Early Life Adversity Predicts Reduced Hippocampal Volume in the Adolescent Brain Cognitive Development Study.

PURPOSE: Cross-sectional studies in adults have demonstrated associations between early life adversity (ELA) and reduced hippocampal volume, but the timing of these effects is not clear. The present study sought to examine whether ELA predicts changes in hippocampal volume over time in a large sample of early adolescents. METHODS: The Adolescent Brain Cognitive Development Study provides a large dataset of tabulated neuroimaging, youth-reported adverse experiences, and parent-reported financial adversity from a sample of children around the United States. Linear mixed effects modeling was used to determine the relationship between ELA and hippocampal volume change within youth (n = 7036) from ages 9-10 to 11-12 years. RESULTS: Results of the models indicated that the number of early adverse events predicted bilateral hippocampal volume change (ß = -0.02, t = -2.02, p < .05). Higher adversity was associated with lower hippocampal volume at Baseline (t = 5.55, p < .01) and at Year 2 (t = 6.14, p < .001). DISCUSSION: These findings suggest that ELA may affect hippocampal development during early adolescence. Prevention and early intervention are needed to alter the course of this trajectory. Future work should examine associations between ELA, hippocampal development, and educational and socioemotional outcomes.

Single-nucleus chromatin landscape dataset of mouse brain development and aging.

The development and aging of the brain constitute a lifelong dynamic process, marked by structural and functional changes that entail highly coordinated cellular differentiation and epigenetic regulatory mechanisms. Chromatin accessibility serves as the foundational basis for genetic activity. However, the holistic and dynamic chromatin landscape that spans various brain regions throughout development and ageing remains predominantly unexplored. In this study, we employed single-nucleus ATAC-seq to generate comprehensive chromatin accessibility maps, incorporating data from 69,178 cells obtained from four distinct brain regions - namely, the olfactory bulb (OB), cerebellum (CB), prefrontal cortex (PFC), and hippocampus (HP) - across key developmental time points at 7 P, 3 M, 12 M, and 18 M. We delineated the distribution of cell types across different age stages and brain regions, providing insight into chromatin accessible regions and key transcription factors specific to different cell types. Our data contribute to understanding the epigenetic basis of the formation of different brain regions, providing a dynamic landscape and comprehensive resource for revealing gene regulatory programs during brain development and aging.

Effects of nanoplastic exposure during pregnancy and lactation on neurodevelopment of rat offspring.

Microplastics have emerged as a prominent global environmental contaminant, and they have been found in both human placenta and breast milk. However, the potential effects and mechanisms of maternal exposure to microplastics at various gestational stages on offspring neurodevelopment remain poorly understood. This investigation delves into the potential neurodevelopmental ramifications of maternal exposure to polystyrene nanoplastics (PS-NPs) during distinct phases of pregnancy and lactation. Targeted metabolomics shows that co-exposure during both pregnancy and lactation primarily engendered alterations in monoamine neurotransmitters within the cortex and amino acid neurotransmitters within the hippocampus. After prenatal exposure to PS-NPs, fetal rats showed appreciably diminished cortical thickness and heightened cortical cell proliferation. However, this exposure did not affect the neurodifferentiation of radial glial cells and intermediate progenitor cells. In addition, offspring are accompanied by disordered neocortical migration, typified by escalated superficial layer neurons proliferation and reduced deep layer neurons populations. Moreover, the hippocampal synapses showed significantly widened synaptic clefts and diminished postsynaptic density. Consequently, PS-NPs culminated in deficits in anxiolytic-like behaviors and spatial memory in adolescent offspring, aligning with concurrent neurotransmitter and synaptic alterations. In conclusion, this study elucidates the sensitive windows of early-life nanoplastic exposure and the consequential impact on offspring neurodevelopment.

Hydrogen peroxide in breast milk is crucial for gut microbiota formation and myelin development in neonatal mice.

Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating a deeper understanding of early life factors on children's brain development. This study introduces a mouse model, LAO1 knockout mice, to investigate the relationship between breast milk, the gut microbiome, and brain development. The results reveal that breast milk's reactive oxygen species (ROS) are vital in shaping the neonatal gut microbiota. Decreased hydrogen peroxide (H2O2) levels in milk disrupt the gut microbiome and lead to abnormal metabolite production, including D-glucaric acid. This metabolite inhibits hippocampal myelin formation during infancy, potentially contributing to behavioral abnormalities observed in adulthood. These findings suggest that H2O2 in breast milk is crucial for normal gut microbiota formation and brain development, with implications for understanding and potentially treating neurodevelopmental disorders in humans.

Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology.

N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B subunit incorporation to a later predominance of GluN2A. This GluN2B to GluN2A shift alters NMDAR calcium conductance dynamics and intracellular molecular signaling that are individually regulated by distinct GluN2 signaling domains and temporally align with developmental alterations in dendritic and synaptic plasticity. However, the impacts of individual GluN2B to GluN2A signaling domains on neuronal development remain unknown. Ionotropic and intracellular signaling domains of GluN2 subunits were separated by creating chimeric GluN2 subunits that were expressed in two transgenic mouse lines. Western blot and immunoprecipitation revealed that roughly one third of native synaptic NMDARs were replaced by transformed NMDARs without altering total synaptic NMDAR content. Schaffer collateral synaptic strength was transiently increased in acutely prepared hippocampal slices at just over 3 weeks of age in animals overexpressing the GluN2B carboxy terminus. Long-term potentiation (LTP) induction following lower frequency stimulation was regulated by GluN2 ionotropic signaling domains in an age-dependent manner and LTP maintenance was enhanced by overexpression of the GluN2B CTD in mature animals. After higher frequency stimulation, the induction and maintenance of LTP were increased in young adult animals overexpressing the GluN2B ionotropic signaling domains but reduced in juveniles just over 3 weeks of age. Confocal imaging of green fluorescent protein (GFP)- labeled CA1 pyramidal neurons revealed no alterations in dendritic morphology or spine density in mice expressing chimeric GluN2 subunits. These results illustrate how individual GluN2 subunit signaling domains do or do not control physiological and morphological development of hippocampal excitatory neurons and better clarify the neurobiological factors that govern hippocampal maturation. SIGNIFICANCE STATEMENT: A developmental reduction in the magnitude of hippocampal long-term synaptic potentiation (LTP) and a concomitant improvement in spatial maze performance coincide with greater incorporation of GluN2A subunits into synaptic NMDARs. Corroborating our prior discovery that overexpression of GluN2A-type ionotropic signaling domains enables context-based navigation in immature mice, GluN2A-type ionotropic signaling domain overexpression reduces LTP induction threshold and magnitude in immature mice. Also, we previously found that GluN2B carboxy terminal domain (CTD) overexpression enhances long-term spatial memory in mature mice and now report that the GluN2B CTD is associated with greater amplitude of LTP after induction in mature mice. Thus, the late postnatal maturation of context encoding likely relies on a shift toward GluN2A-type ionotropic signaling and a reduction in the threshold to induce LTP while memory consolidation and LTP maintenance are regulated by GluN2B subunit CTD signaling.

Faster pace of hippocampal growth mediates the association between perinatal adversity and childhood depression.

Early life adversity has been posited to influence the pace of structural neurodevelopment. Most research, however, has relied on cross-sectional data, which do not reveal whether the pace of neurodevelopmental change is accelerated or slowed following early exposures. In a birth cohort study that included neuroimaging data obtained at 4.5, 6, and 7.5 years of age (N = 784), we examined associations among a cumulative measure of perinatal adversity relative to resources, nonlinear trajectories of hippocampal and amygdala volume, and children's subsequent depressive symptoms at 8.5 years of age. Greater adversity was associated with reduced bilateral hippocampal body volume in early childhood, but also to faster growth in the right hippocampal body across childhood. Further, the association between adversity and childhood depressive symptoms was mediated by faster hippocampal body growth. These findings suggest that perinatal adversity is biologically embedded in hippocampal structure development, including an accelerated pace of change in the right hippocampal body that is implicated in children's psychopathology risk. In addition, our findings suggest that reduced hippocampal volume is not inconsistent with accelerated hippocampal change; these aspects of structural development may typically co-occur, as smaller regional volumes in early childhood were associated with faster growth across childhood.

Mixing energy drinks and alcohol during adolescence impairs brain function: A study of rat hippocampal plasticity.

In the last decades, the consumption of energy drinks has risen dramatically, especially among young people, adolescents and athletes, driven by the constant search for ergogenic effects, such as the increase in physical and cognitive performance. In parallel, mixed consumption of energy drinks and ethanol, under a binge drinking modality, under a binge drinking modality, has similarly grown among adolescents. However, little is known whether the combined consumption of these drinks, during adolescence, may have long-term effects on central function, raising the question of the risks of this habit on brain maturation. Our study was designed to evaluate, by behavioral, electrophysiological and molecular approaches, the long-term effects on hippocampal plasticity of ethanol (EtOH), energy drinks (EDs), or alcohol mixed with energy drinks (AMED) in a rat model of binge-like drinking adolescent administration. The results show that AMED binge-like administration produces adaptive hippocampal changes at the molecular level, associated with electrophysiological and behavioral alterations, which develop during the adolescence and are still detectable in adult animals. Overall, the study indicates that binge-like drinking AMED adolescent exposure represents a habit that may affect permanently hippocampal plasticity.

Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

Perinatal compromise affects development, form, and function of the hippocampus part two; preclinical studies.

The hippocampus is a vital brain structure deep in the medial temporal lobe that mediates a range of functions encompassing emotional regulation, learning, memory, and cognition. Hippocampal development is exquisitely sensitive to perturbations and adverse conditions during pregnancy and at birth, including preterm birth, fetal growth restriction (FGR), acute hypoxic-ischaemic encephalopathy (HIE), and intrauterine inflammation. Disruptions to hippocampal development due to these conditions can have long-lasting functional impacts. Here, we discuss a range of preclinical models of prematurity and FGR and conditions that induce hypoxia and inflammation, which have been critical in elucidating the underlying mechanisms and cellular and subcellular structures implicated in hippocampal dysfunction. Finally, we discuss potential therapeutic targets to reduce the burden of these perinatal insults on the developing hippocampus. IMPACT: The review explores the preclinical literature examining the association between pregnancy and birth complications, and hippocampal form and function. The developmental processes and cellular mechanisms that are disrupted within the hippocampus following perinatal compromise are described, and potential therapeutic targets are discussed.

Perinatal compromise affects development, form, and function of the hippocampus part one; clinical studies.

The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. IMPACT: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.

OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3ß/ß-catenin pathway after subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening neurological disease that usually has a poor prognosis. Neurogenesis is a potential therapeutic target for brain injury. Ketone metabolism also plays neuroprotective roles in many neurological disorders. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme of ketone body oxidation. In this study, we explored whether increasing ketone oxidation by upregulating OXCT1 in neurons could promote neurogenesis after SAH, and evaluated the potential mechanism involved in this process. METHODS: The ß-hydroxybutyrate content was measured using an enzymatic colorimetric assay. Adeno-associated virus targeting neurons was injected to overexpress OXCT1, and the expression and localization of proteins were evaluated by western blotting and immunofluorescence staining. Adult hippocampal neurogenesis was evaluated by dual staining with doublecortin and 5-Ethynyl-2'-Deoxyuridine. LY294002 was intracerebroventricularly administered to inhibit Akt activity. The Morris water maze and Y-maze tests were employed to assess cognitive function after SAH. RESULTS: The results showed that OXCT1 expression and hippocampal neurogenesis significantly decreased in the early stage of SAH. Overexpression of OXCT1 successfully increased hippocampal neurogenesis via activation of Akt/GSK-3ß/ß-catenin signaling and improved cognitive function, both of which were reversed by administration of LY294002. CONCLUSIONS: OXCT1 regulated hippocampal ketone body metabolism and increased neurogenesis through mechanisms mediated by the Akt/GSK-3ß/ß-catenin pathway, improving cognitive impairment after SAH.

RAB35 is required for murine hippocampal development and functions by regulating neuronal cell distribution.

RAB35 is a multifunctional small GTPase that regulates endocytic recycling, cytoskeletal rearrangement, and cytokinesis. However, its physiological functions in mammalian development remain unclear. Here, we generated Rab35-knockout mice and found that RAB35 is essential for early embryogenesis. Interestingly, brain-specific Rab35-knockout mice displayed severe defects in hippocampal lamination owing to impaired distribution of pyramidal neurons, although defects in cerebral cortex formation were not evident. In addition, Rab35-knockout mice exhibited defects in spatial memory and anxiety-related behaviors. Quantitative proteomics indicated that the loss of RAB35 significantly affected the levels of other RAB proteins associated with endocytic trafficking, as well as some neural cell adhesion molecules, such as contactin-2. Collectively, our findings revealed that RAB35 is required for precise neuronal distribution in the developing hippocampus by regulating the expression of cell adhesion molecules, thereby influencing spatial memory.

Prenatal development of the human entorhinal cortex.

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high-order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan-axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13-14th w.g. At 14 w.g., the superficial lamina dissecans (LD) is visible, which divides the CP into the lamina principalis externa (LPE) and interna (LPI). Simultaneously, the rostral LPE separates into vertical cell-dense islands, whereas in the LPI, the deep LD emerges as a clear acellular layer. In the 16th w.g., the LPE remodels into vertical cell-dense and cell-sparse zones with a caudorostral gradient. At 20 w.g., NeuN immunoreactivity is most pronounced in the islands of layer II cells, whereas migration and differentiation inside-out gradients are seen simultaneously in both the upper (LPE) and the lower (LPI) pyramidal layers. At this stage, the EC adopts for the first time an adult-like cytoarchitectural organization, the superficial LD becomes discernible by 3T MRI, MBP-expressing oligodendrocytes first appear in the fimbria and the perforant path (PP) penetrates the subiculum to reach its molecular layer and travels along through the Cornu Ammonis fields to reach the suprapyramidal blade of the dentate gyrus, whereas the entorhinal-dentate branch perforates the hippocampal sulcus about 2-3 weeks later. The first AChE reactivity appears as longitudinal stripes at 23 w.g. in layers I and II of the rostrolateral EC and then also as AChE-positive in-growing fibers in islands of superficial layer III and layer II neurons. At 40 w.g., myelination of the PP starts as patchy MBP-immunoreactive oligodendrocytes and their processes. Our results refute the possibility of an inside-out pattern of the EC development and support the key role of layer II prospective stellate cells in the EC lamination. As the early cytoarchitectural differentiation of the EC is paralleled by the neurochemical development, these developmental milestones in EC structure and connectivity have implications for understanding its normal function, including its puzzling modular organization and potential contribution to consciousness content (awareness), as well as for its insufficiently explored deficits in developmental, psychiatric, and degenerative brain disorders.

Kv1.1 preserves the neural stem cell pool and facilitates neuron maturation during adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897­914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel Kv1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al., eLife 10, e58779 (2021)]. To assess the role of Kv1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove Kv1.1 from adult neural stem cells via tamoxifen administration. We determined that Kv1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.

Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3ß.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 ß activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 ß during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.SIGNIFICANCE STATEMENT Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Terreros-Roncal et al. investigated the impacts of human neurodegeneration on immunostainings assumed to be associated with neurogenesis. However, the study provides no evidence that putative proliferating cells are linked to neurogenesis, that multipolar nestin+ astrocytes are progenitors, or that mature-looking doublecortin+ neurons are adult-born. Their histology-marker expression differs from what is observed in species where adult hippocampal neurogenesis is well documented.

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis.

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known. Here, we identify oleic acid (18:1ω9 monounsaturated fatty acid) as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

Maternal exposure to silicon dioxide nanoparticles reduces hippocampal neurogenesis and synaptogenesis and induces neurodegeneration in rat offspring hippocampus.

Silicon dioxide nanoparticles (SiO2-NPs) are among the most widely used nanoparticles because of their chemical-physical properties. Since most brain maturation occurs in the neonatal period in humans and many mammals, it is important to understand how NPs may affect this process. This study tested the hypothesis that SiO2-NPs from treated dams could affect the hippocampus of neonatal rats during lactation. Twenty-four pregnant rats, after delivery, were divided into three groups of control, SiO2-NPs (25 mg/kg) and SiO2-NPs (100 mg/kg). The rats were treated from 2nd to 21st days post-delivery by gavage and the effects of these NPs were evaluated in the offspring's hippocampi to reveal the effects of maternal exposure to SiO2-NPs during lactation on the offspring's hippocampi. The offspring in the SiO2-NPs groups had higher malondialdehyde concentration and lower antioxidant activity in the hippocampi than the non-treated control group. The mean number of doublecortin positive (DCX+) cells and synaptophysin expression in the hippocampi of the SiO2-NPs groups were significantly lower than the control group, whereas the mean number of dark neurons was significantly higher. Also, animals in the SiO2-NPs groups had a weak cognitive performance in adulthood. In conclusion, maternal exposure to SiO2-NPs via breastfeeding could affect offspring's hippocampal neurogenesis and synaptogenesis, leading to impaired cognitive performance.

The effect of Alzheimer's disease risk factors on brain aging in normal Chineses: Cognitive aging and cognitive reserve.

Aging has been recognized as a major driving force of the Alzheimer's disease's (AD) progression, however, the relationship between brain aging and AD is still unclear. There is also a lack of studies investigating the influence of AD risk factors on brain aging in cognitively normal people. Here, the "Brain Age Gap Estimation" (BrainAGE) framework was applied to investigate the effects of AD risk factors on individual brain aging. Across a total of 165 cognitively normal elderly subjects, although no significant difference was observed in the BrainAGE scores among the three groups, AD risk dose (i.e., the number of AD risk factors) is tend to associated with an increased BrainAGE scores (high-risk > middle risk > low risk). Female exhibited more advanced brain aging (P = 0.004), and higher education years were associated with preserved brain aging (P < 0.001). APOE-ɛ4 (P = 0.846) and family history (FH) of dementia (P = 0.209) did not increase BrainAGE scores. When comparing 52 aMCI patients with 38 cognitively normal controls from ADNI dataset, aMCI patients showed significantly increased BrainAGE scores. BrainAGE scores were negatively correlated with CSF Aß42 levels in the aMCI group (r = -0.275, P = 0.048). With an accuracy of 68.9%, BrainAGE outperformed APOE-ɛ4 and hippocampus gray matter volume (GMV) in predicting aMCI. In conclusion, AD is independently associated with structural changes in the brain that reflect advanced aging. Potentially, BrainAGE combined with APOE-ɛ4 and hippocampus GMV could be used as a pre-screening tool in early-stage AD.

Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction.

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.