Network biology:A promising approach for drug target identification against neurodevelopmental disorders

Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions.Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis,prognosis,and treatment.The network of biological entities can help us predict drug targets for several diseases.The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease.The novel strategical approach of system biologyassisted pharmacology coupled with computer-aided drug discovery(CADD)can help drugs fight multifactorial diseases efficiently.In the present review,we have summarized the role and application of network biology for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD,Autism,Epilepsy,and Intellectual Disability.Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of neurodevelopmental disorders.

Neural stem cell replacement: a possible therapy for neurodevelopmental disorders?

Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments in learning and memory, speech disorders and repetitive behavior （Telias and Ben-Yosef, 2014）. Common major neurodevelopmental disorders include autism and autism spectrum disorders （ASDs）, fragile X syndrome （FXS）, Down syndrome （DS）, and Rett syndrome （RTT）. They can be collectively described as disorders in which the plasticity of the brain has been severely impaired. The concept of plasticity refers to the brain＇s ability to adapt to and process new information and react accordingly, and it can be classified into three categories： a） molecular plasticity, whenever specific receptors, ion channels, enzymes,

Ultrasonic vocalizations in mice: relevance for ethologic and neurodevelopmental disorders studies

Mice use ultrasonic vocalizations(USVs)to communicate each other and to convey their emotional state.USVs have been greatly characterized in specific life phases and contexts,such as mother isolation-induced USVs for pups or female-induced USVs for male mice during courtship.USVs can be acquired by means of specific tools and later analyzed on the base of both quantitative and qualitative parameters.Indeed,different ultrasonic call categories exist and have already been defined.The understanding of different calls meaning is still missing,and it will represent an essential step forward in the field of USVs.They have long been studied in the ethological context,but recently they emerged as a precious instrument to study pathologies characterized by deficits in communication,in particular neurodevelopmental disorders(NDDs),such as autism spectrum disorders.This review covers the topics of USVs characteristics in mice,contexts for USVs emission and factors that modulate their expression.A particular focus will be devoted to mouse USVs in the context of NDDs.Indeed,several NDDs murine models exist and an intense study of USVs is currently in progress,with the aim of both performing an early diagnosis and to find a pharmacological/behavioral intervention to improve patients’quality of life.

Neurodevelopmental disorders:An innovative perspective via the response to intervention model

Neurodevelopmental disorders are a group of conditions classified together by the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders which include intellectual disability,communication disorders,autism spectrum disorder,attention-deficit/hyperactivity disorder,specific learning disorder(SLD),and motor disorders.SLD is present in many students,who exhibit significant difficulties in the acquisition of reading,written expression,and mathematics,mostly due to problems with executive functions(EF).The present study is a review of the current situation of neurodevelopmental disorders and SLD focusing on the benefits of the response to intervention model(RtI),which allows the combination of evaluation and intervention processes.It also addresses the key role of EF.The importance of adapting RtI to new possibilities such as the use of virtual reality is discussed and a theoretical framework for carrying that out is provided.

Management of sleep disorders among children and adolescents with neurodevelopmental disorders: A practical guide for clinicians

There is a complex relationship between sleep disorders and childhood neurodevelopmental,emotional,behavioral and intellectual disorders(NDEBID).NDEBID include several conditions such as attention deficit/hyperactivity disorder,autism spectrum disorder,cerebral palsy,epilepsy and learning(intellectual)disorders.Up to 75%of children and young people(CYP)with NDEBID are known to experience different types of insomnia,compared to 3%to 36%in normally developing population.Sleep disorders affect 15%to 19%of adolescents with no disability,in comparison with 26%to 36%among CYP with moderate learning disability(LD)and 44%among those with severe LD.Chronic sleep deprivation is associated with significant risks of behavioural problems,impaired cognitive development and learning abilities,poor memory,mood disorders and school problems.It also increases the risk of other health outcomes,such as obesity and metabolic consequences,significantly impacting on the wellbeing of other family members.This narrative review of the extant literature provides a brief overview of sleep physiology,aetiology,classification and prevalence of sleep disorders among CYP with NDEBIDs.It outlines various strategies for the management,including parenting training/psychoeducation,use of cognitive-behavioral strategies and pharmacotherapy.Practical management including assessment,investigations,care plan formulation and follow-up are outlined in a flow chart.

Postnatal therapeutic approaches in genetic neurodevelopmental disorders

Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.

Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141,DDHD2,and LHFPL5

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation.Here,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and deafness.Homozygosity mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,p.Trp90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,p.Leu84^(*))were identified.A Tmem141^(p.Trp90^(*)/p.Trp90^(*))mouse model was generated.Behavioral studies showed impairments in learning ability and motor coordination.Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells.Transmission electron microscopy showed abnormal mitochondrial morphology.Furthermore,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model.Conclusively,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in patient.Notably,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

The microbiota-gut-brain axis and neurodevelopmental disorders

The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis,regulating various physiological processes.In recent years,the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated.The gut microbiota is commonly considered to regulate neurodevelopment through three pathways,the immune pathway,the neuronal pathway,and the endocrine/systemic pathway,with overlaps and crosstalks in between.Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder,attention deficit hyperactivity disorder,and Rett Syndrome.Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders(NDDs).This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs.Furthermore,we analyzed both the current state of research progress and discuss future perspectives in this field.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

From Signals to Solutions: Exploring Early Detection of Neuropsychiatric and Neurodevelopment Disorders through Biomarkers

In 2013, the percentage of children ranging from 5 to 17 years who reported being diagnosed with autism surged to 1.2% from 0.1% in 1997 [1]. Alongside this increase in the incidence of autism in children, there were findings of a 21% increase in children who displayed behavioral and conduct problems from 2019 to 2020 [2]. Early detection of neuropsychiatric and neurodevelopmental disorders in children is critical for timely intervention and improved long-term outcomes. With early intervention, there is better aptitude to support healthy development and give proper treatment to attain a better quality of life. This paper explores studies aimed at enhancing the early detection of these disorders through the use of biomarkers with the aim of creating a bridge between the worlds of research and clinical practice. The disorders in this paper specifically discussed are Major Depressive Disorder, Bipolar Disorder, and Autism Spectrum Disorder. With this bridge, we can foster collaborations and encourage further advancement in the field of early detection and intervention.

Perinatal Morbidity, Mortality, and Neurodevelopmental Outcomes of Neonates with Fetal Growth Restriction

Objective: This study aimed to assess perinatal morbidity, mortality rates, and neurodevelopmental outcomes in the management of fetal growth restriction (FGR) at a single tertiary institute. Methods: Among 2465 deliveries between 2013 and 2019, 109 cases of FGR were reviewed retrospectively for causes, indications for pregnancy termination, perinatal death, overall neonatal outcomes, and long-term prognosis. Results: Excluding FGR due to congenital anomalies (n = 17), the mortality rate was 3.3% (3/92). One neonate delivered at 23 weeks developed cerebral palsy (1.1%). Retinopathy of prematurity occurred in four neonates (4.3%). Neurodevelopmental disorders were present in six neonates (6.5%), all of whom were delivered at 32 - 38 weeks. Significantly lower gestational age at delivery, lower birth weight, and higher umbilical artery resistance indices were observed in neonates with neurodevelopmental disorders. Conclusions: Intact survival before 27 weeks of gestation at delivery with FGR is uncommon. Neurodevelopmental disorders may still develop after delivery at 32 - 38 weeks;consideration should be given to the timing of delivery usingfetal ductus venosus Doppler waveforms measurements to reduce neurodevelopmental disorders.

Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Function and dysfunction of GEMIN5:understanding a novel neurodevelopmental disorder

The recent identification of a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction(NEDCAM)has resulted in an increased interest in GEMIN5,a multifunction RNA-binding protein.As the largest member of the survival motor neuron complex,GEMIN5 plays a key role in the biogenesis of small nuclear ribonucleoproteins while also exhibiting translational regulatory functions as an independent protein.Although many questions remain regarding both the pathogenesis and pathophysiology of this new disorder,considerable progress has been made in the brief time since its discovery.In this review,we examine GEMIN5 within the context of NEDCAM,focusing on the structure,function,and expression of the protein specifically in regard to the disorder itself.Additionally,we explore the current animal models of NEDCAM,as well as potential molecular pathways for treatment and future directions of study.This review provides a comprehensive overview of recent advances in our understanding of this unique member of the survival motor neuron complex.

A negative regulator of synaptic development:MDGA and its links to neurodevelopmental disorders

Background Formation of protein complexes across synapses is a critical process in neurodevelopment,having direct implications on brain function and animal behavior.Here,we present the understanding,importance,and potential impact of a newly found regulator of such a key interaction.Data sources A systematic search of the literature was conducted on PubMed(Medline),Embase,and Central-Cochrane Database.Results Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins(MDGAs)were recently discovered to regulate synaptic development and transmission via suppression of neurexins-neuroligins transsynaptic complex formation.MDGAs also regulate axonal migration and outgrowth.In the context of their physiological role,we begin to consider the potential links to the etiology of certain neurodevelopmental disorders.We present the gene expression and protein structure of MDGAs and discuss recent progress in our understanding of the neurobiological role of MDGAs to explore its potential as a therapeutic target.Conclusion MDGAs play a key role in neuron migration,axon guidance and synapse development,as well as in regulating brain excitation and inhibition balance.

Classification,prevalence and integrated care for neurodevelopmental and child mental health disorders:A brief overview for paediatricians

‘Neurodevelopmental disorders’comprise a group of congenital or acquired longterm conditions that are attributed to disturbance of the brain and or neuromuscular system and create functional limitations,including autism spectrum disorder,attention deficit/hyperactivity disorder,tic disorder/Tourette’s syndrome,developmental language disorders and intellectual disability.Cerebral palsy and epilepsy are often associated with these conditions within the broader framework of paediatric neurodisability.Co-occurrence with each other and with other mental health disorders including anxiety and mood disorders and behavioural disturbance is often the norm.Together these are referred to as neurodevelopmental,emotional,behavioural,and intellectual disorders(NDEBIDs)in this paper.Varying prevalence rates for NDEBID have been reported in developed countries,up to 15%,based on varying methodologies and definitions.NDEBIDs are commonly managed by either child health paediatricians or child/adolescent mental health(CAMH)professionals,working within multidisciplinary teams alongside social care,education,allied healthcare practitioners and voluntary sector.Fragmented services are common problems for children and young people with multi-morbidity,and often complicated by subthreshold diagnoses.Despite repeated reviews,limited consensus among clinicians about classification of the various NDEBIDs may hamper service improvement based upon research.The recently developed“Mental,Behavioural and Neurodevelopmental disorder”chapter of the International Classification of Diseases-11 offers a way forward.In this narrative review we search the extant literature and discussed a brief overview of the aetiology and prevalence of NDEBID,enumerate common problems associated with current classification systems and provide recommendations for a more integrated approach to the nosology and clinical care of these related conditions.

Targeted sequencing and integrative analysis of 3,195 Chinese patients with neurodevelopmental disorders prioritized 26 novel candidate genes

Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.

Autophagy in neural stem cells and glia for brain health and diseases

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation,maturation,and survival.Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells.Autophagy arbitrates structural and functional remodeling during the cell differentiation process.Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases.Only recently,studies have begun to shed light on autophagy regulation in glia(microglia,astrocyte,and oligodendrocyte)in the brain.Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development,synaptic function,brain metabolism,cellular debris clearing,and restoration of damaged or injured tissues.Thus,this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions,neurodevelopmental disorders,and neurodegenerative diseases.This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

Transcriptional regulation in the development and dysfunction of neocortical projection neurons

Glutamatergic projection neurons generate sophisticated excitatory circuits to integrate and transmit information among different cortical areas,and between the neocortex and other regions of the brain and spinal cord.Appropriate development of cortical projection neurons is regulated by certain essential events such as neural fate determination,proliferation,specification,differentiation,migration,survival,axonogenesis,and synaptogenesis.These processes are precisely regulated in a tempo-spatial manner by intrinsic factors,extrinsic signals,and neural activities.The generation of correct subtypes and precise connections of projection neurons is imperative not only to support the basic cortical functions(such as sensory information integration,motor coordination,and cognition)but also to prevent the onset and progression of neurodevelopmental disorders(such as intellectual disability,autism spectrum disorders,anxiety,and depression).This review mainly focuses on the recent progress of transcriptional regulations on the development and diversity of neocortical projection neurons and the clinical relevance of the failure of transcriptional modulations.

A Prospective Study on Evaluating the Long-Term Effects of Childhood Vaccination from Birth to 13 Years Old in Kuwait

Background: To prevent infectious diseases and deaths of children, vaccinations play a crucial role in public health strategies in Kuwait. However, it remained uncertain to demonstrate the potential long-term health outcomes of vaccination, including neurodevelopmental disorders (NDD) and autism. This study aimed to evaluate the long-term health outcomes of vaccination among Kuwait children from birth to thirteen years old. Objectives: This study included the significant objectives: (1) to compare long-term health effects, including chronic and acute conditions for unvaccinated, partially vaccinated, and vaccinated children, and (2) to evaluate the association of vaccination with the neurodevelopmental disorders (NDD) and autism, and the preventable illnesses. Methods: This prospective study involved a sample of 976 children from Kuwait based on mothers’ reporting. Data collection about the vaccination status of children and various health outcomes relevant to chronic and acute illnesses was performed based on structured questionnaires through an online survey. However, participants were classified into unvaccinated (n = 40), partially vaccinated (n = 222), and fully vaccinated (n = 714). Statistical analyses, including the chi-square test, Odds Ratios (OR), 95% Confidence Interval (CI), and logistic regression, were performed using SAS (Version 9.4) to determine the associations between vaccination status and health outcomes among children. Results: The study disclosed that vaccinated children showed an increased diagnosis of chronic (allergic rhinitis, allergies, autism spectrum, eczema, neuro-developmental disorders, learning disability, ADHD, and any chronic condition) and acute (whooping cough, pneumonia, rubella, hepatitis A or B, measles, mumps, meningitis, influenza, rotavirus, cancer, chronic fatigue, Crohn’s disease, inflammatory bowel disease, conduct disorder, diabetes type 1 or 2, rheumatoid arthritis, obesity, seizures, hearing loss, polio, diphtheria, tetanus, and depression) illnesses than unvaccinated children. The fully vaccinated children showed an increased prevalence of influenza diagnosis, while partially vaccinated children were more likely to be diagnosed with rheumatoid arthritis than unvaccinated children. In contrast, unvaccinated were more likely to have been diagnosed with chickenpox and encephalopathy than fully and partially vaccinated. Males with chronic and acute conditions had a lower incidence of allergies and pneumonia, respectively, whereas females had a reduced prevalence of acute illnesses, such as whooping cough, inflammatory bowel disease, and hepatitis A or B among vaccinated (n = 936;combination of partially vaccinated and fully vaccinated) children. Regarding medication use and health service applications, vaccinated children were more likely to use medications for fever, antibiotics, and allergies. In addition, they showed an increased rate of sick visits and emergency visits in the past twelve months. On the other hand, factors like age (2 - 5 years, 6 - 9 years, and 10 - 13 years), birth type (cesarian), and mother suffering during pregnancy (gestational diabetes) were significantly associated with NDD (learning disability, autism spectrum, and attention deficient hyperactivity disorder) in the adjusted analysis. In the interaction model of age and birth type, age (6 - 9 years;OR 5.3, 95% CI: 1.1, 25.3) and mother suffering (gestational diabetes;OR 2.5, 95% CI: 1.2, 5.2) during pregnancy were associated with NDD. Conclusion: The findings of this study showed that there are some cases where the infection rate is higher among the vaccinated compared to unvaccinated children, or there are no significant differences between the two groups in Kuwait. Upon controlling the factors in the interaction model, the age of 6 to 9 years and gestational diabetic mothers during pregnancy were associated with the synergistic increment of odds with NDD. These data findings are recommended to verify a larger and diverse group of samples to optimize the vaccination on health outcomes in Kuwait children.

Adverse effects of early-life stress:focus on the rodent neuroendocrine system

Early-life stress is associated with a high prevalence of mental illnesses such as post-traumatic stress disorders,attention-deficit/hyperactivity disorder,schizophrenia,and anxiety or depressive behavior,which constitute major public health problems.In the early stages of brain development after birth,events such as synaptogenesis,neuron maturation,and glial differentiation occur in a highly orchestrated manner,and external stress can cause adverse long-term effects throughout life.Our body utilizes multifaceted mechanisms,including neuroendocrine and neurotransmitter signaling pathways,to appropriately process external stress.Newborn individuals first exposed to early-life stress deploy neurogenesis as a stress-defense mechanism;however,in adulthood,early-life stress induces apoptosis of mature neurons,activation of immune responses,and reduction of neurotrophic factors,leading to anxiety,depression,and cognitive and memory dysfunction.This process involves the hypothalamus-pituitary-adrenal axis and neurotransmitters secreted by the central nervous system,including norepinephrine,dopamine,and serotonin.The rodent early-life stress model is generally used to experimentally assess the effects of stress during neurodevelopment.This paper reviews the use of the early-life stress model and stress response mechanisms of the body and discusses the experimental results regarding how early-life stress mediates stress-related pathways at a high vulnerability of psychiatric disorder in adulthood.