Perinatal Insults Research Articles

Animal Model of Autism Induced by Valproic Acid Combined with Maternal Deprivation: Sex-Specific Effects on Inflammation and Oxidative Stress.

Autism spectrum disorder (ASD) etiology probably involves a complex interplay of both genetic and environmental risk factors, which includes pre- and perinatal exposure to environmental stressors. Thus, this study evaluated the effects of prenatal exposure to valproic acid (VPA) combined with maternal deprivation (MD) on behavior, oxidative stress parameters, and inflammatory state at a central and systemic level in male and female rats. Pregnant Wistar rats were exposed to VPA during gestation, and the offspring were submitted to MD. Offspring were tested for locomotor and social behavior; rats were euthanized, where the cerebellum, posterior cortex, prefrontal cortex, and peripheric blood were collected for oxidative stress and inflammatory analysis. It was observed that young rats (25-30days old) exposed only to VPA presented a lower social approach when compared to the control group. VPA + MD rats did not present the same deficit. Female rats exposed to VPA + MD presented oxidative stress in all brain areas analyzed. Male rats in the VPA and VPA + MD groups presented oxidative stress only in the cerebellum. Regarding inflammatory parameters, male rats exposed only to MD exhibited an increase in pro-inflammatory cytokines in the blood and in the cortex total. The same was observed in females exposed only to VPA. Animals exposed to VPA + MD showed no alterations in the cytokines analyzed. In summary, gestational (VPA) and perinatal (MD) insults can affect molecular mechanisms such as oxidative stress and inflammation differently depending on the sex and brain area analyzed. Combined exposition to VPA and MD triggers oxidative stress especially in female brains without evoking an inflammatory response.

Wada Demonstrates Ipsilateral Language Function in Dyke-Davidoff-Masson Syndrome

AbstractDyke-Davidoff-Masson syndrome (DDMS) is usually described secondary to prenatal or perinatal insult and is characterized by seizures, cerebral hemiatrophy, hemiparesis/facial asymmetry, and learning disability. We report an adolescent-onset case who presented with drug-refractory seizures and was considered for hemispherotomy on the dominant side. This is the first case report of DDMS where Wada helped in lateralizing the language to the ipsilateral dominant hemisphere despite the atrophy of the left inferior frontal gyrus. Thus, Wada is recommended in all patients without language regression who are considered for dominant hemispherotomy.

A Cross-Sectional Study Examining the Relationship Between Malnutrition and Gross Motor Function in Cerebral Palsy.

Introduction Cerebral palsy (CP) characterizes a range of permanent, nonprogressive symptoms of postural and motor dysfunction caused by an insult to the developing central nervous system in a fetus or an infant. CP manifests early in life, often within the first two to three years of age. CP is associated with poor growth, that is the deviation from the normal growth parameters. The prevalence of CP ranges from 2.0 to 3.5 per 1000 live births in high-income countries which is comparable to the estimates from low-income countries. Antenatal and perinatal insults are among the most commonly reported causes of CP; however, a large number of cases do not have an identifiable etiology of CP. The current study aims to examine the relationship between malnutrition and gross motor function in children with CP. Materials and Methods This study was conducted at the Department of Pediatrics and Neonatology, Nehru Hospital, Baba Raghav Das (BRD) Medical College, Gorakhpur (UP) over a period of one year (August 2020 to July 2021) after obtaining ethical clearance from the College Research Council. Children of age 1-15 years with CPattending the pediatric outpatient and inpatient departmentswere enrolled as the study participants after obtaining informed consent from a legal guardian. Assessment of motor function was done using the gross motor function classification system (GMFCS). Associations of malnutrition across levels of gross motor function were tested using Chi-square or Fisher's exact test whichever was applicable. Statistical significance was set at p< 0.05 as significant. Data was analyzed using IBM SPSS Statistics for Windows, Version 21 (Released 2012; IBM Corp., Armonk, New York, United States). Result We analyzed 110 children with a diagnosis of CP (median age 6.5 years, interquartile range (IQR) 4.4-9.0 years). The majority (65/110; 59%) of the patients were male, and 68 (61.8%) delivered at term gestation. The most common presenting symptom among children with CP was seizures (79/110; 72.3%), the second most common being delayed milestones among 73 (66.8%), followed by difficulty in breathing among 63 (57.5%). The association between the anthropometric index of participants and GMFCS was found to be highly significant. Conclusion Most CP patients were facing gross motor disturbances. Spastic type of CP was most frequent, and more than half of the patients experienced feeding difficulty. A statistically significant association was found between gross motor functioning and the prevalence of malnutrition and stunting.

Cold-inducible RNA binding protein alleviates iron overload-induced neural ferroptosis under perinatal hypoxia insult

Cold-inducible RNA binding protein (CIRBP), a stress response protein, protects cells from mild hypothermia or hypoxia by stabilizing specific mRNAs and promoting their translation. Neurons subjected to hypobaric hypoxia insult trigger various cell death programs. One of these is ferroptosis, a novel non-apoptotic form of programmed cell death, which is characterized by excessive iron ion accumulation and lipid peroxidation. Here, we establish that CIRBP can regulate neuronal ferroptosis both in vivo and in vitro. We observe that hypoxia leads to neuronal death via intracellular ferrous iron overload and impaired antioxidant systems, accompanied by suppressed CIRBP expression. Genetic enrichment of CIRBP in hippocampal neurons CIRBPTg mice bred with Emx1-Cre mice attenuates hypoxia-induced cognitive deficits and neuronal degeneration. Mechanistically, CIRBP alleviates neuronal ferroptosis and intracellular ferrous ion accumulation by binding to the mitochondrial ferritin (FTMT) 3’UTR to stabilize mRNA and promote its translation. Our novel study shows the critical role of CIRBP in the progression of ferroptosis, and provides promising therapeutic target for hypoxia-induced neurological diseases.

Elevated blood pressure among children born to women with obstructed labour in Eastern Uganda: a cohort study

BackgroundGlobally, high systolic blood pressure accounts for 10.8 million deaths annually. The deaths are disproportionately higher among black people. The reasons for this disparity are poorly understood, but could include a high burden of perinatal insults such as birth asphyxia. Therefore, we aimed to assess the incidence of elevated blood pressure and to explore associated factors among children born to women with obstructed labour.MethodsWe followed up children born to women with obstructed labour aged 25 to 44 months at Mbale regional referral hospital that had participated in the sodium bicarbonate trial ( Trial registration number PACTR201805003364421) between October 2021 and April 2022. Our primary outcome was elevated blood pressure defined as blood pressure (either systolic or diastolic or both) ≥ the 90th percentile for age, height, and sex in the reference population based on the clinical practice guideline for screening and management of high blood pressure in children and adolescents. We used logistic regression to estimate odds ratios between selected exposures and elevated blood pressure.ResultsThe incidence of elevated blood pressure was (39/140, 27.9%: 95% (CI: 20.6–36.1)). Participants aged three years and above had twice the odds of elevated blood pressure as those aged less than three years (Adjusted odds ratio (AOR) 2.46: 95% CI (1.01–5.97). Female participants had 2.81 times the odds of elevated blood pressure as their male counterparts (AOR 2.81 95% CI (1.16–6.82). Participants with reduced estimated glomerular filtration rate had 2.85 times the odds of having elevated blood pressure as those with normal estimated glomerular filtration rate (AOR 2.85 95% CI (1.00–8.13). We found no association between arterial cord lactate, stunting, wealth index, exclusive breastfeeding, food diversity and elevated blood pressure.ConclusionOur findings show a high incidence of elevated blood pressure among children. We encourage routine checking for elevated blood pressure in the pediatric population particularly those with known risk factors.

Role of Microglial Modulation in Therapies for Perinatal Brain Injuries Leading to Neurodevelopmental Disorders.

Neurodevelopmental disorders (NDDs) encompass various conditions stemming from changes during brain development, typically diagnosed early in life. Examples include autism spectrum disorder, intellectual disability, cerebral palsy, seizures, dyslexia, and attention deficit hyperactivity disorder. Many NDDs are linked to perinatal events like infections, oxygen disturbances, or insults in combination. This chapter outlines the causes and effects of perinatal brain injury as they relate to microglia, along with efforts to prevent or treat such damage. We primarily discuss therapies targeting microglia modulation, focusing on those either clinically used or in advanced development, often tested in large animal models such as sheep, non-human primates, and piglets-standard translational models in perinatal medicine. Additionally, it touches on experimental studies showcasing advancements in the field.

Clinicoradiological Profile of Incomplete Hippocampal Inversion Diagnosed on MR Neuroimaging.

Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy subjects. IHI has also been reported with malformations of cortical development (MCDs) and corpus callosal agenesis that have association with neuropsychiatric disorders such as autism spectrum disorder (ASD). This study aims to describe the clinical profile of magnetic resonance imaging (MRI)-diagnosed IHI. We studied patients with IHI who were identified after a retrospective review of the MRI archives of the past 3 years. The MRI findings of partial and total IHI were included. The clinical profiles associated with IHI were classified into epilepsy and non-epilepsy categories. A retrospective review of MRI done over 3 years revealed 54 cases of IHI (32 left-sided, 20 bilateral, and 2 isolated right-sided), and out of 74 IHI, 59 were of total type and 15 partial. Thirty-six subjects (61.1%) had epilepsy (9 with neurodevelopmental problems), 17 subjects (31.5%) had ASD, and 4 subjects (7.4%) had only neurodevelopmental disorders. MCDs were seen in 7 (12.9%): polymicrogyria (4), periventricular heterotopia (2), and pachygyria (1). Hippocampal volume loss was seen in 10, and contralateral mesial temporal sclerosis was seen in 2 patients. Hippocampal inversion has been reported in MRI scans of patients with epilepsy, ASD, MCDs, and many other related disorders. Further studies are required to know its occurrence among patients who get MRI scans due to many other disorders such as headaches, psychiatric disorders, minor hear trauma, and perinatal insults. If possible, studies among normal populations also need to be done.

Chronic traumatic encephalopathy-neuropathologic change in a routine neuropathology service: 7-year follow-up.

To follow our 2016 study of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in our forensic autopsy service, we prospectively screened all cases with clinical histories of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries from 2016 to 2022 inclusive using hyperphosphorylated tau (p-tau) immunostaining. The cases had routine brain sampling plus 4-6 additional lateral hemisphere samples. When "pathognomonic" CTE-NC lesions were identified, additional p-tau immunostaining was done for CTE-NC staging. Of ∼1100 adult brains aged 18-65 years examined, 85 were screened, and 16 were positive for CTE-NC (2 women, 14 men, ages 35-61 years, median 47 years). Alcohol abuse was documented in 14 of 16 (8 in combination with other substances); 5 had developmental brain anomalies (2 presumed genetic, 3 from acquired perinatal insults). Widespread p-tau deposits (high CTE-NC) were found in 7 of 16. Old brain contusions were present in 9 of 16, but CTE-NC did not colocalize. Of particular interest were (1) a man with FGFR3 mutation/hypochondroplasia and life-long head banging, (2) a woman with cerebral palsy and life-long head banging, and (3) a man with bilateral peri-Sylvian polymicrogyria, alcohol abuse, and multiple head injuries. Thus, CTE-NC occurs in association with repeated head trauma outside contact sports. Substance abuse is a common determinant of risk behavior. The utility of diagnosing mild-/low-stage CTE-NC in this population remains to be determined.

Cerebral visual impairment and effect of phase-wise stimulation strategies-An interim analysis.

Cerebral visual impairment (CVI) is an overarching term, defined as a brain-based visual impairment with onset in childhood, unexplained by an ocular disorder and associated with unique visual and behavioral characteristics. Good vision and awareness of visual function in a child are highly essential as neuroplasticity is maximum in the first three years of life and response to intervention is utmost in this period. Awareness is lacking regarding CVI, and the diagnosis is largely missed. This can be easily addressed if a structured approach is employed. This study aims to evaluate the etiology and radiological correlation with the severity of CVI and outcome after structured intervention in children with CVI. Prospective-interventional study. Children attending the Child Development Centre (CDC) of a tertiary care hospital in North Karnataka and diagnosed with CVI in the age group of six months to 12 years and meeting the sampling criteria were screened and enrolled consecutively after obtaining parental consent/assent. Statistical analysis used is nonparametric test with SPSS software. Age showed a significant association with the phase of CVI. Perinatal insult was associated significantly with the severity of CVI. Magnetic resonance imaging (MRI) findings did not hamper the recovery of CVI. Enrolment in early intervention programs tailored according to child's specific needs should be encouraged, with stress on ophthalmic screening of preterm and high-risk babies with perinatal hypoxia and history of convulsions, as early as six months.

Preterm infant retinal OCT markers of perinatal health and retinopathy of prematurity.

The increasing survival of preterm infants has led to the importance of improving long-term outcomes associated with preterm birth. Antenatal and perinatal insults not only impact mortality, but also long-term disability. While in the intensive care nursery, preterm infants are also exposed to various stressors that lead to long-term cognitive deficits. It is therefore critical to identify early, low-stress, non-invasive biomarkers for preterm infant health. Optical coherence tomography (OCT) is a powerful imaging modality that has recently been adapted to the infant population and provides noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside with low stress relative to conventional examination. In this review we delve into discussing the associations between preterm systemic health factors and OCT-based retinal findings and their potential contribution to the development of non-invasive biomarkers for infant health and for retinopathy of prematurity (ROP).

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease.

Chronic airway diseases, such as wheezing and asthma, remain significant sources of morbidity and mortality in the pediatric population. This is especially true for preterm infants who are impacted both by immature pulmonary development as well as disproportionate exposure to perinatal insults that may increase the risk of developing airway disease. Chronic pediatric airway disease is characterized by alterations in airway structure (remodeling) and function (increased airway hyperresponsiveness), similar to adult asthma. One of the most common perinatal risk factors for development of airway disease is respiratory support in the form of supplemental oxygen, mechanical ventilation, and/or CPAP. While clinical practice currently seeks to minimize oxygen exposure to decrease the risk of bronchopulmonary dysplasia (BPD), there is mounting evidence that lower levels of oxygen may carry risk for development of chronic airway, rather than alveolar disease. In addition, stretch exposure due to mechanical ventilation or CPAP may also play a role in development of chronic airway disease. Here, we summarize the current knowledge of the impact of perinatal oxygen and mechanical respiratory support on the development of chronic pediatric lung disease, with particular focus on pediatric airway disease. We further highlight mechanisms that could be explored as potential targets for novel therapies in the pediatric population.

Early changes in cerebral metabolism after perinatal hypoxia-ischemia: a study in normothermic and hypothermic piglets.

Hypoxic ischemic encephalopathy (HIE) after a perinatal insult is a dynamic process that evolves over time. Therapeutic hypothermia (TH) is standard treatment for severe to moderate HIE. There is a lack of evidence on the temporal change and interrelation of the underlying mechanisms that constitute HIE under normal and hypothermic conditions. We aimed to describe early changes in intracerebral metabolism after a hypoxic-ischemic insult in piglets treated with and without TH and in controls. Three devices were installed into the left hemisphere of 24 piglets: a probe measuring intracranial pressure, a probe measuring blood flow and oxygen tension, and a microdialysis catheter measuring lactate, glucose, glycerol, and pyruvate. After a standardized hypoxic ischemic insult, the piglets were randomized to either TH or normothermia. Glycerol, a marker of cell lysis, increased immediately after the insult in both groups. There was a secondary increase in glycerol in normothermic piglets but not in piglets treated with TH. Intracerebral pressure, blood flow, oxygen tension, and extracellular lactate remained stable during the secondary increase in glycerol. This exploratory study depicted the development of the pathophysiological mechanisms in the hours following a perinatal hypoxic-ischemic insult with and without TH and controls.

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors.

With the umbrella term 'neurodevelopmental disorders' (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions.

Profile of cerebral visual impairment in children less than 7 years – A prospective observational study

To study the incidence of cerebral visual impairment among children with history of perinatal neurological insult and congenital brain anomalies and to analyze the outcome following visual intervention programme. A prospective interventional study, examining 100 children less than 7 years over a period of 1 year. All children with history of perinatal hypoxia, neonatal hypoglycemia, neonatal seizures, infantile spasm, epilepsy, congenital hydrocephalus, congenital brain anomalies, CNS infections, traumatic brain injury and post cardiac surgery, excluding children with ocular visual impairment. Of the 100 children studied, the incidence of CVI was 87%. The associated ocular problems were found to be low visual acuity seen in 85%, strabismus in 25%, refractive error in 39%, Nystagmus in 21% and oculomotor apraxia in 6%. The most common etiology was hypoxic ischemic encephalopathy, contributing to 30% of the cases and most common MRI findings were periventricular leukomalacia, seen in 42%. CVI Range was used for functional visual assessment. Visual intervention rather than visual stimulation was taught to the primary care giver and children were followed up every 3 months. 26% of children had improved in their functional vision after 6 months of Individualized intervention. Early identification and individualized visual intervention, integrating them into many activities of the child across the whole day, form a crucial part of the visual outcome. Improvement in vision creates access to a world of cognitive and motor development.

Hereditary Spastic Paraparesis presenting as a Cerebral Palsy Mimic via Telemedicine (P13-9.009)

<h3>Objective:</h3> N/A <h3>Background:</h3> Cerebral palsy (CP) manifests after a perinatal injury, but symptoms can progress with age. A family history of CP phenotype or early progression should alert the clinician to potential CP mimics like the hereditary spastic paraplegias (HSPs), a heterogeneous group of conditions with representatives of all modes of genetic inheritance. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> The patient was born at full term with no perinatal complications. He had delayed motor development, beginning to walk at 2 years of age, and had learning disability requiring modified classes in school. Gait difficulties became apparent in adolescence, progressing to being wheelchair bound in adulthood. He presented to our clinic at age 48 carrying a diagnosis of CP, with bilateral leg spasticity and urinary urgency/incontinence. On camera, he was sitting with leg contractures and dependent edema. No associated oculomotor, facial, or arm weakness, no ataxia or tremor, and no speech or vision abnormalities were detected. Neither of his parents or his nine siblings (7 sisters and 2 brothers) had similar symptoms. He did report having a maternal uncle and nephew with a similar phenotype. MRI brain and thoracic spine were obtained but were unremarkable. Adrenomyeloneuropathy (AMN) was considered but laboratory and genetic testing were not revealing. A genetic panel for hereditary spastic paraplegias was ordered, detecting a pathogenic heterozygous variant, SPAST c.1496G&gt;A (p.Arg499His), causative for SPG4. <h3>Conclusions:</h3> This case highlights the incomplete penetrance of SPG4 and supports the concept of female carriers of SPG4 being less penetrant, as none of his 7 sisters had clinical symptoms. When the presented history and exam are not consistent with a diagnosis of CP, the clinician should search for potential mimics. Inconsistencies include lack of history of perinatal insult, onset of symptoms outside of the perinatal period, and progressive symptoms. In particular, treatable CP mimics, such as adrenomyeloneuropathy, cannot be missed. <b>Disclosure:</b> Dr. Del Papa has nothing to disclose. Dr. Flores-Gonzalez has nothing to disclose. Dr. Margolesky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion . The institution of Dr. Margolesky has received research support from NeuroNext.

Teaching NeuroImages: Ohtahara Syndrome due to Unilateral Perisylvian Polymicrogyria

A 10-month-old boy, born of nonconsanguineous parents, without any perinatal insult, presented with tonic spasms from the 13th day of life. He started having tonic seizures from 4 months of age, with global developmental delay. On examination, there were no neurocutaneous markers, facial dysmorphism, or focal neurologic deficits. EEG (figure) showed generalized and multifocal epileptiform discharges along with burst-suppression pattern. MRI of brain revealed left perisylvian polymicrogyria (figure).

Clinical, radiological and electrophysiological predictors for drug-resistant epilepsy

BackgroundEpilepsy is the third chronic brain illness worldwide. About a third of the epileptic patients will be drug resistant. Early identification of these patients is critical for appropriate treatment selection and prevention of the devastating consequences of recurrent seizures. The objective of this study aims to detect clinical, electrophysiological, and radiological predictors for drug-resistant epilepsy patients.ResultsOne hundred fifty-five patients were included in this study, divided into a well-controlled epilepsy group (103 patients) and a drug-resistant group (52 patients). Both groups were compared regarding clinical, electrophysiological, and neuro-radiological data. Younger age at onset, history of delayed milestones, history of perinatal insult (especially hypoxia), mental retardation, neurological deficits, depression, status epilepticus (SE), complex febrile seizures, focal seizure to bilateral tonic–clonic convulsion as well as multiple seizures and high seizure frequency (daily) at onset, poor response to first anti-seizure drug (ASD), structural and metabolic etiology, abnormal brain imaging, and slow background and multifocal epileptiform discharges in EEG were significant risk factors for the development of drug-resistant epilepsy.ConclusionMRI abnormalities are the most significant predictor for drug-resistant epilepsy. Drug-resistant epilepsy is associated with clinical, electrophysiological, and radiological risk factors that can be used to diagnose drug-resistant patients early and choose the best treatment option and time.

Study of electroencephalogram characteristics in neurological conditions in pediatric tertiary care hospital

Background: Electroencephalogram (EEG) remains a veritable tool in the diagnostic workup of seizures and childhood epileptic syndromes. EEG has a significant role in substantiating the clinical suspicion of epilepsy, the classification of seizures, and the management of childhood epilepsy. Methods: This study was retrospective descriptive with convenience sampling where two-years EEG recordings were included and the reporting were reviewed. The desired variables were encrypted and descriptive analysis made via statistical software SPSS version 20. Results: There was 499 EEG done in a two-year time period where the female children were (n=205, 41.1%) and mean age was 66 months. There were (n=317, 63.5%) children from out of Kathmandu valley. The most common indication for EEG recommendation was seizure without impaired consciousness (69.7%) and least common indication was seizure with impaired consciousness (8.4%). The rate of detection of EEG abnormalities in seizure without impaired consciousness was 43.9% while that in seizure with impaired consciousness was 38.1%. Among the most common EEG abnormality, abnormal sleep EEG record suggestive of generalized epilepsy most of the children had a history of seizure without impaired consciousness (71.4%) and least presented with seizure with impaired consciousness. Conclusions: The abnormality detection rate of epilepsy was higher in chance if done in early ages. The possibility of findings in EEG are higher with the history of seizures and the perinatal insult as well as birth asphyxia. EEG should be carried out to support the diagnosis of epilepsy in children, and a normal EEG won't be totally excluding epilepsy.

Time-resolved transcriptomic profiling of the developing rabbit’s lungs: impact of premature birth and implications for modelling bronchopulmonary dysplasia

BackgroundPremature birth, perinatal inflammation, and life-saving therapies such as postnatal oxygen and mechanical ventilation are strongly associated with the development of bronchopulmonary dysplasia (BPD); these risk factors, alone or combined, cause lung inflammation and alter programmed molecular patterns of normal lung development. The current knowledge on the molecular regulation of lung development mainly derives from mechanistic studies conducted in newborn rodents exposed to postnatal hyperoxia, which have been proven useful but have some limitations.MethodsHere, we used the rabbit model of BPD as a cost-effective alternative model that mirrors human lung development and, in addition, enables investigating the impact of premature birth per se on the pathophysiology of BPD without further perinatal insults (e.g., hyperoxia, LPS-induced inflammation). First, we characterized the rabbit’s normal lung development along the distinct stages (i.e., pseudoglandular, canalicular, saccular, and alveolar phases) using histological, transcriptomic and proteomic analyses. Then, the impact of premature birth was investigated, comparing the sequential transcriptomic profiles of preterm rabbits obtained at different time intervals during their first week of postnatal life with those from age-matched term pups.ResultsHistological findings showed stage-specific morphological features of the developing rabbit’s lung and validated the selected time intervals for the transcriptomic profiling. Cell cycle and embryo development, oxidative phosphorylation, and WNT signaling, among others, showed high gene expression in the pseudoglandular phase. Autophagy, epithelial morphogenesis, response to transforming growth factor β, angiogenesis, epithelium/endothelial cells development, and epithelium/endothelial cells migration pathways appeared upregulated from the 28th day of gestation (early saccular phase), which represents the starting point of the premature rabbit model. Premature birth caused a significant dysregulation of the inflammatory response. TNF-responsive, NF-κB regulated genes were significantly upregulated at premature delivery and triggered downstream inflammatory pathways such as leukocyte activation and cytokine signaling, which persisted upregulated during the first week of life. Preterm birth also dysregulated relevant pathways for normal lung development, such as blood vessel morphogenesis and epithelial-mesenchymal transition.ConclusionThese findings establish the 28-day gestation premature rabbit as a suitable model for mechanistic and pharmacological studies in the context of BPD.

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology.

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ9-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.