Critical Developmental Period Research Articles

Relationship between macro- and micronutrient intakes with undernutrition among toddlers aged 12-23 months in Aceh, Indonesia

Introduction: Foods consumed contain macro- and micronutrients necessary for the growth and development of children. This study aimed to analyse the relationship between macronutrient and micronutrient intakes with undernutrition in toddlers aged 12-23 months. Methods: This cross-sectional study was conducted in 18 Integrated Healthcare Centres (Posyandu) in Simpang Tiga, Aceh Besar Regency. A total of 138 toddlers were selected using simple random sampling technique. Data collected included family demographics, characteristics, nutritional status of children, and food consumption for macro- and micronutrient intake analyses. Results: Prevalence of malnutrition in toddlers was relatively high – severe underweight and underweight totaled 23.2%, severe wasting and wasting 18.1%, and severe stunting and stunting 27.5%. Significant associations (p<0.05) were found between underweight and intakes of energy, protein, carbohydrates, fat, calcium, phosphorus, zinc, thiamin, and niacin. Wasting was significantly associated (p<0.05) with intakes of energy, protein, and vitamin A. Stunting was significantly associated (p<0.05) with intakes of energy, protein, carbohydrates, fat, calcium, phosphorus, iron, calcium, zinc, vitamin A, thiamine, riboflavin, niacin, and vitamin C. Conclusion: Certain macro- and micronutrient intakes were correlated with undernutrition in toddlers. The results of this study can be used as a reference for planning the development of supplementary feeding programmes for children aged 12-23 months, considering that the critical period of child growth and development is in the first 1000 days of life.

Pubertal maternal presence reduces anxiety and increases adult neurogenesis in Kunming mice offspring

Puberty is a critical period of emotional development and neuroplasticity. However, most studies have focused on early development, with limited research on puberty, particularly the parental presence. In this study, four groups were established, and pubertal maternal presence (PMP) was assessed until postnatal days 21 (PD21), 28 (PD28), 35 (PD35), and 42 (PD42), respectively. The social interaction and anxiety behaviors, as well as the expression of oxytocin (OT) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), and the number of new generated neurons and the expression of estrogen receptor alpha (ERα) in the dentate gyrus (DG) were assessed. The results suggest that there is a lot of physical contact between the mother and offspring from 21 to 42 days of age, which reduces anxiety in both female and male offspring in adulthood; for example, the PMP increased the amount of time mice spent in the center area in the open field experiment and in the bright area in the light-dark box experiment. PMP increased OT expression in the PVN and SON and the number of newly generated neurons in the DG. However, there was a sexual difference in ERα, with ERα increasing in females but decreasing in males. In conclusion, PMP reduces the anxiety of offspring in adulthood, increases OT in the PVN and SON, and adult neurogenesis; ERα in the DG may be involved in this process.

Pubertal stress in male rats: Effects on juvenile play behavior and adult sexual partner preference

Puberty is a period of brain organization impacting the expression of social and sexual behaviors. Here, we assessed the effects of an acute pubertal stressor (immune challenge) on the expression of juvenile play (short-term) and sexual partner preference (long-term) in male rats. Juvenile play was assessed over ten trials at postnatal days (PND) (31–40) with age- and sex-matched conspecifics, and at PND35 males received a single injection of lipopolysaccharide (LPS, 1.5 mg/kg i.p.) or saline. Then, sexual partner preference was assessed at PND 60, 64, and 68, in a three-compartment chamber with a sexually receptive female and a male as potential partners simultaneously. The results confirmed that a single injection of LPS during puberty induced sickness signs indicative of an immune challenge. However, juvenile play was not affected by LPS treatment during the following days (PND36–40), nor was sexual behavior and partner preference for females in adulthood. These findings highlight that, while other studies have shown that LPS-induced immunological stress during puberty affects behavior and neuroendocrine responses, it does not affect juvenile play and sexual behavior in male rats. This suggests a remarkable resilience of these behavioral systems for adaptation to stressful experiences mediated by immune challenges during critical periods of development. These behaviors, however, might be affected by other types of stress.

Frontoparietal and salience network synchronizations during nonsymbolic magnitude processing predict brain age and mathematical performance in youth.

The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills.

The Impact of Non-Physical Bullying on Adolescents' Self-Concept: An Observational Study in the Adolescent Community in Sausapor, Tambrauw Regency, West Papua, Indonesia

Introduction: Non-physical bullying, often subtle and insidious, poses a significant threat to adolescents' self-concept during a critical developmental period. This study investigates the prevalence and impact of non-physical bullying on adolescents' self-concept within the unique cultural context of Sausapor, Tambrauw Regency, West Papua, Indonesia. Methods: A cross-sectional observational study was conducted among adolescents aged 12-17 years in Sausapor. Data were collected using validated questionnaires assessing non-physical bullying experiences and self-concept dimensions (self-esteem, self-efficacy, and body image). Descriptive statistics, chi-square tests, and regression analyses were employed to examine the relationship between non-physical bullying and self-concept. Results: The study revealed a significant prevalence of non-physical bullying in the Sausapor adolescent community, with verbal abuse and social exclusion being the most common forms. Non-physical bullying was significantly associated with lower self-esteem, reduced self-efficacy, and negative body image among adolescents. Regression analyses confirmed the detrimental impact of non-physical bullying on self-concept, even after controlling for sociodemographic factors. Conclusion: Non-physical bullying is a pervasive issue in Sausapor, with profound negative consequences for adolescents’ self-concept. Culturally sensitive interventions are urgently needed to prevent and address non-physical bullying, promote positive self-concept development, and foster a supportive environment for adolescents in this community.

Children's Memory for Events: The Challenge of Free Recall.

Early childhood is a critical period for episodic memory development, with sharp behavioral improvements between ages 4 to 7 years. Prior work has demonstrated this extensively with prompted memory tasks, but we explored performance on unprompted, free recall of a naturalistic experience in children, and how their performance relates to other cognitive measures. We asked children and adults to view a television episode, a naturalistic task for which there exists a ground truth, and assessed their free recall memory for the episode. Children's free recall performance improved dramatically with age, with many young children producing no verbal free recall whatsoever, although prompted recognition memory measures showed retention of material. However, the detail in free recall was related to both recognition and temporal order forced-choice memory performance in our full sample, showing agreement among memory measures. Free recall was strongly predicted by verbal skills, suggesting that children's sparse recall reflects verbal skill development rather than a pure mnemonic deficit. We propose that free recall has a more protracted developmental trajectory because it requires more substantial verbal skills as well as metacognitive skills that direct memory search, as compared with forced-choice memory tasks.

Post-weaning social isolation alters sociability in a sex-specific manner.

Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting effects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions. The current study utilized this model to determine the impact of adolescent social isolation on a three-chamber social interaction task both during adolescence and adulthood. We found that while post-weaning isolation does not alter social interaction during adolescence (PND45), it has sex-specific effects on social interaction in adulthood (PND60), potentiating social interaction in male mice and decreasing it in female mice. As early life stress can activate microglia leading to alterations in neuronal pruning, we next examined the impact of inhibiting microglial activation with daily minocycline administration during the first three weeks of social isolation on these changes in social interaction. During adolescence, minocycline dampened social interaction in male mice, while having no effect in females. In contrast, during adulthood, minocycline did not alter the impact of adolescent social isolation in males, with socially isolated males exhibiting higher levels of social interaction compared to their group housed counterparts. In females, adolescent minocycline treatment reversed the effect of social isolation leading to increased social interaction in the social isolation group, mimicking what is seen in naïve males. Taken together, adolescent social isolation leads to sex-specific effects on social interaction in adulthood and adolescent minocycline treatment alters the effects of social isolation in females, but not males.

Empathy Capacity-Building through a Community of Practice Approach: Exploring Perceived Impacts and Implications

Empathy can be a powerful catalyst for caring action toward wildlife and nature more broadly. Given the critical developmental period of early childhood, interventions that build the capacity of educators to support empathy development in young children are needed. We report on an evaluation of an empathy-focused Community of Practice (CoP) that engaged 15 regional early childhood professionals (including four zoo preschool staff) in the co-creation of empathy practices that are deepened through a ‘Two-Worlds’ (Indigenous and Western) approach. Ripple effect mapping was the evaluation approach used, as its participatory nature and emphasis on reflection were well aligned with the CoP approach. The results suggest CoP participation influenced teachers’ capacity for supporting empathy development, which rippled outward from teacher-level impacts to positive impacts on children, families, and beyond. We also offer reflections on the use of a CoP approach to build individual, organizational, and community capacity for supporting empathy, as well as on the conduciveness of ripple effect mapping for evaluating capacity-building professional learning in the context of empathy conservation.

Acute social defeat during adolescence promotes long-lasting aggression through activation of the medial amygdala.

Traumatic stress, particularly during critical developmental periods such as adolescence, has been strongly linked to an increased propensity and severity of aggression. Existing literature underscores that being a victim of abuse can exacerbate aggressive behaviors, with the amygdala playing a pivotal role in mediating these effects. Historically, animal models have demonstrated that traumatic stressors can increase attack behavior, implicating various amygdala nuclei. Building on this foundation, our previous work has highlighted how traumatic stress invokes long-lasting aggression via an excitatory pathway within the posterior ventral medial amygdala (MeApv). In the current study, we sought to further delineate this mechanism by examining the effects of acute social defeat during adolescence on aggressive behaviors and neural activation in mice. Using a common social defeat paradigm, we first established that acute social defeat during late adolescence indeed promotes long-lasting aggression, measured as attack behavior 7 days after the defeat session. Immunolabeling with c-Fos demonstrated that acute social defeat activates the MeApv and ventrolateral aspect of the ventromedial hypothalamus (VmHvl), consistent with our previous studies that used foot shock as an acute stressor. Finally, chemogenetically inhibiting excitatory MeApv neurons during social defeat significantly mitigated the aggression increase without affecting non-aggressive social behavior. These results strongly suggest that the MeApv plays a critical role in the onset of aggression following traumatic social experience, and offer the MeA as a potential target for therapeutic interventions.

Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways.

Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic and environmental factors contributing to its development, a strong genetic basis is widely recognized. Recent research has identified numerous genetic mutations and genomic rearrangements associated with ASD-characterizing genes involved in brain development. Alterations in developmental programs are particularly harmful during critical periods of brain development. Notably, studies have indicated that genetic disruptions occurring during the second trimester of pregnancy affect cortical development, while disturbances in the perinatal and early postnatal period affect cerebellar development. The developmental defects must be viewed in the context of the role of the cerebellum in cognitive processes, which is now well established. The present review emphasizes the genetic complexity and neuropathological mechanisms underlying ASD and aims to provide insights into the cerebellar involvement in the disorder, focusing on recent advances in the molecular landscape governing its development in humans. Furthermore, we highlight when and in which cerebellar neurons the ASD-associated genes may play a role in the development of cortico-cerebellar circuits. Finally, we discuss improvements in protocols for generating cerebellar organoids to recapitulate the long period of development and maturation of this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could provide a valuable approach to elucidate the contribution of defective genes to ASD pathology and inform diagnostic and therapeutic strategies.

Temperature-Dependent Sex Determination in Crocodilians and Climate Challenges.

The sex of crocodilians is determined by the temperature to which the eggs, and hence the developing embryo are exposed during critical periods of development. Temperature-dependent sex determination is a process that occurs in all crocodilians and numerous other reptile taxa. The study of artificial incubation temperatures in different species of crocodiles and alligators has determined the specific temperature ranges that result in altered sex ratios. It has also revealed the precise temperature thresholds at which an equal number of males and females are generated, as well as the specific developmental period during which the sex of the hatchlings may be shifted. This review will examine the molecular basis of the sex-determination mechanism in crocodilians elucidated during recent decades. It will focus on the many patterns and theories associated with this process. Additionally, we will examine the consequences that arise after hatching due to changes in incubation temperatures, as well as the potential benefits and dangers of a changing climate for crocodilians who display sex determination based on temperature.

Discrimination experiences and problematic alcohol and cannabis use in young adulthood.

Limited research has examined how discrimination in young adulthood relates to substance use. We examined how multiple and specific types (e.g., race-based) of experiences of unfair treatment are related to problematic alcohol and cannabis use. We analyzed cross-sectional data from a diverse cohort of young adults (mean age 24.7) predominantly residing in southern California (n = 2303) to examine associations of multiple (count) and specific experiences (race-, sexual orientation-, gender-based) of perceived everyday discrimination with self-reported alcohol and cannabis use outcomes (consequences, use disorders, and solitary use). We also tested interactions between the three specific discrimination experiences and sociodemographic characteristics (e.g., race-based discrimination × race/ethnicity). In this diverse sample (e.g., 47% Latinx/o and 22% Asian; 22% sexual/gender diverse; 56% female) of young adults, about 46% reported up to four different discrimination experiences and 27% reported race-, 26% gender-, and 5% sexual orientation-based discrimination. Race- and gender-based discrimination and experiencing more types of discrimination were associated with worse cannabis use outcomes. Race-based discrimination was associated with fewer alcohol consequences and lower Alcohol Use Disorders Identification Test (AUDIT) scores. Associations with sexual orientation-based discrimination and the interactions were not significant. Findings build on limited research on associations of discrimination with cannabis use in young adults. More work is needed to understand the mechanisms by which discrimination influences drinking behaviors. This study advances the field by examining the unique contributions of specific and multiple types of discrimination experiences in young adulthood, a critical developmental period in which substance use peaks.

Research progress on the association between screen content and mental health issue in children and adolescents

With the wide use of screen media, screen exposure shows a trend of younger age, and the screen exposure of children and adolescents has become a global public health issue of concern. Childhood and adolescence are important stages of growth and development, as well as critical periods of cognitive ability, emotional development and socialization. Previous studies have shown that screen time is closely related to the mental health of children and adolescents, but few studies have focused on the correlation between screen content and their mental health. The screen content for children and adolescents mainly comes from traditional TV and emerging interactive electronic media. Children and adolescents are highly sensitive to screen content. This paper summarizes the current situation of screen content for children and adolescents and reviews the correlation between screen content and their mental health issues. It also reveals the potential mechanism of the correlation between the two to provide a theoretical basis for the selection and supervision of screen content for children and adolescents.

Adaptation and Validation of the Post-Pandemic Health Promotion Behavior of Young Adults in the Digital Age (PS-SGD) Scale in the Turkish Population.

Young adulthood is a critical developmental period in which individuals establish life-long health behaviors and take responsibility for their own health care. Health promotion strategies tailored to young adults, leveraging digital tools, and addressing challenges exacerbated by events like the COVID-19 pandemic are needed. The aim of this study was to adapt the post-pandemic health promotion behavior of young adults in the digital age (PS-SGD) scale to the Turkish population in order to assess and compare the health behavior of young adults after the pandemic. A total of 312 participants, aged between 19 and 29 years, were included in the study via non-probabilistic criterion sampling, while the Turkish adaptation process started with translation and back translation methods performed with three language and two health science experts. For statistical analysis, EFA and CFA were conducted to evaluate internal consistency and structural validity. Confirmatory factor analysis was utilized to confirm the structure of the six sub-dimensions. Additionally, measurement invariance was examined regarding participants' gender to determine if the scale accurately captured similar traits across diverse groups. The relationship between the test-retest data was tested by Pearson correlation to measure consistency and its invariance over time. The gender distribution of the sample was found to be 61.3% female and 38.7% male. According to the results of EFA, items 8 and 18 were removed from the Turkish-adapted version. As a result of the reliability analysis conducted with the Turkish version of the scale, the Cronbach alpha coefficient was obtained as 0.851 for the post-pandemic health promotion behavior. Additionally, the scale was rated as reliable with the following Cronbach alpha values: 0.79 for the "personal hygiene", 0.78 for "dietary habits", 0.72 for "using mobile devices", 0.70 for "emotional health", 0.68 for "health care and physical activity", and 0.51 for "social health" sub-dimensions. To examine the six sub-dimension factor structures of the scale, fit indices were calculated as χ2/df (1.722), GFI (0.894), IFI (0.908), TLI (0.892), CFI (0.907), RMSEA (0.048), and SRMR (0.057) and were within acceptable limits. Findings of the multi-group confirmatory factor analysis for measurement invariance were less than or equal to 0.01 for the ∆CFI and ∆RMSEA values across all indices. Consequently, it was observed that the item-factor structure, factor loadings, variances, covariances, and error variances of the scale were equivalent for both male and female young adults, while test-retest results showed a high positive correlation. The Turkish version of the post-pandemic health promotion behavior scale of young adults in the digital age scale, consisting of 25 items and six subscales, was proven to be a valid and reliable tool to measure health promotion behavior in young adults aged 19-29 years.

Glia control experience-dependent plasticity in an olfactory critical period.

Sensory experience during developmental critical periods has lifelong consequences for circuit function and behavior, but the molecular and cellular mechanisms through which experience causes these changes are not well understood. The Drosophila antennal lobe houses synapses between olfactory sensory neurons (OSNs) and downstream projection neurons (PNs) in stereotyped glomeruli. Many glomeruli exhibit structural plasticity in response to early-life odor exposure, indicating a general sensitivity of the fly olfactory circuitry to early sensory experience. We recently found that glia regulate the development of the antennal lobe in young adult flies, leading us to ask if glia also drive experience-dependent plasticity. Here we define a critical period for structural and functional plasticity of OSN-PN synapses in the ethyl butyrate (EB)-sensitive glomerulus VM7. EB exposure for the first two days post-eclosion drives large-scale reductions in glomerular volume, presynapse number, and post-synaptic activity. The highly conserved engulfment receptor Draper is required for this critical period plasticity. Specifically, ensheathing glia upregulate Draper expression, invade the VM7 glomerulus, and phagocytose OSN presynaptic terminals in response to critical-period EB exposure. Crucially, synapse pruning during the critical period has long-term consequences for circuit function since both OSN-PN synapse number and spontaneous activity of PNs remain persistently decreased. These data demonstrate experience-dependent pruning of synapses in olfactory circuitry and argue that the Drosophila antennal lobe will be a powerful model for defining the function of glia in critical period plasticity.

Floral Response to Heat: A Study of Color and Biochemical Adaptations in Purple Chrysanthemums.

Chrysanthemums are among the world's most popular cut flowers, with their color being a key ornamental feature. The formation of these colors can be influenced by high temperatures. However, the regulatory mechanisms that control the fading of chrysanthemum flower color under high-temperature stress remain unclear. This study investigates the impact of high temperatures on the color and biochemical responses of purple chrysanthemums. Four purple chrysanthemum varieties were exposed to both normal and elevated temperature conditions. High-temperature stress elicited distinct responses among the purple chrysanthemum varieties. 'Zi Feng Che' and 'Chrystal Regal' maintained color stability, whereas 'Zi Hong Tuo Gui' and 'Zi lian' exhibited significant color fading, particularly during early bloom stages. This fading was associated with decreased enzymatic activities, specifically of chalcone isomerase (CHI), dihydroflavonol 4-reductase (DFR), and anthocyanidin synthase (ANS), indicating a critical period of color development under heat stress. Additionally, the color fading of 'Zi Lian' was closely related to the increased activity of the peroxidase (POD) and polyphenol oxidase (PPO). Conversely, a reduction in β-glucosidase (βG) activity may contribute significantly to the color steadfastness of 'Zi Feng Che'. The genes Cse_sc027584.1_g010.1 (PPO) and Cse_sc031727.1_g010.1 (POD) might contribute to the degradation of anthocyanins in the petals of 'Zi Hong Tuo Gui' and 'Zi Lian' under high-temperature conditions, while simultaneously maintaining the stability of anthocyanins in 'Zi Feng Che' and 'Chrystal Regal' at the early bloom floral stage. The findings of this research provide new insights into the physiological and biochemical mechanisms by which chrysanthemum flower color responds to high-temperature stress.

Chronic Adolescent Restraint Stress Downregulates miRNA-200a Expression in Male and Female C57BL/6J and BALB/cJ Mice.

Adolescence is a critical developmental period when the brain is plastic, and stress exposure can have lasting physiological consequences. One mechanism through which adolescent stress may have lasting effects is by altering microRNAs (miRNAs), leading to wide-scale gene expression changes. Three prior independent studies used unbiased approaches (RNA sequencing or microarray) to identify miRNAs differentially expressed by chronic variable stress in male rodents. In all three studies, miRNA-200a was differentially expressed in areas of the brain associated with emotion regulation. The current study extends this research to determine if chronic non-variable adolescent stress downregulates miRNA-200a expression by looking at two strains (BALB/cJ and C57BL/6J) of male and female mice. We utilized a 14-day (2 h/day) restraint stress protocol and verified stress effects on adolescent body weight gain and circulating corticosterone concentrations relative to non-restraint controls. Mice were then left undisturbed until they were euthanized in adulthood, at which time brains were collected to measure miRNA-200a in the ventral hippocampus. Three weeks after adolescent stress ended, differences in body weight between groups were no longer significant; however, animals exposed to stress had less miRNA-200a expression in the ventral hippocampus than control animals. These data implicate miRNA-200a expression as a potential mechanism by which adolescent stress can have persistent impacts on multiple outcomes in both male and female mice.

Tutor auditory memory for guiding sensorimotor learning in birdsong.

Memory-guided motor shaping is necessary for sensorimotor learning. Vocal learning, such as speech development in human babies and song learning in bird juveniles, begins with the formation of an auditory template by hearing adult voices followed by vocally matching to the memorized template using auditory feedback. In zebra finches, the widely used songbird model system, only males develop individually unique stereotyped songs. The production of normal songs relies on auditory experience of tutor's songs (commonly their father's songs) during a critical period in development that consists of orchestrated auditory and sensorimotor phases. "Auditory templates" of tutor songs are thought to form in the brain to guide later vocal learning, while formation of "motor templates" of own song has been suggested to be necessary for the maintenance of stereotyped adult songs. Where these templates are formed in the brain and how they interact with other brain areas to guide song learning, presumably with template-matching error correction, remains to be clarified. Here, we review and discuss studies on auditory and motor templates in the avian brain. We suggest that distinct auditory and motor template systems exist that switch their functions during development.

Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6 J).

Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.

Purinosomes and Purine Metabolism in Mammalian Neural Development: A Review.

Neural stem/progenitor cells (NSPCs) in specific brain regions require precisely regulated metabolite production during critical development periods. Purines-vital components of DNA, RNA, and energy carriers like ATP and GTP-are crucial metabolites in brain development. Purine levels are tightly controlled through two pathways: de novo synthesis and salvage synthesis. Enzymes driving de novo pathway are assembled into a large multienzyme complex termed the "purinosome." Here, we review purine metabolism and purinosomes as spatiotemporal regulators of neural development. Notably, around postnatal day 0 (P0) during mouse cortical development, purine synthesis transitions from the de novo pathway to the salvage pathway. Inhibiting the de novo pathway affects mTORC1 pathway and leads to specific forebrain malformations. In this review, we also explore the importance of protein-protein interactions of a newly identified NSPC protein-NACHT and WD repeat domain-containing 1 (Nwd1)-in purinosome formation. Reduced Nwd1 expression disrupts purinosome formation, impacting NSPC proliferation and neuronal migration, resulting in periventricular heterotopia. Nwd1 interacts directly with phosphoribosylaminoimidazole-succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine synthesis. We anticipate this review will be valuable for researchers investigating neural development, purine metabolism, and protein-protein interactions.