Adult Neuropsychiatric Disorders Research Articles

Prenatal SARS-CoV-2 infection results in neurodevelopmental and behavioral outcomes in mice.

Prenatal exposure to viral pathogens has been known to cause the development of neuropsychiatric disorders in adulthood. Furthermore, COVID-19 has been associated with a variety of neurological manifestations, raising the question of whether in utero SARS-CoV-2 exposure can affect neurodevelopment, resulting in long-lasting behavioral and cognitive deficits. Using a human ACE2-knock-in mouse model, we have previously shown that prenatal exposure to SARS-CoV-2 at later stages of development leads to fetal brain infection and gliosis in the hippocampus and cortex. In this study, we aimed to determine whether infection of the fetal brain results in long-term neuroanatomical alterations of the cortex and hippocampus or in any cognitive deficits in adulthood. Here, we show that infected mice developed slower and weighed less in adulthood. We also found altered hippocampal and amygdala volume and aberrant newborn neuron morphology in the hippocampus of adult mice infected in utero. Furthermore, we observed sex-dependent alterations in anxiety-like behavior and locomotion, as well as hippocampal-dependent spatial memory. Taken together, our study reveals long-lasting neurological and cognitive changes as a result of prenatal SARS-CoV-2 infection, identifying a window for early intervention and highlighting the importance of immunization and antiviral intervention in pregnant women.

Anterior cingulate cortex orexin signaling mediates early-life stress-induced social impairment in females

Early-life stress has long-term impacts on the structure and function of the anterior cingulate cortex (ACC), and raises the risk of adult neuropsychiatric disorders including social dysfunction. The underlying neural mechanisms, however, are still uncertain. Here, we show that, in female mice, maternal separation (MS) during the first three postnatal weeks results in social impairment accompaniedwith hypoactivity in pyramidal neurons (PNs) of the ACC. Activation of ACC PNs ameliorates MS-induced social impairment. Neuropeptide Hcrt, which encodes hypocretin (orexin), is the top down-regulated gene in the ACC of MS females. Activating ACC orexin terminals enhances the activity of ACC PNs and rescues the diminished sociability observed in MS females via an orexin receptor 2 (OxR2)-dependent mechanism. Our results suggest orexin signaling in the ACC is critical in mediating early-life stress-induced social impairment in females.

Regional superficial amygdala resting-state functional connectivity in adults infers childhood maltreatment severity.

Childhood maltreatment (CM) is a potential risk factor for some neuropsychiatric disorders in adulthood (e.g. depression and anxiety) and alters trajectories of brain development. Accumulating evidence suggests that functional connectivity of the limbic system, especially the amygdala, is highly associated with childhood maltreatment, although not all studies have found this. These inconsistent results may be due to differential alterations of amygdala resting-state functional connectivity (rsFC) following childhood maltreatment. Our aim was to investigate the relationship between the rsFC of amygdala subregions and CM severity, as well as to develop a stable rsFC-based model for inferring the severity of CM. In this study, we employed the Childhood Trauma Questionnaire (CTQ) to assess CM severity in each individual. We explored the relationship between the rsFC of amygdala subregions (i.e. centromedial -CMA, basolateral -BLA, superficial-SFA amygdala) and CM experience in a discovery dataset of n=110 healthy Chinese participants by linear multiple regression analysis. Subsequent dimensional and categorical approach were performed to elucidate the relationship between rsFCs and CM severity and CM subtypes, respectively. A support vector regression model was then conducted to validate the associations between rsFCs and total CTQ scores. Moreover, we also verified the model into another independent replication dataset (n=38). Our findings suggested that childhood maltreatment was negatively associated with rsFC between the right superficial amygdala and perigenual anterior cingulate cortex (pgACC)/postcentral gyrus (PCG) but not the other two amygdala subregions. Moreover, SFA-pgACC coupling was more associated with physical neglect whereas the SFA-PCG was more related to emotional neglect. In addition, supervised machine learning confirmed that using these two rsFCs as predictors could stably estimate continuous maltreatment severity in both discovery and replication datasets. The current study supports that the rsFCs of superficial amygdala are related to childhood maltreatment and which may be a potential biomarker for the effects of childhood maltreatment-related psychiatric disorders (i.e. depression and anxiety).

Innate immune tolerance against adolescent intermittent alcohol exposure-induced behavioral abnormalities in adult mice

It has been reported that pre-stimulation of the innate immune system in animals can prevent chronic stress-induced depression- and anxiety-like behaviors in animals, suggesting the possibility that innate immune stimulants may prevent the pathogenesis of neuropsychiatric disorders. Alcohol use, especially when it begins in adolescence, is a risk factor for the development of neuropsychiatric disorders in adulthood. Preventing the pathological changes induced by alcohol exposure in adolescence could be of great importance for improving human mental health. Here, we investigated whether pre-stimulation of the innate immune system can prevent the behavioral abnormalities in a disease model induced by adolescent intermittent alcohol exposure (AIE). The results showed that a single injection of lipopolysaccharide (LPS) injection (100 μg/kg) one day before alcohol exposure prevented the AIE-induced depression- and anxiety-like behaviors in the tail suspension test, forced swimming test, sucrose preference test, elevated pluz maze test, light–dark test, and open field test in adult mice. Single LPS injection (100 μg/kg) before alcohol exposure also transformed the AIE-induced neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice to an anti-inflammatory phenotype. Suppression of the innate immune response by minocycline pretreatment abolished the preventive effect of LPS on AIE-induced abnormalities and neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice. These results indicate that pre-stimulation of the innate immune system may prevent the AIE-induced depression- and anxiety-like behaviors in adult mice by preventing neuroinflammation. This may help to develop new strategies to prevent neuropsychiatric disorders induced by adolescent alcohol exposure.

Teenage drinking and adult neuropsychiatric disorders: An epigenetic connection.

Targeted epigenetic remodeling in the rat amygdala reverses the effects of adolescent alcohol consumption on excessive drinking and anxiety-like behavior in adulthood.

Maternal DHA supplementation influences sex-specific disruption of placental gene expression following early prenatal stress

Early life adversity is widely recognized as a key risk factor for early developmental perturbations and contributes to the presentation of neuropsychiatric disorders in adulthood. Neurodevelopmental disorders exhibit a strong sex bias in susceptibility, presentation, onset, and severity, although the underlying mechanisms conferring vulnerability are not well understood. Environmental perturbations during pregnancy, such as malnutrition or stress, have been associated with sex-specific reprogramming that contribute to increased disease risk in adulthood, whereby stress and nutritional insufficiency may be additive and further exacerbate poor offspring outcomes. To determine whether maternal supplementation of docosahexanoic acid (DHA) exerts an effect on offspring outcome following exposure to early prenatal stress (EPS), dams were fed a purified 10:1 omega-6/omega-3 diet supplemented with either 1.0% preformed DHA/kg feed weight (DHA-enriched) or no additional DHA (denoted as the control diet, CTL). Dams were administered chronic variable stress during the first week of pregnancy (embryonic day, E0.5–7.5), and developmental milestones were assessed at E 12.5. Exposure to early prenatal stress (EPS) decreased placenta and embryo weight in males, but not females, exposed to the CTL diet. DHA enrichment reversed the sex-specific decrease in placenta and embryo weight following EPS. Early prenatal exposure upregulated expression of genes associated with oxygen and nutrient transport, including hypoxia inducible factor 3α (HIF3α), peroxisome proliferator-activated receptor alpha (PPARα), and insulin-like growth binding factor 1 (IGFBP1), in the placenta of CTL diet males exposed to EPS. DHA enrichment in EPS-exposed animals abrogated the male-specific upregulation of PPARα, HIF3α, and IGFBP1. Taken together, these studies suggest that maternal dietary DHA enrichment may buffer against maternal stress programming of sex-specific outcomes during early development.

Prevalence of Survival Without Major Comorbidities Among Adults Born Prematurely

(Abstracted from JAMA 2019;322(16):1580–1588) More than 95% of preterm infants in developed countries now survive into adulthood. However, with a worldwide preterm birth rate of 10.6%, associated increased relative risks of cardiometabolic, respiratory, and neuropsychiatric disorders in adulthood prove concerning.

Prevalence of Survival Without Major Comorbidities Among Adults Born Prematurely

Preterm birth has been associated with cardiometabolic, respiratory, and neuropsychiatric disorders in adulthood. However, the prevalence of survival without any major comorbidities is unknown. To determine the prevalence of survival without major comorbidities in adulthood among persons born preterm vs full-term. National cohort study of all 2 566 699 persons born in Sweden from January 1, 1973, through December 31, 1997, who had gestational age data and who were followed up for survival and comorbidities through December 31, 2015 (ages 18-43 years). Gestational age at birth. Survival without major comorbidities among persons born extremely preterm (22-27 weeks), very preterm (28-33 weeks), late preterm (34-36 weeks), or early term (37-38 weeks), compared with full-term (39-41 weeks). Comorbidities were defined using the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) Comorbidity Index, which includes conditions that commonly manifest in adolescence or young adulthood, including neuropsychiatric disorders; and the Charlson Comorbidity Index (CCI), which includes major chronic disorders predictive of mortality in adulthood. Poisson regression was used to determine prevalence ratios and differences, adjusted for potential confounders. In this study population, 48.6% were female, 5.8% were born preterm, and the median age at end of follow-up was 29.8 years (interquartile range, 12.6 years). Of all persons born preterm, 54.6% were alive with no AYA HOPE comorbidities at the end of follow-up. Further stratified, this prevalence was 22.3% for those born extremely preterm, 48.5% for very preterm, 58.0% for late preterm, 61.2% for early term, and 63.0% for full-term. These prevalences were significantly lower for earlier gestational ages vs full-term (eg, adjusted prevalence ratios: extremely preterm, 0.35 [95% CI, 0.33 to 0.36; P < .001]; all preterm, 0.86 [95% CI, 0.85 to 0.86; P < .001]; adjusted prevalence differences: extremely preterm, -0.41 [95% CI, -0.42 to -0.40; P < .001]; all preterm, -0.09 [95% CI, -0.09 to -0.09; P < .001]). Using the CCI, the corresponding prevalences were 73.1% (all preterm), 32.5% (extremely preterm), 66.4% (very preterm), 77.1% (late preterm), 80.4% (early term), and 81.8% (full-term) (adjusted prevalence ratios: extremely preterm, 0.39 [95% CI, 0.38 to 0.41; P < .001]; all preterm, 0.89 [95% CI, 0.89 to 0.89; P < .001]; adjusted prevalence differences: extremely preterm, -0.50 [95% CI, -0.51 to -0.49; P < .001]; all preterm, -0.09 [95% CI, -0.09 to -0.09; P < .001]). Among persons born preterm in Sweden between 1973 and 1997, the majority survived to early to mid-adulthood without major comorbidities. However, outcomes were worse for those born extremely preterm.

Association of childhood traumatization and neuropsychiatric outcomes with altered plasma micro RNA-levels.

Childhood traumatization (CT) is associated with the development of several neuropsychiatric disorders in later life. Experimental data in animals and observational data in humans revealed evidence for biological alterations in response to CT that may contribute to its long-term consequences. This includes epigenetic changes in miRNA levels that contribute to complex alterations of gene expression. We investigated the association between CT and 121 miRNAs in a target sample of N = 150 subjects from the general population and patients from the Department of Psychiatry. We hypothesized that CT exhibits a long-term effect on miRNA plasma levels. We supported our findings using bioinformatics tools and databases. Among the 121 miRNAs 22 were nominally significantly associated with CT and four of them (let-7g-5p, miR-103a-3p, miR-107, and miR-142-3p) also after correction for multiple testing; most of them were previously associated with Alzheimer's disease (AD) or depression. Pathway analyses of target genes identified significant pathways involved in neurodevelopment, inflammation and intracellular transduction signaling. In an independent general population sample (N = 587) three of the four miRNAs were replicated. Extended analyses in the general population sample only (N = 687) showed associations of the four miRNAs with gender, memory, and brain volumes. We gained increasing evidence for a link between CT, depression and AD through miRNA alterations. We hypothesize that depression and AD not only share environmental factors like CT but also biological factors like altered miRNA levels. This miRNA pattern could serve as mediating factor on the biological path from CT to adult neuropsychiatric disorders.

Fetal exposure to high levels of maternal glucocorticoids alters reelin signaling in the prefrontal cortex of rat pups

Maternal stress (MS) is associated with various neuropsychiatric disorders and cognitive impairment in the offspring. However, it is unclear how early life stress alters the pup’s brain development and how it contributes to the pathology of neuropsychiatric disorders later in life. Reelin is a large extracellular matrix glycoprotein that plays essential roles in early brain development such as neural migration, synaptic development, and maturation. Dysregulation of reelin and its signaling proteins is associated with the emergence of neuropsychiatric disorders in adulthood. This study examined the effect of repeated maternal Carbenoxolone (CBX) injection during late gestation on reelin signaling in the prefrontal cortex (PFC) of rat pups. CBX is a selective 11β-HSD2 enzyme inhibitor that promotes the direct transfer of maternal corticosteroids (CORT) to the fetus. Therefore, treatment with CBX can mimic the animal model of early life exposure to high levels of maternal stress hormone. In this study, pregnant rats were injected daily with either saline or CBX during gestation day (GD) 14–21, and the levels of reelin and its signaling proteins were examined in the PFC of rat pups at different postnatal age from P0-P21. The main result of this study is the repeated maternal CBX injections during GD14-21 acutely increase reln mRNA and protein expression in the PFC of rat pups at birth (P0) and follow by a significant decrease during P7-P14. The treatment also causes long term decreases in the amount of VLDLR and Dab1 which are the downstream signaling proteins for the reelin pathway, at least until P21. Our results indicated that fetal exposure to high levels of maternal CORT interferes with reelin signaling which might have profound effects on cortical development associated with neuropsychiatric disorders later in life.

Defect in Synaptic Pruning of Motor Cortex Neurons is Associated with Early Perturbed Dopaminergic System

Background: Early stress exposure during neurodevelopmental stages has been linked to some adult neuropsychiatric disorders. The dopaminergic system which has been implicated in movement and reward system has been linked to movement and mood disorders when perturbed at early development. This study is designed to check the mechanisms involved in movement disorders such as dyskinesia, associated with early perturbed dopaminergic system in the motor cortex Methods: Haloperidol was used to block D2R in neonatal albino Wistar rats in utero by administering 20 mg/kg BW (intraperitoneally) to pregnant adult wistar rats (n=8) in the third week of gestation. Behavioural studies such as the rotarod test were carried out on the neonatal animals (n=5) to test their motor function at postnatal day twentyeight (P28). Electrophysiological recordings were carried out on the motor cortex (M1) to determine the significance of D2R inhibition on calcium neural activity. Immunofluorescence was done to demonstrate synaptic vesicle protein (SV) and microtubule associated protein kinases (MAP K) as a measure of synapses count and microtubule phosphorylation respectively. Results: Behavioural studies showed a decline in motor function of animals exposed to haloperidol in utero compared to the control. This motor deficit was accompanied by a significant increase in the Ca2+ neural activity of the motor cortex as shown by electrophysiological recordings. Immunofluorescence staining showed there was significant increase in the number of MAPK+ and SV+ cells in the motor cortex of haloperidol exposed animals compared to the control. Conclusion: These findings showed that early perturbation in dopaminergic system is associated with an increase in synapses and neuronal density, as well as an increase in phosphorylation of microtubules of neurons in the motor cortex.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach.

Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented. An ongoing protocol will enroll participants aged 16-35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing. EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD.

Perinatal reduction of functional serotonin transporters results in developmental delay

While there is strong evidence from rodent and human studies that a reduction in serotonin transporter (5-HTT) function in early-life can increase the risk for several neuropsychiatric disorders in adulthood, the effects of reduced 5-HTT function on behavior across developmental stages are underinvestigated. To elucidate how perinatal pharmacological and lifelong genetic inactivation of the 5-HTT affects behavior across development, we conducted a battery of behavioral tests in rats perinatally exposed to fluoxetine or vehicle and in 5-HTT−/− versus 5-HTT+/+ rats. We measured motor-related behavior, olfactory function, grooming behavior, sensorimotor gating, object directed behavior and novel object recognition in the first three postnatal weeks and if possible the tests were repeated in adolescence and adulthood. We also measured developmental milestones such as eye opening, reflex development and body weight. We observed that both pharmacological and genetic inactivation of 5-HTT resulted in a developmental delay. Except for hypo-locomotion, most of the observed early-life effects were normalized later in life. In adolescence and adulthood we observed object directed behavior and decreased novel object recognition in the 5-HTT−/− rats, which might be related to the lifelong inactivation of 5-HTT. Together, these data provide an important contribution to the understanding of the effects of perinatal and lifelong 5-HTT inactivation on behavior across developmental stages.

Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/β-catenin signaling

It has been suggested that synapse-associated protein of 97-kDa molecular weight (SAP97) is a susceptibility factor for childhood and adult neuropsychiatric disorders. SAP97 is a scaffolding protein that shares direct and indirect binding partners with the Disrupted in Schizophrenia 1 (DISC1) gene product, a gene with strong association with neuropsychiatric disorders. Here we investigated the possibility that these two proteins converge upon a common molecular pathway. Since DISC1 modifies Wnt/β-catenin signaling via changes in glycogen synthase kinase 3 beta (GSK3β) phosphorylation, we asked if SAP97 impacts Wnt/β-catenin signaling and GSK3β phosphorylation. We find that SAP97 acts as inhibitor of Wnt signaling activity and can suppress the stimulatory effects of DISC1 on β-catenin transcriptional activity. Reductions in SAP97 abundance also decrease GSK3β phosphorylation. In addition, we find that over expression of DISC1 leads to an increase in the abundance of SAP97, by inhibiting its proteasomal degradation. Our findings suggest that SAP97 and DISC1 contribute to maintaining Wnt/β-catenin signaling activity within a homeostatic range by regulating GSK3β phosphorylation.

Lactation and the Marijuana-Using Mother

The following is a commentary on the recently published guidelines for breastfeeding in women with substance use disorders. Delta-9-tetrahydrocannabinol (DTHC) is the major compound in marijuana, but there are many other toxic compounds in marijuana, and it may be laced with harmful adulterants. THC is psychoactive, is distributed into breastmilk and to the brain, and is lipophilic/stored in body fat. Therefore, active, passive and cumulative exposures to the breastfed infant all must be considered. THC can be concentrated in breastmilk up to eight times the level in plasma in heavy users and is absorbed and metabolized by the breastfed infant; metabolites are found in infant stool. Physiologic effects including sedation and poor feeding have been described in infants receiving breastmilk from marijuana-using mothers. Explorations of the effects of marijuana exposure via breastmilk on longer-term child development have led to conflicting results; however, this research was done in a time period in which the potency of marijuana was approximately fourfold less than it is today. Cannabinoid CB1 receptors emerge early in brain development and are the major targets for the action of cannabinoids. They are abundantly expressed in certain brain regions that play key roles in neural development. THC delivered via lactation to the infant may therefore affect the ontogeny of various neurotransmitter systems, leading to changes in neurobiological functioning. THC is present in exhaled breath for 2–4 hours after a single marijuana cigarette, and indirect passive smoking exposures can be significant. Prenatal marijuana exposures should not be discounted in this discussion, as it is important to consider that, for the mother using marijuana during lactation, exposures throughout gestation are likely. Gestational marijuana use is not uncommon: among pregnant women, nearly 4% used marijuana in the past month. THC readily crosses the placenta. Infant neurobehavior is altered in prenatally marijuana-exposed infants, and prenatal cannabis exposure is associated with adolescent behavioral abnormalities as well as increased vulnerability to neuropsychiatric disorders in adulthood, indicating an ‘‘unmasking’’ of earlier deficits. Additional postnatal exposures to the rapidly developing infant brain may compound prenatally acquired deficits. Finally, the identification of the lactating mother as a chronic marijuana user and potentially a person with a substance use disorder in the postnatal period presents additional difficulties. Maternal self-report of marijuana use in the perinatal period is inaccurate. Urine toxicology screening, used by many institutions to identify substance use among women in the perinatal period, is not a useful tool for detecting marijuana use due to its long half-life in urine and relays no information regarding quantification or patterns of use. Chronic marijuana use and dependence are associated with a wide range of psychiatric concerns, making identification important for the provision of services for at-risk dyads. Although there are no data to point to use by women in the perinatal period as indicative of chronic or heavy use, we do know that use of marijuana declines over the course of gestation, making users of marijuana at term likely to be chronic or dependent users. In a large U.S. sample between 2007 and 2012, among past-year marijuana users, 12.8% of nonpregnant women used nearly daily, and 11.4% met criteria for abuse/dependence. These figures jump to 16.2% and 18.1% for pregnant women. The breastfed infant must necessarily be in the company of his or her mother, and people with substance use disorders can have periodically altered sensoriums, chaotic environments, and poor judgment regarding their own safety and the safety of their children, portending immediate physical harm for the infant and potentially long-term developmental harm as well. It is necessary to consider that it may represent a missed opportunity to assist a newly postpartum woman with finding acceptable treatment for a substance use and/or an underlying psychiatric disorder, to provide intensive postnatal services to at-risk dyads, or to detect an infant at risk for physical or developmental harm by minimizing marijuana use detected at the time of delivery. In conclusion, the cumulative evidence above supports that when an empirically derived approach to the issue of maternal marijuana use and lactation is taken, the recent new recommendation by the Academy of Breastfeeding Medicine is both erroneous and disappointing. It is unclear why a recommendation would err on the side of breastfeeding with potentially toxic exposures and other risk factors that could portend shortand long-term infant harm. Perhaps this view reflects a lack of understanding of substance use disorders in general. What is clear is the need for future research to fully establish the risk–benefit of breastfeeding with active

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

Adolescence as a vulnerable period to alter rodent behavior

Adolescence and puberty are highly important periods for postnatal brain maturation. During adolescence, drastic changes of neuronal architecture and function occur that concomitantly lead to distinct behavioral alterations. Unsurprisingly in view of the multitude of ongoing neurodevelopmental processes in the adolescent brain, most adult neuropsychiatric disorders have their roots exactly during this time span. Adolescence and puberty are therefore crucial developmental periods in terms of understanding the causes and mechanisms of adult mental illness. Valid animal models for adolescent behavior and neurodevelopment might offer better insights into the underlying mechanisms and help to identify specific time windows with heightened susceptibility during development. In order to increase the translational value of such models, we urgently need to define the detailed timing of adolescence and puberty in laboratory rodents. The aim of the present review is to provide a more precise delineation of the time course of these developmental periods during postnatal life in rats and mice and to discuss the impact of adolescence and related neurodevelopmental processes on the heightened susceptibility for mental disorders.

A systematic review on olfaction in child and adolescent psychiatric disorders

There is substantial evidence that olfactory function may serve as biomarker in adult neuropsychiatric disorders, e.g. overall diminished olfaction in Parkinson's disease as parameter for early pre-motor and differential diagnosis. Here, we present data from a systematic literature review in olfactory function in child and adolescent psychiatric disorders and report two unpublished data sets of autism and obsessive-compulsive disorder. The overall number of olfaction studies is low-even after taking into account adult samples. In addition, heterogeneity of findings is high due to methodological limitations such as the use of different olfactory tests and odours targeting the olfactory and/or the trigeminal system and neglecting possible confounders, e.g., intelligence or oto-rhino-laryngological affections. Despite these limitations, there is some indication for specific alterations of olfactory function especially in disorders with dopaminergic pathology (e.g. attention deficit/hyperactivity disorder, autism, schizophrenia, 22q11 deletion syndrome). Dopamine is a relevant modulator of early processes in the olfactory bulb. Our systematic review provides the basis for future confirmatory studies investigating olfaction as putative biomarker in child and adolescent psychiatric disorders. We further propose studies of thorough and elaborate methodological standards in combination with imaging techniques and the investigation of the influence of genetic variation on olfactory function.

Early-life social experiences in mice affect emotional behaviour and hypothalamic-pituitary-adrenal axis function

RationaleEarly-life stressful experiences are associated to alterations in behavioural responses and development of psychiatric and neurodegenerative diseases. In rodents, individual housing is considered as a stressful condition whilst enriched environment can protect against stress and its negative consequences. Neuroendocrine responses to stress can also be altered by early-life experiences and seem to contribute to behavioural alterations induced by changes in housing conditions. ObjectiveTo develop an improved procedure of social isolation throughout development (from pre-adolescence to adulthood) in CD1 mice and to elucidate its effects on behavioural parameters related to stress and neuroendocrine responses compared to enriched or social conditions. Materials and methodsCD1 male mice (PND 21) were housed in social/standard conditions, enriched conditions or isolated conditions during seven weeks. After that, different relevant behaviours were evaluated, including locomotor activity, anxiety-like and despair behaviour. Levels of plasma corticosterone were also analysed before and after a stressful event. ResultsCD1 mice exposed to an isolated environment exhibited higher locomotion and anxiety-like responses than animals exposed to social or enriched conditions. In addition, isolated animals showed lower basal plasma corticosterone than social or enriched ones but after a stressful event the elevation of plasma corticosterone was higher, suggesting an enhanced response of the HPA axis to a novel and stressful situation. ConclusionsSocial interaction is an important feature to display an appropriate behavioural and neuronal development. Habituation to novel stimuli is impaired in subjects exposed to social isolation and induces increased excitability response to stressful events. Social deprivation increases the possibility of altered neuronal function and could facilitate the development of neuropsychiatric disorders in adulthood.

Neuroimaging of Brain Development - Discovering the Origins of Neuropsychiatric Disorders?

Recent discoveries by prominent neuroimaging scientists (1) claim that many of the adult neuropsychiatric disorders, such as schizophrenia, have their origin during brain development. Most of these disorders have no distinct neuropathological features, or the features described after years of disease are nonspecific and influenced by years of medication. Advanced neuroimaging, using magnetic resonance imaging combined with sophisticated mathematically-based image analysis tools, have given scientists the opportunity to study the disease early in its presentation, or even before clinical manifestations, in families with high risk of disease development. With this approach, researchers have been able to define Endophenotypes, or brain structural features, of specific diseases such as schizophrenia, ADHD or bipolar disorders and autism. Young schizophrenic patients showed a loss of gray matter in comparison with age-matched controls, and siblings of patients showed a similar trend to reduced cortical and cerebellar gray matter and hippocampal volume, which indicates underlying genetic predisposition to disease Serial studies of both cortical gray matter volume, as well as of gray matter surface, have allowed researchers to follow human brain development in vivo (2). The dramatic increase of cortical gray matter, both antenatally during the third trimester of pregnancy and throughout the early years of childhood, is an expression of rapid brain growth (3) The organization of cortical lamination and establishment of millions of synapses, which is genetically controlled, along with distinct environmental influences such as placental insufficiency leads to smaller brains in the newborn with a loss of cortical gray matter volume and smaller hippocampi (4). From detailed cohort studies of normal children and adolescents we know that cortical growth in adolescents enters into a plateau phase after which gray matter starts to decline in volume (2). This is thought to be an expression of the higher complexity and functional synaptic pruning that takes place during this time. Recent data from researchers at UCLA (1) and National Institutes of Health (5) now indicate that in children and adolescents with neuropsychiatric disorders these normal anatomic developmental processes are disrupted. A loss of gray matter during adolescence occurs in young schizophrenic patients exceeding that of normal teenagers. This indicates that the developmental trajectory of brain development has been altered in these young patients, either by a distinct abnormality of the pruning process or by earlier developmental alterations. A decreased overall gray matter growth in early development would link the occurrence of schizophrenia to pathologies occurring during pregnancy. Poor birth weight has been clearly identified as a risk factor for schizophrenia in later life. Changes in cortical development during adolescence are not only markers of neuropsychiatric disorders, but also indicate structural changes underlying IQ development. Highly intelligent children have thinner cortical frontal gray matter in infancy but express steeper and longer increase in cortical thickness during adolescence (6). Despite impressive new knowledge in the area of neuroimaging, caution should be used in applying these findings directly for diagnostic purposes as disease expression in neuropsychiatric disorders is multifactorial.