Disruption Of Development Research Articles

Developmental disruptions.

Developmental disruptions.

Developmental Trauma and the Bad Object: Attachment, Identity, Reenactments

The author explores how continuous violations of a child’s subjectivity may influence his or her defensive strategies and maintenance of identity in adult life as well as how this may be supported through the use of interpersonal relationships. Effects of potential developmental disruptions are addressed along with the resulting formation of the false self. Defensive strategies in the form of clinging and distancing as a means of maintaining internal object relations, along with the symptomatic self, are described. In addition, the function of the internalized bad object is considered along with the importance of the individual’s attachment to it.

Developmental alterations in the transcriptome of three distinct rodent models of schizophrenia.

Schizophrenia is a debilitating disorder affecting just under 1% of the population. While the symptoms of this disorder do not appear until late adolescence, pathological alterations likely occur earlier, during development in utero. While there is an increasing literature examining transcriptome alterations in patients, it is not possible to examine the changes in gene expression that occur during development in humans that will develop schizophrenia. Here we utilize three distinct rodent developmental disruption models of schizophrenia to examine potential overlapping alterations in the transcriptome, with a specific focus on markers of interneuron development. Specifically, we administered either methylazoxymethanol acetate (MAM), Polyinosinic:polycytidylic acid (Poly I:C), or chronic protein malnutrition, on GD 17 and examined mRNA expression in the developing hippocampus of the offspring 18 hours later. Here, we report alterations in gene expression that may contribute to the pathophysiology of schizophrenia, including significant alterations in interneuron development and ribosome function.

MK-801 Exposure during Adolescence Elicits Enduring Disruption of Prefrontal E-I Balance and Its Control of Fear Extinction Behavior.

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.

Prelimbic medial prefrontal cortex disruption during adolescence increases susceptibility to helpless behavior in adult rats

Major depressive disorder (MDD) is a disabling mental disorder worldwide. Several animal models have been used to study the neurobiology of this disorder, including the learned helplessness (LH) paradigm, in which susceptible animals show helpless behavior indicated by fails to escape a controllable footshock. This behavior has been associated with a downregulation of ventral tegmental area (VTA) dopamine (DA) system activity. The prelimbic portion of the prefrontal cortex (plPFC) plays an important role in the modulation of helpless behavior, but so far there is no evidence indicating that its developmental disruption alters susceptibility to helpless behavior. We investigated the impact of plPFC lesion performed at adolescence (postnatal day 31–33) or adulthood (postnatal day 70–72) on anxiety responses (elevated plus-maze), susceptibility to helpless behavior, and the VTA DA system activity in adult Sprague-Dawley rats. Whereas adult plPFC lesions induced neither anxiety responses nor increased susceptibility to helpless behavior (plPFC lesion: 33.3% of helplessness; controls: 30.8% of helplessness rats), adolescent plPFC lesions induced anxiety responses and increased the proportion of rats showing helpless at adulthood (plPFC lesion: 92.3% helplessness; controls: 42.1% helplessness rats). Moreover, only helpless rats in the groups showed a decreased VTA DA system population activity that was confined to the medial portion of the VTA. These findings suggest that the impairment of plPFC activity during adolescence occurs during a critical window for the development of helpless behavior in adult rats, indicating that predisposition or early life adverse events that impair plPFC activity may enhance susceptibility to depression in adulthood.

An Efficient Method for Generating Murine Hypothalamic Neurospheres for the Study of Regional Neural Progenitor Biology.

The hypothalamus is a key homeostatic brain region and the primary effector of neuroendocrine signaling. Recent studies show that early embryonic developmental disruption of this region can lead to neuroendocrine conditions later in life, suggesting that hypothalamic progenitors might be sensitive to exogenous challenges. To study the behavior of hypothalamic neural progenitors, we developed a novel dissection methodology to isolate murine hypothalamic neural stem and progenitor cells at the early timepoint of embryonic day 12.5, which coincides with peak hypothalamic neurogenesis. Additionally, we established and optimized a culturing protocol to maintain multipotent hypothalamic neurospheres that are capable of sustained proliferation or differentiation into neurons, oligodendrocytes, and astrocytes. We characterized media requirements, appropriate cell seeding density, and the role of growth factors and sonic hedgehog (Shh) supplementation. Finally, we validated the use of fluorescence activated cell sorting of either Sox2GFPKI or Nkx2.1GFPKI transgenic mice as an alternate cellular isolation approach to enable enriched selection of hypothalamic progenitors for growth into neurospheres. Combined, we present a new technique that yields reliable culturing of hypothalamic neural stem and progenitor cells that can be used to study hypothalamic development in a controlled environment.

Dynamic Recovery from Depression Enables Rate Encoding in Inhibitory Synapses.

SummaryParvalbumin-expressing fast-spiking interneurons (PV-INs) control network firing and the gain of cortical response to sensory stimulation. Crucial for these functions, PV-INs can sustain high-frequency firing with no accommodation. However, PV-INs also exhibit short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles). In most synapses the rate of replenishment of depleted vesicles is constant, determining an inverse relationship between depression levels and the activation rate, which theoretically, severely limits rate-coding capabilities. We examined STD of the PV-IN to pyramidal cell synapse in the mouse visual cortex and found that in these synapses the recovery from depression is not constant but increases linearly with the frequency of use. By combining modeling, dynamic clamp, and optogenetics, we demonstrated that this recovery enables PV-INs to reduce pyramidal cell firing in a linear manner, which theoretically is crucial for controlling the gain of cortical visual responses.

Uncovering sources of maternal variability: Inherited and environmental contributions to maternal phenotype.

Intergenerational patterns of parental behavior, especially maternal behavior, have been observed across mammalian species including humans, non-human primates, and rodents. These patterns are largely experience-dependent as opposed to genetically induced, with experiences in early-life serving an essential role in directing maternal behavior expressed later in life. Environmental conditions can also alter maternal behavior with consequences for offspring neurodevelopment and interactions with the next generation. Here, we describe effects of lineage during developmental environmental disruption using a limited bedding and nesting material manipulation during the first 2weeks of life. Dams from three lineages were placed in environments containing either abundant nesting material or reduced nesting material. Environmental condition affected eight measures of maternal behavior and dam lineage affected 12 measures of maternal behavior during the first two postnatal weeks. Lineage, condition, and pup sex predicted pup body weight immediately following the manipulation, with lineage accounting for the largest portion of variance in body weight. Although from a limited sample, these data are the first to examine effects of lineage and environment simultaneously and suggest dam lineage may be a better predictor of maternal behavior than current environmental conditions with important implications for pup outcomes.

Genital abnormalities associated to lack of uterine adenogenesis or endometrial gland dysgenesis of female dromedary camels (Camelus dromedarius).

Background:The developmental disruption of the müllerian duct and the endometrial dynamic can generate genital lesions that could contribute to infertility.Aim:This paper discusses two cases of genital conditions associated to endometrial gland pathologies in nulliparous female camels.Methods:Macroscopic examinations and histopathological description were performed on congenital and acquired genital abnormalities with endometrial gland anomalies.Results:The first case is endometrial gland agenesis associated to unilateral uterine aplasia, and the second case is endometrial gland dysgenesis associated to metritis. The prevalence of each case is estimated to be 0.6%. The most specific microscopic features associated to the endometrial gland agenesis were the presence of endometrial stromal proliferation and homogenous hyalinization of the myometrium. The acute metritis was associated to endometrial-activated stroma with focal infiltration with inflammatory cells on the endometrium and myometrium and the spontaneous endometrial gland dysgenesis.Conclusion:This study reveals the importance of congenital abnormalities during the routine reproductive examination of peripubertal animals, as well as the association of histopathological complementary examination for the research functional and inflammatory anomalies of the uterus. Genetic screening of breeders would be very important in the search for genetic risk factors associated with these congenital pathologies, which can be disseminated by reproductive biotechnologies.

Atypical neuromagnetic resting activity associated with thalamic volume and cognitive outcome in very preterm children.

Children born very preterm, even in the absence of overt brain injury or major impairment, are at increased risk of cognitive difficulties. This risk is associated with developmental disruptions of the thalamocortical system during critical periods while in the neonatal intensive care unit. The thalamus is an important structure that not only relays sensory information but acts as a hub for integration of cortical activity which regulates cortical power across a range of frequencies. In this study, we investigate the association between atypical power at rest in children born very preterm at school age using magnetoencephalography (MEG), neurocognitive function and structural alterations related to the thalamus using MRI. Our results indicate that children born extremely preterm have higher power at slow frequencies (delta and theta) and lower power at faster frequencies (alpha and beta), compared to controls born full-term. A similar pattern of spectral power was found to be associated with poorer neurocognitive outcomes, as well as with normalized T1 intensity and the volume of the thalamus. Overall, this study provides evidence regarding relations between structural alterations related to very preterm birth, atypical oscillatory power at rest and neurocognitive difficulties at school-age children born very preterm.

Hox Genes Polymorphism Depicts Developmental Disruption of Common Sole Eggs.

In sole aquaculture production, consistency in the quality of produced eggs throughout the year is unpredictable. Hox genes have a crucial role in controlling embryonic development and their genetic variation could alter the phenotype dramatically. In teleosts genome duplication led paralog hox genes to become diverged. Direct association of polymorphism in hoxa1a, hoxa2a & hoxa2b of Solea solea with egg viability indicates hoxa2b as a potential genetic marker. High Resolution Melt (HRM) analysis was carried out in 52 viable and 61 non-viable eggs collected at 54±6 hours post fertilization (hpf). Allelic and genotypic frequencies of polymorphism were analyzed and results illustrated a significantly increased risk for non-viability for minor alleles and their homozygous genotypes. Haplotype analysis demonstrated a significant recessive effect on the risk of non-viability, by increasing the odds of disrupting embryonic development up to three-fold. Phylogenetic analysis showed that the paralog genes hoxa2a and hoxa2b, are separated distinctly in two clades and presented a significant ω variation, revealing their diverged evolutionary rate.

PREDICTORS FOR DEVELOPMENTAL DELAY IN CHILDREN WITH CEREBRAL PALSY AND AT-RISK CHILDREN

The first three years of life (zero to three) are a period of great importance when discovering the congenital, as well as the acquired disorders and developmental delays. Recognizing milestones and manifestations of certain behaviors helps us identify developmental delays and disruptions. With this research we intended to determine the segments of developmental achievements and developmental discrepancies of psycho-motor development (general development achievements, motor functions, surrounding motor functions and communication) in infancy and early childhood (zero to three years old) in three groups of respondents. The research sample included 104 respondents. Sixty-three of them had been diagnosed with cerebral palsy (thirty-three were without comorbidity convulsions, and thirty were with comorbidity convulsions-epilepsy), and forty-one respondents were born with a risk factor for a developmental delay. The research was conducted using the standardized developmental instrument Chuturic Developmental Scale for evaluation of the psycho-motor development, which encompasses oculomotorics, emotional development, speech, hearing-motor reactions, communication, socialization and verbalization, of infants and small children. The analysis of results concluded that there is a discrepancy in the developmental achievements of the three groups of respondents. Based on analysis of the values of the Global Development Coefficient (GDC), we have determined that the most affected group is the group of children with cerebral palsy and comorbidity convulsions where the average value of GDC is 47.77. Early and precision diagnostics, as well as knowledge of the developmental characteristics of different categories of developmental delays will improve the prognosis and contribute to better utilization of the brain plasticity in children with cerebral damage and children born at risk. Early intervention and stimulation are more than necessary to maximize the child's full potential, reduce the primary effects of the damage or prevent secondary damages and difficulties.

Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior

Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling, altered neurotransmitter control of nervous system function, and fundamental changes in behaviors such as learning, memory, and social interactions. Human cohort studies reveal correlations between maternal/fetal exposure to endocrine disruptors and incidence of neurodevelopmental disorders. Here, we summarize the major literature findings of endocrine disruption of neurodevelopment and concomitant changes in behavior by four major endocrine disruptor classes:bisphenol A, polychlorinated biphenyls, organophosphates, and polybrominated diphenyl ethers. We specifically review studies of gestational and/or lactational exposure to understand the effects of early life exposure to these compounds and summarize animal studies that help explain human correlative data.

Behavioral effects in adult zebrafish after developmental exposure to carbaryl

Chemical exposure during the early life stages of development may have long lasting effects on organisms that are rarely studied. The present work intended to evaluate the effect of embryonic exposure to the pesticide carbaryl on adult fish behavior. Zebrafish (Danio rerio) embryos were exposed, for 4 days, to sublethal concentrations of carbaryl (0.01, 0.1 and 1.0 mg/L) plus a control and then kept in standard cultivation conditions until adulthood. A battery of behavioral tests was then performed to assess anxiety-like behavior (locomotor activity, thigmotaxis and novel tank diving test), social behavior, and feeding. Developmental exposure of zebrafish to sublethal concentrations of carbaryl produced important behavioral alterations in the adulthood. Main effects included decreased locomotion/hypoactivity (increase in slow movements and decrease of medium and rapid movements), especially in the light periods. Moreover, spatial pattern also changed: while during dark periods control fish increased activity in the outer zone of the tank, this was not observed in exposed fish. Overall, this demonstrated the importance of life stage exposure, clearly demonstrating long lasting effects of a (chemical) stress event at embryonic stages. This data supports the need of considering this scenario in environmental risk evaluations. Further work should focus on the mechanistic effects of developmental disruption responsible for the effects observed.

Marijuana Use in Pregnancy: A Review.

Marijuana is the most commonly used dependent substance in pregnancy. The main active chemical of marijuana (delta-9-tetrahydrocannabinol [THC]) readily crosses the placenta, and cannabinoid receptors have been identified in fetal brain and placenta. As a result, prenatal marijuana use could potentially have detrimental impact on fetal development. This review aims to summarize the existing literature and current recommendations for marijuana use while pregnant or lactating. A PubMed literature search using the following terms was performed to gather relevant data: "cannabis," "cannabinoids," "marijuana," "fetal outcomes," "perinatal outcomes," "pregnancy," "lactation." Available studies on marijuana exposure in pregnancy were reviewed and support some degree of developmental disruption, including an increased risk of fetal growth restriction and adverse neurodevelopmental consequences. However, much of the existing prenatal marijuana research was performed in the 1980s, when quantities of THC were lower and the frequency of use was less. Additionally, most human studies are also limited and conflicting as most studies have been observational or retrospective, relying primarily on patient self-report and confounded by polysubstance abuse and small sample sizes, precluding determination of a causal effect specific for marijuana. Given the paucity of evidence, it is currently recommended to avoid using marijuana while pregnant or when breastfeeding. There is a critical need for research on effects in pregnancy using present-day THC doses. Once the adverse perinatal effects of marijuana exposure are identified and well characterized, patient education and antenatal surveillance can be developed to predict and mitigate its impact on maternal and fetal health.

Validation of endogenous reference genes in rat cerebral cortex for RT-qPCR analyses in developmental toxicity studies

Relative gene expression data obtained from quantitative RT-PCR (RT-qPCR) experiments are dependent on appropriate normalization to represent true values. It is common to use constitutively expressed endogenous reference genes (RGs) for normalization, but for this strategy to be valid the RGs must be stably expressed across all the tested samples. Here, we have tested 10 common RGs for their expression stability in cerebral cortex from young rats after in utero exposure to thyroid hormone (TH) disrupting compounds. We found that all 10 RGs were stable according to the three algorithms geNorm, NormFinder and BestKeeper. The downstream target gene Pvalb was significantly downregulated in brains from young rats after in utero exposure to propylthiouracil (PTU), a medicinal drug inhibiting TH synthesis. Similar results were obtained regardless of which of the 10 RGs was used for normalization. Another potential gene affected by developmental TH disruption, Dio2, was either not affected, or significantly upregulated about 1.4-fold, depending on which RG was used for normalization. This highlights the importance of carefully selecting correct RGs for normalization and to take into account the sensitivity of the RT-qPCR method when reporting on changes to gene expression that are less than 1.5-fold. For future studies examining relative gene expression in rat cerebral cortex under toxicological conditions, we recommend using a combination of either Rps18/Rpl13a or Rps18/Ubc for normalization, but also continuously monitor any potential regulation of the RGs themselves following alterations to study protocols.

431 Through the Eyes of Burn-Injured Youth - How Burn Camp Helps Survivors Thrive

Improvement in acute burn care has increased the probability of survival of severely burned children who often experience disfigurement and physical/emotional pain. Recreational camps whose goal is to help them deal with their burn injuries have existed for several decades. This includes helping burned children cope with disfigurement and the psycho/social challenges of burn survival. Few studies have delineated the actual benefits of camp from the participants’ point of view. This study asked attendees to identify and rank reasons they would recommend camp attendance to a burn-injured peer. Burn-injured youth attending four regional burn camps completed a survey asking, “If you were to invite a burn survivor to burn camp how would you rate the following 10 items recently identified by your burn peers as benefits of attending?” Items included Increased Confidence, Making Friends, Help with Scarring, No Judgement Zone, Supportive Counselors, Trying New Things, Being Part of a Community, Getting Away from Home and Being Outside. Participants rated each item on a scale of 1(Not at all) to 4 (Really a lot) and then chose the 3 most important benefits they get from burn camp. Participants (n=164) had a mean age of 13.7 years; female (n=88), male (n=74). The main cause of injury was fire/flame (40%) and scald (42%). The average age at burn was 6.1 yrs.; average years of attending camp was 4.6 and 76% had visible scars. All items received an average score of 3 or higher. The highest rated items were Increasing My Confidence (3.63) and Supportive Counselors (3.59). The lowest were, Time Away from Home (3.08) and Spending Time Outside (3.21). All items were ranked significantly higher than the two lowest ranking items (p=<001). The three responses endorsed as most important included Increasing My Confidence (46%), Making Friends-Building Connections (45%) and Helping Me Accept My Scars (44%). Campers endorsed many aspects of burn camp as positive. Importantly, the highest rated items support the development of meaningful relationships, which has been shown to buffer children from developmental disruption and help them adjust to trauma. The high levels of endorsement suggest that camp is helping children adjust to their burns in many ways, the key goal of burn camps. Burn care professionals should be proactive in encouraging pediatric patients to attend burn camp as it provides multiple reported benefits. Coordination between health care providers, survivors and parents in promoting attendance at burn camp is highly recommended by the very youth who espouse the benefits of attending.

Stress during critical periods of development and risk for schizophrenia

Schizophrenia is a neurodevelopmental disorder with genetic predisposition, and stress has long been linked to its etiology. While stress affects all stages of the illness, increasing evidence suggests that stress during critical periods of development may be particularly detrimental, increasing individual's vulnerability to psychosis. To thoroughly understand the potential causative role of stress, our group has been focusing on the prenatal methylazoxymethanol acetate (MAM) rodent model, and discovered that MAM offspring display abnormal stress reactivity and heightened anxiety prepubertally, prior to the manifestation of a hyperdopaminergic state. Furthermore, pharmacologically treating anxiety during prepuberty prevented the emergence of the dopamine dysfunction in adulthood. Interestingly, sufficiently strong stressors applied to normal rats selectively during early development can recapitulate multiple schizophrenia-related phenotypes of MAM rats, whereas the same stress paradigm during adulthood only produced short-term depression-related deficits. Altogether, the evidence is thus converging: developmental disruption (genetic or environmental) might render animals more susceptible to the deleterious effects of stress during critical time windows, during which unregulated stress can lead to the emergence of psychosis later in life. As an important region regulating the midbrain dopamine system, the ventral hippocampus is particularly vulnerable to stress, and the distinct maturational profile of its fast-spiking parvalbumin interneurons may largely underlie such vulnerability. In this review, by discussing emerging evidence spanning clinical and basic science studies, we propose developmental stress vulnerability as a novel link between early predispositions and environmental triggering events in the pathophysiology of schizophrenia. This promising line of research can potentially provide not only insights into the etiology, but also a “roadmap” for disease prevention.

Toward Understanding Developmental Disruption of Default Mode Network Connectivity Due to Early Life Stress

Toward Understanding Developmental Disruption of Default Mode Network Connectivity Due to Early Life Stress

Acquisition and reconstruction of 4D surfaces of axolotl embryos with the flipping stage robotic microscope

We have designed and constructed a Flipping Stage for a light microscope that can view the whole exterior surface of a 2 mm diameter developing axolotl salamander embryo. It works by rapidly inverting the bottom-heavy embryo, imaging it as it rights itself. The images are then montaged to reconstruct the whole 3D surface versus time, for a full 4D record of the surface. Imaging early stage axolotl development will help discover how cell differentiation and movement takes place in the early embryo. For example, the switch from ectodermal to neural plate cells takes place on the top, animal surface portion the egg/embryo and can be observed using the flipping stage microscope. Detailed pictures of the whole surface need to be obtained so that cell tracking and event histories, such as cell divisions and participation in differentiation waves, of individual cells can be recorded. Imaging the whole exterior of the eggs/embryos will allow for the analysis of cell behavior and the forces the cells experience in their natural setting in the intact or manipulated embryo. This will give insights into embryogenesis, development, developmental disruptions, birth defects, cell differentiation and tissue engineering.