reverse abnormal hippocampus cell patterns. These findings underscore the potential for environmental interventions to mitigate the effects of early=life nutritional stress on brain development and behavior.

animal behavior and cognition↗

bioRxiv2022

Impact of maternal protein restriction on hypoxia-inducible factor (HIF) expression in male fetal kidney development

BackgroundThe kidney ontogenesis is the most structurally affected by gestational protein restriction, reducing close to 30% of their functional units. The reduced nephron number is predictive of hypertension and cardiovascular dysfunctions generally observed in the adult age of most fetal programming models. We demonstrate HIF-1 predicts molecular pathway changes may be associated with the decreased nephron numbers in the 17 gestational days (17GD) low protein (LP) intake male fetal kidney compared to regular protein (NP) progeny intake. Here, we evaluated the predicted targets and related pathways in the fetal kidneys of 17-GD LP offspring to elucidate the molecular modulations during nephrogenesis. MethodsPregnant Wistar rats were allocated into two groups: NP (regular protein diet -17%) or LP (diet-6%). Taking into account miRNA transcriptome sequencing previous study (miRNA-Seq) in 17-GD male offspring kidneys using previously described methods, was investigated predicted target genes and proteins, in particular, related to HIF-1 pathway by RT-qPCR and immunohistochemistry. Results and conclusionsThe current study data supported that nephron onset impairment in the 17-DG fetuss kidney, programmed by gestational low-protein intake, is, at least in part, related to alterations in the HIF-1 signaling pathway. Factors that facilitate the transposition of HIF-1 to the mesenchymal cells nucleus, such as NOS, Ep300, and HSP90, may have an essential role in this regulatory process. This alteration leads to the inhibition of adaptive responses to the adverse environment, secondary to an increase in ungraded HIF-1, possibly associated with a reduction in the transcription factor elF-4 and proteins of their respective signaling pathways. Consequently, we may suggest an early maturation process of renal cells, inhibition of nephron progenitor cell division, and reduction of renal functional units in the offspring of rats submitted to severe gestational protein restriction.

developmental biology↗

bioRxiv2021

Precocious hippocampal structural and functional changes in gestational protein-restricted male elderly offspring: an Alzheimer-simile disease model?

BackgroundMaternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment. Considering the lack of evidence for this, we aimed to analyze the effects of gestational protein restriction on learning and memory function later in life. This research associates behavioral findings with hippocampal cell numbers and protein content related to neurodegenerative brain disease. MethodsExperiments were conducted in animals subjected to a low-protein (LP, 6% casein) or regular-protein (NP, 17% casein) diet throughout their pregnancy. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime tests were performed. The results confirmed that the birthweight of LP male pups significantly reduced relative to NP male pups and that hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. We used the Morris water maze proximity measure, which is the sum of 10 distances each second between rat position and location of a hidden platform target, as a suitable test for assessing age-related learning or memory impairment in aged offspring. ResultsThe results showed an increased proximity measure in 87-week-old LP rats (52.6 x 104 {+/-} 10.3 x 104 mm) as compared to NP rats (47.0 x 104 {+/-} 10.6 x 103 mm, p = 0.0007). In addition, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86 weeks of life. Additionally, the estimated neuron number was unaltered in LP rats; however, glial and other cell numbers increased in LP compared to NP rats. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, {beta}-amyloid peptide (A{beta}), and tau protein in 88-week-old LP compared to age-matched NP offspring. To date, no predicted studies showed changes in hippocampal neuron and glial cell numbers in maternal protein-restricted elderly offspring. The current data suggest that maternal protein restriction has a high impact on lifespan and brain structure, and function. Conclusionthe gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimers disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be a probable, elegant, and novel method for constructing an AD-like model in adult male offspring.

developmental biology↗

bioRxiv2018

miRNAs, target genes expression and morphological analysis on the heart in gestational protein-restricted offspring

BACKGROUNDGestational protein restriction was associated with low birth weight, hypertension and higher prevalence of cardiac disorders in adults. Several mechanisms, including epigenetics, could be related with the cardiovascular phenotype on protein-restricted offspring. Thus, we investigated the morphological cardiac effects of gestational protein restriction and left ventricle miRNAs and target genes expression pattern in both 12-day and 16-week old gestational protein-restricted male offspring.\n\nMETHODSPregnant Wistar rats were allocated into two groups, according to protein supply during pregnancy: NP (normal protein diet-17%) or LP (low protein diet - 6%). The study evaluates the effects of maternal protein restriction on food consumption and body weight of both pregnant dams and offspring, systolic blood pressure in 16-wk old offspring and on cardiac morphometric and molecular parameters in both 12-d and 16-wk old offspring.\n\nRESULTSDams on the gestational protein-restricted diet had lower body weight gain and higher food intake. Gestational protein-restricted offspring had low birth weight, followed by rapidly body weight recovery, hypertension, and increased myocytes crosssectional area and collagen fraction at 16-week old age. At 12-days old, miR-184, miR-192, miR-376c, miR-380-3p, miR-380-5p, miR-451, and miR-582-3p had increased expression, and miR-547 and miR-743 a had decreased expression in the gestational protein-restricted left ventricle. At 16-week old, let-7b, miR-125a-3p, miR-142-3p, miR-182 and miR-188-5p had increased expression and let-7g, miR-107, miR-127, miR-181a, miR-181c, miR-184, miR-324-5p, miR-383, miR-423-5p and miR-484 had decreased expression in gestational protein-restricted left ventricle. Target predicted gene expression analysis shown higher expression of Dnmt3a, Oxct1, Rictor and Trps1 and lower expression of Bbs1 and Calml3 in 12-day old protein-restricted offspring. 16-week old protein-restricted offspring had higher expression of Adrbk1, Bbs1, Dnmt3a, Gpr22, Inppl1, and Oxct1 genes.\n\nCONCLUSIONGestational protein restriction leads to offspring low birth weight, increased systolic blood pressure and morphological heart alterations that could be related to early heart miRNA expression changes that perpetuate into adulthood and which are associated with the regulation of essential genes involved in cardiovascular development, heart morphology, function, and metabolism.

developmental biology↗

bioRxiv2017

Gestational low-protein intake enhances the whole kidney miR-192 and miR-200 family expression and epithelial-to-mesenchymal transition in adult male offspring

BackgroundStudies have been showed that maternal protein-restricted adult offspring, present pronounced reduction of nephron number associated with decreased fractional urinary sodium excretion and arterial hypertension. Also, recent advances in our understanding of the molecular pathways that govern the association of gestational nutritional restriction, intrauterine growth retardation inflammation with impaired nephrogenesis, nephron underdosing and kidney fibrosis point to the epithelial to mesenchymal transition (EMT) as the common.\n\nMethodIn the current study, the protein and sodium urinary excretion rates were evaluated and immunohistochemistry and western blot techniques were used to characterize the whole kidney structure changes in 16-wk old male LP offspring compared with age-matched controls. We also verify the expression of miRNAs, mRNAs and proteins markers of fibrosis and epithelial-to-mesenchymal transition in entire kidney prepared from LP offspring.\n\nResultsIn the current study, we may assume that arterial hypertension and long-term hyperfiltration process manifests, itself by proteinuria was accompanied by increased whole kidney mRNA expression of TGF-{beta}1, ZEB1, type I collagen and, fibronectin in parallel to decreased expression of E-cadherin in 16-wk old LP offspring. Surprisingly, the renal tissue miR-129, miR-141, miR-200c and miR-429 were significantly upregulated in LP offspring compared to age-matched NP rats.\n\nConclusionConsidering that the overload in remaining nephrons, we may state that hypertension and proteinuria development following maternal protein restriction, may be a preponderant factor for the development of EMT and fibrous process and altered kidney ultrastructure in rat offspring. However, further studies are required to assess the contribution of miRNAs on renal injury progression in gestational protein-restricted model of fetal programming.

developmental biology↗