Disruption Of Development Research Articles

Sex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental "Two-Hit" Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation.

Neurodevelopmental disorders are thought to be caused by a combination of adverse genetic and environmental insults. The “two-hit” hypothesis suggests that an early first “hit” primes the developing brain to be vulnerable to a second “hit” during adolescence which triggers behavioral dysfunction. We have previously modeled this scenario in mice and found that the combined effect of a genetic hapolinsuffuciency in the brain-derived neurotrophic factor (BDNF) gene (1st hit) and chronic corticosterone (CORT) treatment during adolescence (2nd hit), caused spatial memory impairments in adulthood. Environmental enrichment (EE) protocols are designed to stimulate experience-dependent plasticity and have shown therapeutic actions. This study investigated whether EE can reverse these spatial memory impairments. Wild-type (WT) and BDNF heterozygous (HET) mice were treated with corticosterone (CORT) in their drinking water (50 mg/L) from weeks 6 to 8 and exposed to EE from 7 to 9 weeks. Enriched housing included open top cages with additional toys, tunnels, housing, and platforms. Y-maze novel preference testing, to assess short-term spatial memory, was performed at 10 weeks of age. At week 16 dorsal hippocampus tissue was obtained for Western blot analysis of expression levels of BDNF, the BDNF receptor TrkB, and NMDA receptor subunits, GluNR1, 2A and 2B. As in our previous studies, spatial memory was impaired in our two-hit (BDNF HET + CORT) mice. Simultaneous EE prevented these impairments. However, EE appeared to worsen spatial memory performance in WT mice, particularly those exposed to CORT. While BDNF levels were lower in BDNF HET mice as expected, there were no further effects of CORT or EE in males but a close to significant female CORT × EE × genotype interaction which qualitatively corresponded with Y-maze performance. However, EE caused both sex- and genotype-specific effects on phosphorylated TrkB residues and GluNR expression within the dorsal hippocampus, with GluNR2B levels in males changing in parallel with spatial memory performance. In conclusion, beneficial effects of EE on spatial memory emerge only following two developmental disruptions. The mechanisms by which EE exerts its effects are likely via regulation of multiple activity-dependent pathways, including TrkB and NMDA receptor signaling.

Medial septum activation produces opposite effects on dopamine neuron activity in the ventral tegmental area and substantia nigra in MAM vs. normal rats

The medial septum (MS) differentially impacts midbrain dopamine (DA) neuron activity via the ventral hippocampus, a region implicated in DA-related disorders. However, whether MS regulation of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is disrupted in a developmental disruption model of schizophrenia is unknown. Male Sprague-Dawley rats were exposed at gestational day 17 to methylazoxymethanol (MAM) or saline. As adults, NMDA (0.75 µg/0.2 µL) was infused into the MS, and either DA neuron activity in the VTA and SNc (7–9 anesthetized rats per group) or amphetamine-induced hyperlocomotion (AIH, 11-13 rats per group) was measured. MS activation produced a 58% increase in the number of spontaneously active DA neurons in VTA and a 37% decrease in SNc in saline rats. However, MS activation produced opposite effects on DA population activity in MAM rats, decreasing VTA DA activity by 51% and increasing SNc DA activity by 47%. MS activation also increased AIH by 113% in MAM rats, opposite of what is seen in intact rats. The effect in behavioral output may be due to disrupted GABAergic regulation of SNc as bicuculline infusion into vSub, which selectively prevented the MS activation-induced decrease in SNc DA activity in intact rats, prevented the increase in AIH and SNc DA activity in MAM rats. These findings demonstrate that the regulation of midbrain DA neurons by the MS is disrupted in this well-validated animal model, suggesting that it could be a potential locus for pharmacological intervention in disorders such as schizophrenia.

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

ObjectiveMice with congenital loss of the glucagon receptor gene (Gcgr−/− mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM. MethodsWe induced experimental T1DM by injecting the beta-cell cytotoxin streptozotocin (STZ) in mice with congenital or temporally-controlled Gcgr loss-of-function using tamoxifen (TMX). ResultsDisruption of Gcgr expression, using either an inducible approach in adult mice or animals with congenital knockout, abolished the response to a long-acting Gcgr agonist. Mice with either developmental Gcgr disruption or inducible deletion several weeks before STZ treatment maintained normoglycemia. However, mice with inducible knockout of the Gcgr one week after the onset of STZ diabetes had only partial correction of hyperglycemia, an effect that was reversed by GLP-1 receptor blockade. Mice with Gcgr deletion for either 2 or 6 weeks had similar patterns of gene expression, although the changes were generally larger with longer GCGR knockout. ConclusionsThese findings demonstrate that the effects of glucagon to mitigate diabetic hyperglycemia are not through acute signaling but require compensations that take weeks to develop.

Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders.

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD.SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.

Parallel Development of Chromatin Patterns, Neuron Morphology, and Connections: Potential for Disruption in Autism.

The phenotype of neurons and their connections depend on complex genetic and epigenetic processes that regulate the expression of genes in the nucleus during development and throughout life. Here we examined the distribution of nuclear chromatin patters in relation to the epigenetic landscape, phenotype and connections of neurons with a focus on the primate cerebral cortex. We show that nuclear patterns of chromatin in cortical neurons are related to neuron size and cortical connections. Moreover, we point to evidence that reveals an orderly sequence of events during development, linking chromatin and gene expression patterns, neuron morphology, function, and connections across cortical areas and layers. Based on this synthesis, we posit that systematic studies of changes in chromatin patterns and epigenetic marks across cortical areas will provide novel insights on the development and evolution of cortical networks, and their disruption in connectivity disorders of developmental origin, like autism. Achieving this requires embedding and interpreting genetic, transcriptional, and epigenetic studies within a framework that takes into consideration distinct types of neurons, local circuit interactions, and interareal pathways. These features vary systematically across cortical areas in parallel with laminar structure and are differentially affected in disorders. Finally, based on evidence that autism-associated genetic polymorphisms are especially prominent in excitatory neurons and connectivity disruption affects mostly limbic cortices, we employ this systematic approach to propose novel, targeted studies of projection neurons in limbic areas to elucidate the emergence and time-course of developmental disruptions in autism.

Adolescent Developmental Disruptions: Haunted by the Future, Guarded by Haunting Ancestors

ABSTRACTThis article will explore two potentially disruptive developmental phenomena that occur during life transitions. One is the role of anticipatory haunting during adolescence, and the other is the strict adherence to an already defined life narrative at the gate to young adulthood (Levy-Warren, 2016a, 2016b). Historically, in psychoanalytic theory, we have looked at flaws in an adolescent’s foundation as causal in adolescent paralysis. Anticipatory haunting, fearing what is to come, also can be traumatic enough to disrupt an adolescent’s development. Similarly, in the transition from late adolescence to young adulthood, we have assumed that the past must be left behind for the youth to progress in development and that focusing on the past can inhibit the envisioning of a future. In this instance, the necessity for a particular kind of reworking of the young adult’s history so that a future can be envisioned is articulated. Each of these points of view represents a departure from traditional ways of understanding and treating developmental disruptions.

Organophosphorus poisoning in animals and enzymatic antidotes.

Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture. In complement, various laboratory models, from invertebrates to aquatic organisms, rodents and primates, have been chosen to study chronic and acute toxicity as well as neurobehavioral impact, immune response, developmental disruption, and other pathological signs. Several decontamination approaches were developed to counteract the poisoning effects of OPs. Among these, enzyme-based strategies are particularly attractive as they allow efficient external decontamination without toxicity or environmental impact and may be of interest for treatment. Approaches using bioscavengers for prophylaxis, treatment, and external decontamination are emphasized and their potential is discussed in the light of toxicological observations from various animal models. The relevance of animal models, regarding their cholinergic system and the abundance of naturally protecting enzymes, is also discussed for better extrapolation of results to human.

Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity.

Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA.

Promises and perils of collective land tenure in promoting urban resilience: Learning from China's urban villages

New frameworks for “urban resilience” frequently overlook the role of property rights and tenure security in shaping vulnerability, as well as how different property rights regimes shape societal capacity to adapt to environmental and developmental disruptions. We contribute to these discussions by examining how collective urban land tenure affects community-scale resilience, defined as environmental wellbeing, productive livelihoods, and empowered governance. We use urban villages in Shenzhen to study how this widespread phenomenon of collective land ownership in Chinese cities allowed rural villagers to adapt as cities spread around them over time. Drawing on a literature review, interviews, and a field visit to Shenzhen, we find that collective tenure in Shenzhen’s urban villages has helped them avoid some of the limitations seen in household-level tenure formalization efforts elsewhere. Collective tenure enabled rural villages to create self-governance mechanisms that allowed them to transform individual and collective assets into vibrant, well-serviced, and mixed-use neighborhoods. Urban villages house most of Shenzhen’s residents and have helped underwrite the region’s industrialization process. However, collective tenure also has hindered integration with Shenzhen’s urban infrastructure, governance, and taxation systems, resulted in astronomical profits for village elites, and repeated historic patterns of unequal land ownership in China. The promises and perils of collective urban property rights seen in Shenzhen call for research on other such models around the world to further inform whether and how such property rights regimes can support equitable and holistic notions of urban resilience.

α7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia.

Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. Thus, we investigated the effects of α7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats. This appeared to be due to effects on DA afferent regulation, in that PNU282987 or SSR180711 infusion into the ventral hippocampus of MAM rats replicated the decrease in the number of spontaneously active VTA DA neurons. In contrast, infusion of the same drugs into the basolateral amygdala increased the number of spontaneously active VTA DA neurons in normal rats without impacting MAM rats. These data suggest that α7 receptors may represent a promising target in the development of new pharmacological therapies for schizophrenia.

T199. DEVIANT CORTICAL SULCATION RELATED TO SCHIZOPHRENIA, BUT NOT COGNITIVE DEFICITS, LIKELY PREDATE BRAIN DEVELOPMENT IN THE SECOND TRIMESTER

BackgroundGestational disruptions are linked to the risk of schizophrenia; but in most cases, there is a lack of a clear history or observable anomaly indicating that the disruptions are likely to be subtle (Murray et al., 2017). The time-locked development of cortical sulci in a human embryo is highly sensitive to developmental disruptions (Chi et al., 1977). We can retrospectively infer the likely timing of embryonic/fetal disruption in schizophrenia by studying the structure of major cortical sulci that represent lobar development in adults with schizophrenia.MethodsAnatomical T1 MRI scans from a publicly available dataset (COBRE) of 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth. 5 major primary sulci that are invariable, representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, interparietal sulcus and inferior frontal sulcus) with formation representing distinct developmental periods (16, 23, 25, 26 and 28 weeks respectively (Chi et al., 1977)) were chosen. Sulcal depth was measured using Morphologist interface of BrainVISA 4.5 (http://brainvisa.info/). Following the construction of 3-dimensional models of cortical folds, various sulci were automatically classified using a probabilistic algorithm with maximum depth computed for each identified sulcus. The 5 sulci were consistently labeled automatically across all subjects. The identified sulci were visually inspected to ensure that the boundaries are in accordance with Ono’s Atlas of Cerebral Sulci (Ono et al., 1990).ResultsA repeated measure ANOVA with 5 sulci and 2 hemispheres as within-subject factors and gender, age and intracranial volume as covariates revealed a significant between-subjects effect for diagnosis (F[1,134]=14.8, p=0.0002). Gender (F[1,134]=7.4, p=0.007) and age (F[1,134]=4.5, p=0.035) also had significant effect in the model. Parameter estimates revealed a significant effect of diagnosis (Controls>Patients) for left superior temporal (t=3.2, p=0.002), right superior temporal (t=2.8, p=0.006), right inferior frontal (t=2.7, p=0.007) and left calcarine (t=2.2, p=0.03) sulci. 5 non-collinear factors representing the 5 bilateral sulci were obtained using varimax rotation, and related to overall MATRICS standardized composite score in patients using multiple regression. The depth of the superior frontal sulcus was the only predictor of the variation in the cognitive score (F[1,54]=8.7, p=0.005).DiscussionThe above findings suggest that the gestational cortical disruption underlying schizophrenia is likely to predate, if not, coincide with the appearance of calcarine sulcus (i.e. 16 weeks, early second trimester) and affects frontal, temporal and occipital lobes. Nevertheless, the burden of cognitive deficits may relate specifically to aberrant superior frontal development occurring in late second trimester.

Loss and Grief Among Persistently Delinquent Youth: The Contribution of Adversity Indicators and Psychopathy-Spectrum Traits to Broadband Internalizing and Externalizing Psychopathology.

Despite profound adversity exposure (loss, trauma) among delinquents, with adversity linked to early-onset persistent delinquency [EOPD], externalizing syndromes (Conduct Disorder) continue to overshadow impairing internalizing syndromes. Three understudied factors potentially contribute to both syndromes among delinquents: bereavement-related distress [BRD] from death-exposures; psychopathy-spectrum traits associated with system-involvement; and emotional abuse, implicated in lifespan morbidities. Therefore, we characterized loss/BRD among 107 EOPD adolescent girls and boys, comparing: 1) psychopathology and maltreatment (emotional, physical and sexual abuse); and 2) adversity-related (BRD, Post-traumatic Stress Disorder [PTSD], maltreatment) and psychopathy-spectrum predictors of internalizing and externalizing syndromes. Death exposure was common, resulting in developmental disruptions (school difficulties: 49.4%) and clinically significant BRD (33.8%), with girls evidencing greater BRD severity. BRD and psychopathy-traits, not PTSD, positively predicted all youths' internalizing, and boys' externalizing, syndromes. More frequent physical abuse increased both syndromes among boys. Emotional abuse alone predicted girls' externalizing syndromes, highlighting the contribution of this overlooked maltreatment-type.

Metabolomics Reveals Aryl Hydrocarbon Receptor Activation Induces Liver and Mammary Gland Metabolic Dysfunction in Lactating Mice.

The liver and the mammary gland have complementary metabolic roles during lactation. Substrates synthesized by the liver are released into the circulation and are taken up by the mammary gland for milk production. The aryl hydrocarbon receptor (AHR) has been identified as a lactation regulator in mice, and its activation has been associated with myriad morphological, molecular, and functional defects such as stunted gland development, decreased milk production, and changes in gene expression. In this study, we identified adverse metabolic changes in the lactation network (mammary, liver, and serum) associated with AHR activation using 1H nuclear magnetic resonance (NMR)-based metabolomics. Pregnant mice expressing Ahrd (low affinity) or Ahrb (high affinity) were fed diets containing beta naphthoflavone (BNF), a potent AHR agonist. Mammary, serum, and liver metabolomics analysis identified significant changes in lipid and TCA cycle intermediates in the Ahrb mice. We observed decreased amino acid and glucose levels in the mammary gland extracts of Ahrb mice fed BNF. The serum of BNF fed Ahrb mice had significant changes in LDL/VLDL (increased) and HDL, PC, and GPC (decreased). Quantitative PCR analysis revealed ∼50% reduction in the expression of key lactogenesis mammary genes including whey acid protein, α-lactalbumin, and β-casein. We also observed morphologic and developmental disruptions in the mammary gland that are consistent with previous reports. Our observations support that AHR activity contributes to metabolism regulation in the lactation network.

The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention.

Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.

Mechanical, Cellular, and Proteomic Properties of Laryngotracheal Cartilage.

The larynx sometimes requires repair and reconstruction due to cancer resection, trauma, stenosis, or developmental disruptions. Bioengineering has provided some scaffolding materials and initial attempts at tissue engineering, especially of the trachea, have been made. The critical issues of providing protection, maintaining a patent airway, and controlling swallowing and phonation, require that the regenerated laryngotracheal cartilages must have mechanical and material properties that closely mimic native tissue. These properties are determined by the cellular and proteomic characteristics of these tissues. However, little is known of these properties for these specific cartilages. This review considers what is known and what issues need to be addressed.

Chapter 27 - The cerebellum from the fetus to the elderly: history, advances, and future challenges

The cerebellum is now at the forefront of research in neuroscience. This is not just a coincidence, occurring about 250 years after the first description of the human cerebellum. The cerebellum contains the majority of neurons in the central nervous system and it is heavily connected with almost all cortical and subcortical areas of the supratentorial region as well as with the brainstem and the spinal cord. Cerebellar circuits are embedded in large-scale networks contributing to motor control and neurocognition. From a phenotypic standpoint, damage to cerebellar lobules interconnected with the sensorimotor cortices leads to a cerebellar motor syndrome, whereas lesions of the posterolateral cerebellum cause cognitive and neuropsychiatric impairments which may or may not be subtle. This topographic rule is valid in children and adults. Midline posterior vermal lesions cause behavioral/affective dysregulation, especially in kids. The extent of the spectrum of human cerebellar disorders is increasingly recognized from the fetus to the elderly, with recognition of consequences for the quality of life and socioeconomic costs due to lifelong morbidity of many cerebellar ataxias/pathologies. The prolonged duration of human cerebellar development makes the cerebellum especially susceptible to developmental disruption, both genetic and nongenetic. This explains the current emphasis on the clarification of the developmental course and impact of the cerebellum. The understanding of how germinal matrix zones and migration of neurons and glial cells end in a highly organized and foliated human cerebellum is essential. This is greatly accelerated by inputs from rodent developmental studies, in particular because cerebellar anatomy is conserved across species. Still, numerous questions on human fetal development remain unanswered. Although both advanced neuroimaging and genetic studies are currently leading to a better definition and understanding of the multitude of cerebellar symptoms, there is a gap, with a great need to develop therapies aiming at first, protection of the cerebellum during development, and second, restoration of cerebellar function in children and in adults. Dynamic profiles of the compensatory processes from newborns to elderly require specific studies.

Emerging Adults, Identity Development, and Suicidality: Implications for Psychoanalytic Psychotherapy

ABSTRACTEmerging adulthood (approximately ages eighteen to twenty-nine) has been identified as the transitional age between adolescence and young adulthood. People in this phase of life face specific issues and pressures in developing and consolidating various aspects of identity. The process of coming to experience oneself as a coherent, whole person, and learning about one’s own attributes, capacities, and potential for growth can be fraught and vulnerable to developmental disruption. Difficulties with identity development and consolidation can lead to experiences of disconnection, aloneness, despair, and harsh self-attack that heighten vulnerability to suicide. The psychotherapeutic relationship can help the patient achieve a degree of self-recognition that might not otherwise have been possible, decreasing vulnerability to suicidal despair and opening up the potential for ongoing development and growth. Together, patient and therapist have the opportunity to more fully recognize aspects of the emerging adult’s identity that are present but have not been fully realized, and also to renegotiate other aspects of identity that are based on old, maladaptive “scripts.” We present clinical material to illustrate how struggles with identity relate to suicidality, and to highlight the challenges and opportunities of psychodynamic work.

Infusions of Nerve Growth Factor Into the Developing Frontal Cortex Leads to Deficits in Behavioral Flexibility and Increased Perseverance.

In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate.

Enzymatic degradation of organophosphorus insecticides decreases toxicity in planarians and enhances survival

Organophosphorus insecticides (OPs) are toxic compounds used for agricultural purposes and responsible for severe types of contamination worldwide. OPs may also induce chronic deleterious effects and developmental disruption. Finding remediation strategies is a major concern to diminish their impact on environment and human health. Enzymes have emerged as a promising eco-friendly route for decontaminating OPs. The enzyme SsoPox from the archaea Sulfolobus solfataricus has been particularly studied, considering both its tremendous stability and phosphotriesterase activity. However, the toxicity of the degradation products generated through enzyme hydrolysis has been poorly investigated. To address both neurotoxicity and developmental perturbation, freshwater planarians from Platyhelminthes were considered to evaluate the impact of OP and degradation product exposure. Planarians have a large proportion of stem cells that give them an unconventional capacity for regeneration. OPs were found to be highly toxic to planarians and enzyme decontamination drastically enhanced survival rate. Although not completely innocuous, the degradation products were found to be less toxic than insecticides and reduced poisoning effects by increasing NOEC values by up to eight-fold. SsoPox also limited detrimental consequences on planarian mobility and enabled them to recover a non-exposed type regeneration process suggesting that enzymatic decontamination is a promising alternative to bioremediation.

Developmental estrogen exposures and disruptions to maternal behavior and brain: Effects of ethinyl estradiol, a common positive control

Due of its structural similarity to the endogenous estrogen 17β-estradiol (E2), the synthetic estrogen 17α-ethinyl estradiol (EE2) is widely used to study the effects of estrogenic substances on sensitive organs at multiple stages of development. Here, we investigated the effects of EE2 on maternal behavior and the maternal brain in females exposed during gestation and the perinatal period. We assessed several components of maternal behavior including nesting behavior and pup retrieval; characterized the expression of estrogen receptor (ER)α in the medial preoptic area (MPOA), a brain region critical for the display of maternal behavior; and measured expression of tyrosine hydroxylase, a marker for dopaminergic cells, in the ventral tegmental area (VTA), a brain region important in maternal motivation. We found that developmental exposure to EE2 induces subtle effects on several aspects of maternal behavior including time building the nest and time spent engaged in self-care. Developmental exposure to EE2 also altered ERα expression in the central MPOA during both early and late lactation and led to significantly reduced tyrosine hydroxylase immunoreactivity in the VTA. Our results demonstrate both dose- and postpartum stage-related effects of developmental exposure to EE2 on behavior and brain that manifest later in adulthood, during the maternal period. These findings provide further evidence for effects of exposure to exogenous estrogenic compounds during the critical periods of fetal and perinatal development.