Mature Neurons Research Articles

Taurine Reverses Arsenic-Induced Inhibition of Hippocampal Neurogenesis and Depression-Like Behavior in Mice.

Arsenic exposure results in damage to the neurological system. We previously demonstrated the arsenic-induced inhibition of hippocampal neurogenesis and its reversibility after exposure is terminated. The present study aimed to reveal whether arsenic-induced inhibition of hippocampal neurogenesis was ameliorated when taurine was co-administered, and we also investigated depression-like behavioral changes using the forced swim test. Mice were randomly divided into four groups. The first group received distilled water only for 4 months (control group), the second group received 4.0 mg/L As2O3 via drinking water for 4 months (arsenic group), the third group received 4.0 mg/L As2O3 and taurine (150 mg/kg body weight, by gavage, twice a week) for 4 months (arsenic + taurine group), and the fourth group received taurine only by gavage for 4 months (taurine group). The percentage of new mature neurons decreased in the arsenic group compared with the control group (64% ± 0.90% vs. 76% ± 1.9%, p < 0.01); however, this percentage was reversed to control levels in the arsenic + taurine group (76% ± 1.4%, p > 0.05). In the forced swim test, the immobility time during the last 4 min was significantly increased in the arsenic group, but restored to control levels in the arsenic + taurine group. The possible mechanisms of this taurine amelioration of hippocampal damage were further investigated, and included a reduction in oxidative stress as indicated by carbonyl content, inflammation, and aquaporin1, 4, and 8 expressions, as well as an increase in Wnt3a and brain-derived neurotrophic factor expression in western blot analyses.

The Deficiency of the ASD-Related Gene CHD8 Disrupts Behavioral Patterns and Inhibits Hippocampal Neurogenesis in Mice.

Chromodomain helicase DNA-binding 8 (CHD8) is a gene that poses a high risk for autism spectrum disorder (ASD) and neurological development delay. Nevertheless, the impact of CHD8 haploinsufficiency on both hippocampus neurogenesis and behavior remains uncertain. Here, we performed behavioral assessments on male and female CHD8 heterozygous mice. The study discovered that both male and female CHD8 heterozygous mice displayed an impairment in preference for social novelty. Concurrently, CHD8 heterozygous mice exhibited anxiety-like behavior. However, its cognitive capacity for learning and memory is within the expected range. Furthermore, we discovered a reduction in the number of both immature and mature new neurons in mice with CHD8 heterozygous, resulting in an impeded neurogenesis process in the hippocampus. Taken together, our findings indicate that CHD8 plays a crucial role in the regulation of hippocampal neurogenesis, and further suggest that ASD-like behaviors observed in CHD8 heterozygous mice may be associated with disruptions in hippocampal neurogenesis.

Molecular Motors in Myelination and Their Misregulation in Disease.

Molecular motors are cellular components involved in the intracellular transport of organelles and materials to ensure cell homeostasis. This is particularly relevant in neurons, where the synaptic components synthesized in the soma need to travel overlong distances to their destination. They can walk on microtubules (kinesins and dyneins) or actin filaments (myosins), themajor components of cell cytoskeleton. While kinesins mostly perform the anterograde transport of intracellular components toward the plus ends of microtubules located distally in cell processes, cytoplasmic dyneins allow the retrograde flux of intracellular cargo toward the minus ends of microtubules located at the cell soma. Axon myelination represents a major aspect of neuronal maturation and is essential for neuronal function, as it speeds up the transmission of electrical signals. Increasing evidence supports a role for molecular motors in the homeostatic control of myelination. This role includes the trafficking of myelin components along the processes of myelinating cells and local regulation of pathways that ensure axon wrapping. Dysfunctional control of the intracellular transport machinery has thereforebeen linked to several brain pathologies, including demyelinating diseases. These disordersinclude a broad spectrum of conditions characterized by pathological demyelination of axons within the nervous system, ultimately leading to axonal degeneration and neuronal death, withmultiple sclerosis representing the most prevalent and studied condition. This review highlights the involvement of molecular motors in the homeostatic control of myelination. It also discusses studies that have yielded insights into the dysfunctional activity of molecular motors in the pathophysiology of multiple sclerosis.

Synergistic effects of human umbilical cord mesenchymal stem cells/neural stem cells and epidural electrical stimulation on spinal cord injury rehabilitation

Spinal cord injury (SCI) is a severe neurological condition marked by a complex pathology leading to irreversible functional loss, which current treatments fail to improve. Epidural electrical stimulation (EES) shows promise in alleviating pathological pain, regulating hemodynamic disturbances, and enhancing motor function by modulating residual interneurons in the lower spinal cord. Cell transplantation (CT), especially using human umbilical cord mesenchymal stem cells (hUCMSCs) and neural stem cells (NSCs), has significantly improved sensory and motor recovery in SCI. However, the limitations of single treatments have driven the exploration of a multifaceted strategy, combining various modalities to optimize recovery at different stages. To comprehensively investigate the effectiveness of in situ transplantation of hUCMSCs/NSCs combined with subacute epidural electrical stimulation in a murine spinal cord crush injury model, providing valuable references for future animal studies and clinical research. In this study, we first examined neural stem cell changes via mRNA sequencing in an in vitro Transwell co-culture model. We then explored cell interaction mechanisms using proliferation assays, differentiation assays, and neuron complexity analysis. For animal experiments, 40 C57BL/6 mice were assigned to four groups (Injury/EES/CT/Combination). Histological evaluations employed HE and immunofluorescence staining, while electrophysiological and behavioral tests assessed motor recovery. Quantitative data were reported as mean ± standard error, with statistical analyses performed using GraphPad Prism and SPSS. Initially, we found that NSCs in the in vitro co-culture model showed a unique expression profile of differentially expressed genes (DEGs) compared to controls. GO/KEGG analysis indicated these DEGs were mainly linked to cell differentiation and growth factor secretion pathways. Neuronal and astrocytic markers further confirmed enhanced NSC differentiation and neuronal maturation in the co-culture model. In vivo, live imaging and human nuclei immunofluorescence staining revealed that transplanted cells persisted for some time post-transplantation. Histological analysis showed that during acute inflammation, both the stem cell and combined therapy groups significantly inhibited microglial polarization. In the chronic phase, these groups reduced fibrotic scar formation and encouraged astrocytic bridging. Behavioral tests, including swimming and gait analysis, demonstrated that combined CT and EES therapy was more effective than either treatment alone. In summary, the combined therapy offers a promising approach for spinal cord injury treatment, providing superior outcomes over individual treatments. Our findings underscore the potential of a combined treatment approach utilizing stem cells transplantation and EES as an effective strategy for the comprehensive management of spinal cord crush injury in mice. This integrated approach holds promise for enhancing functional recovery and improving the quality of life for individuals with spinal cord injury (SCI).

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

Aberrance of GAP43/p-GAP43 Closely Associates with the Pathology of Neuron Loss in Prion-Infected Rodent Models.

Prion diseases are fatal neurodegenerative disorders characterized by neuron damage and loss. Growth-associated protein 43 (GAP43) functions in neuronal plasticity and synaptic function, but its role in prion diseases is not fully elucidated. In this study, we investigated the changes of GAP43 in the central nerve system (CNS) of several prion-infected rodent models and explored the potential relationship of GAP43 with PrPSc deposit and neuron loss using various methods. We found that GAP43 levels were significantly decreased in the brain tissues of scrapie-infected rodent models at the terminal stage of the disease. Immunohistochemical analysis showed that GAP43 colocalized with NeuN-positive cells morphologically, indicating the presence of GAP43 in mature neurons. On contrary, the levels of GAP43 and p-GAP43 increased in a prion-infected cell line SMB-S15 in vitro, accompanying with the increase of intracellular calcium. Stimulation of lipopolysaccharide (LPS) upregulated while removal of PrPSc propagation downregulated the level of GAP43 in SMB-S15 cells. Morphological colocalization and molecular interaction between GAP43 and PrPSc have been addressed in the brains of prion-infected rodents and prion-infected cell line. Histological assays of the serial sections of the whole brains of prion-infected mice proposed that the reduced GAP43 level correlated with large amount of PrPSc deposits and notable neuron damage and loss showing cell crumpled and nuclear pyknosis. The impairment of GAP43 signaling and disturbance of calcium homeostasis by aberrance of brain GAP43/p-GAP43 not only reflect but also likely contribute to the pathology of severe neuron loss at the end of prion disease.

Olfactory Dysfunction in Obesity and Type 2 Diabetes

The article analyzes literature data on the close relationship between energy balance and sense of smell. Olfaction is one of the main modalities of hedonic evaluation of food. Odor is one of the most important sensory signals predicting food quality and plays a key role in food selection and consumption. Appetite can be stimulated by various stimuli, but the leading role belongs to olfactory signals (tasty smells) and levels of hormones that signal hunger and satiety. Olfactory perception is subject to hormonal modulation. In this regard, special attention in the article is paid to the modulating function of insulin. Insulin, one of the main metabolic hormones that controls food intake, has an anorexigenic effect not only at the level of the hypothalamus, but also at the level of the olfactory pathway, especially strong in the olfactory bulb. It has a rate of insulin transport two to eight times higher than in other parts of the brain, and it contains the highest concentration of insulin and the highest density of insulin receptor kinase. Thus, insulin is not only able to penetrate to the site of olfactory information processing, but do so quickly. At the same time, insulin and its receptors are localized in the olfactory epithelium, namely in mature olfactory sensory neurons. Therefore, insulin affects the primary stage of perception of an odorous molecule – odor detection, which occurs at the level of the olfactory epithelium. The sense of smell is impaired up to its complete loss in obesity and type 2 diabetes, worsening the quality of life of such patients. The paper examines the effectiveness of intranasal insulin administration to restore olfactory function in metabolic disorders and other diseases.

In Vitro and In Vivo Methods for Studying Retinal Ganglion Cell Survival and Optic Nerve Regeneration.

Glaucoma is marked by a progressive degeneration of the optic nerve and delayed loss of retinal ganglion cells (RGCs), the projection neurons of the eye. Because RGCs are not replaced and because surviving RGCs cannot regenerate their axons, the visual loss in glaucoma is largely irreversible. Here we describe methods to evaluate treatments that may be beneficial for treating glaucoma using in vitro cell culture models (immunopanning to isolate neonatal RGCs, dissociated mature retinal neurons, retinal explants) and in vivo models that test potential treatments or investigate underlying molecular mechanisms in an intact system. Potentially, the use of these models can help investigators continue to improve treatments to preserve RGCs and restore visual function in patients with glaucoma.

Validation of a functional human AD model with four AD therapeutics utilizing patterned ipsc-derived cortical neurons integrated with microelectrode arrays

Preclinical methods are needed for screening potential Alzheimer’s disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. Long-term potentiation (LTP), which is a correlate of learning and memory, was induced in mature human iPSC-derived cortical neurons cultured on microelectrode arrays utilizing circuit patterns connecting two adjacent electrodes. We demonstrated an LTP system that modeled the MCI and pre-MCI stages of Alzheimer’s and validated this functional system utilizing four AD therapeutics, which was also verified utilizing patch-clamp electrophysiology. LTP was induced by tetanic electrical stimulation, and LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42-induced LTP impairment. The results illustrate the utility of the system as a validated platform to model MCI AD pathology, and potentially for the pre-MCI phase before significant neuronal death. This system also has the potential to become an ideal platform for high-content therapeutic screening for other neurodegenerative diseases.

Biomarkers of mature neuronal differentiation and related diseases.

The nervous system regulates perception, cognition and behavioral responses by serving as the body's primary communication system for receiving, regulating and transmitting information. Neurons are the fundamental structures and units of the nervous system. Their differentiation and maturation processes rely on the expression of specific biomarkers. Neuron-specific intracellular markers can be used to determine the degree of neuronal maturation. Neuronal cytoskeletal proteins dictate the shape and structure of neurons, while synaptic plasticity and signaling processes are intricately associated with neuronal synaptic markers. Furthermore, abnormal expression levels of biomarkers can serve as diagnostic indicators for nervous system diseases. This article reviews the markers of mature neuronal differentiation and their relationship with nervous system diseases.

Complement C5a Implication in Axonal Growth After Injury.

Complement C5a protein has been shown to play a major role in tissue regeneration through interaction with its receptor (C5aR) on target cells. Expression of this receptor has been reported in the nervous system which, upon injury, has no treatment to restore the lost functions. This work aimed at investigating the Complement C5a effect on axonal growth after axotomy in vitro. Primary hippocampal neurons were isolated from embryonic Wistar rats. Cell expression of C5aR mRNA was verified by RT-PCR while its membrane expression, localization, and phosphorylation were investigated by immunofluorescence. Then, the effects of C5a on injured axonal growth were investigated using a 3D-printed microfluidic device. Immunofluorescence demonstrated that the primary cultures contained only mature neurons (93%) and astrocytes (7%), but no oligodendrocytes or immature neurons. Immunofluorescence revealed a co-localization of NF-L and C5aR only in the mature neurons where C5a induced the phosphorylation of its receptor. C5a application on injured axons in the microfluidic devices significantly increased both the axonal growth speed and length. Our findings highlight a new role of C5a in regeneration demonstrating an enhancement of axonal growth after axotomy. This may provide a future therapeutic tool in the treatment of central nervous system injury.

Assessing the Neurodevelopmental Impact of Fluoxetine, Citalopram, and Paroxetine on Neural Stem Cell-Derived Neurons

Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a large amount of research suggesting a potential link to neurodevelopmental disorders in children whose mothers took these drugs during pregnancy, their possible adverse effects are still debated, and results are contradictory. On the other hand, there is an immediate need for improved cell-based models for developmental neurotoxicity studies (DNT) to minimize the use of animals in research. Methods: In this study, we aimed to assess the effects of clinically relevant concentrations of paroxetine (PAR), fluoxetine (FLX), and citalopram (CIT)—on maturing neurons derived from human neural stem cells using multiple endpoints. Results: Although none of the tested concentrations of FLX, CIT, or PAR significantly affected cell viability, FLX (10 µM) exhibited the highest reduction in viability compared to the other drugs. Regarding neurite outgrowth, CIT did not have a significant effect. However, FLX (10 µM) significantly reduced both mean neurite outgrowth and mean processes, PAR significantly reduced mean processes, and showed a trend of dysregulation of multiple genes associated with neuronal development at therapeutic-relevant serum concentrations. Conclusions: Transcriptomic data and uptake experiments found no SERT activity in the system, suggesting that the adverse effects of FLX and PAR are independent of SERT.

Developmental Syngap1 haploinsufficiency in medial ganglionic eminence-derived interneurons impairs auditory cortex activity, social behavior and extinction of fear memory.

Mutations in SYNGAP1, a protein enriched at glutamatergic synapses, cause intellectual disability associated with epilepsy, autism spectrum disorder and sensory dysfunctions. Several studies showed that Syngap1 regulates the time course of forebrain glutamatergic synapse maturation; however, the developmental role of Syngap1 in inhibitory GABAergic neurons is less clear. GABAergic neurons can be classified into different subtypes based on their morphology, connectivity and physiological properties. Whether Syngap1 expression specifically in Parvalbumin (PV) and Somatostatin (SST)-expressing interneurons, which are derived from the medial ganglionic eminence, plays a role in the emergence of distinct brain functions remains largely unknown. We used genetic strategies to generate Syngap1 haploinsufficiency in a) prenatal interneurons derived from the medial ganglionic eminence, b) in postnatal PV cells and c) in prenatal SST interneurons. We further performed in vivo recordings and behavioral assays to test whether and how these different genetic manipulations alter brain function and behavior in mice of either sex.Mice with prenatal-onset Syngap1 haploinsufficiency restricted to Nkx2.1-expressing neurons show abnormal cortical oscillations and increased entrainment induced by 40Hz auditory stimulation, but lack of stimulus-specific adaptation. This latter phenotype was reproduced in mice with Syngap1 haploinsufficiency restricted to PV, but not SST, interneurons. Prenatal-onset Syngap1 haploinsufficiency in Nkx2.1-expressing neurons led to impaired social behavior and inability to extinguish fear memories; however, neither postnatal PV- nor prenatal SST-specific mutant mice show these phenotypes. We speculate that Syngap1 haploinsufficiency in prenatal/perinatal PV interneurons may contribute to cortical activity and cognitive alterations associated with Syngap1 mutations.Significance statement Mutations in the human gene cause a form of developmental epileptic encephalopathy associated with intellectual disability, autism and sensory dysfunctions. Several studies have shown that in addition to playing a major role in the synaptic maturation and plasticity of forebrain excitatory neurons, Syngap1 affects GABAergic circuit function as well. Forebrain GABAergic neurons can be divided into different subtypes. Whether Syngap1 expression specifically in distinct interneuron populations and during specific developmental time windows plays a role in the emergence of distinct brain functions remains largely unknown. Here, we report that early, pre or perinatal Syngap1 expression in developing GABAergic neurons derived from the medial ganglionic eminence promotes the development of auditory cortex function, social behavior and ability to extinguish fear memories.

Chronic Low-Dose-Rate Radiation-Induced Persistent DNA Damage and miRNA/mRNA Expression Changes in Mouse Hippocampus and Blood.

Our previous study demonstrated that the acute high-dose-rate (3.3 Gy/min) γ-ray irradiation (γ-irradiation) of postnatal day-3 (P3) mice with 5 Gy induced depression and drastic neuropathological changes in the dentate gyrus of the hippocampus of adult mice. The present study investigated the effects of chronic low-dose-rate (1.2 mGy/h) γ-irradiation from P3 to P180 with a cumulative dose of 5 Gy on animal behaviour, hippocampal cellular change, and miRNA and mRNA expression in the hippocampus and blood in female mice. The radiation exposure did not significantly affect the animal's body weight, and neuropsychiatric changes such as anxiety and depression were examined by neurobehavioural tests, including open field, light-dark box, elevated plus maze, tail suspension, and forced swim tests. Immunohistochemical staining did not detect any obvious loss of mature and immature neurons (NeuN and DCX) or any inflammatory glial response (IBA1, GFAP, and PDGFRα). Nevertheless, γH2AX foci in the stratum granulosum of the dentate gyrus were significantly increased, suggesting the chronic low-dose-rate irradiation induced persistent DNA damage foci in mice. miRNA sequencing and qRT-PCR indicated an increased expression of miR-448-3p and miR-361-5p but decreased expression of miR-193a-3p in the mouse hippocampus. Meanwhile, mRNA sequencing and qRT-PCR showed the changed expression of some genes, including Fli1, Hs3st5, and Eif4ebp2. Database searching by miRDB and TargetScan predicted that Fli1 and Hs3st5 are the targets of miR-448-3p, and Eif4ebp2 is the target of miR-361-5p. miRNA/mRNA sequencing and qRT-PCR results in blood showed the increased expression of miR-6967-3p and the decreased expression of its target S1pr5. The interactions of these miRNAs and mRNAs may be related to the chronic low-dose-rate radiation-induced persistent DNA damage.

Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.

Transcriptome and acetylome profiling identify crucial steps of neuronal differentiation in Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome (RTS) is a rare and severe genetic developmental disorder characterized by multiple congenital anomalies and intellectual disability. CREBBP and EP300, the two genes known to cause RTS encode transcriptional coactivators with a catalytic lysine acetyltransferase (KAT) activity. Loss of CBP or p300 function results in a deficit in protein acetylation, in particular at histones. In RTS, nothing is known on the consequences of the loss of histone acetylation on the transcriptomic profiles during neuronal differentiation. To address this question, we differentiated induced pluripotent stem cells from RTS patients carrying a recurrent CREBBP mutation that inactivates the KAT domain into cortical and pyramidal neurons. By comparing their acetylome and their transcriptome at different neuronal differentiation time points, we identified 25 specific acetylated histone residues altered in RTS. We also identified the transition between neural progenitors and immature neurons as a critical step of the differentiation process, with a delayed neuronal maturation in RTS. Overall, this study opens new perspectives in the definition of epigenetic biomarkers for RTS, whose methodology could be extended to other chromatinopathies.

Cochlear implant/MXene-based electroacoustic stimulation modulates the growth and maturation of spiral ganglion neurons

Cochlear implantation (CI) offers a dependable treatment for sensorineural hearing loss, with precision electroacoustic stimulation parameters showing great potential in improving auditory outcomes in CI patients. Here, we report the attachment of MXene into CI systems which effectively mimic the neural electrode interface due to MXene's excellent electrical conductivity and biocompatibility. Low-frequency short-term biphasic electrical pulses emitted by the MXenes-based CI promoted the outgrowth of spiral ganglion neuron (SGN) neurites and growth cones, substantially boosting the calcium activity in SGNs. This study lays a theoretical foundation for the precision medicine approaches in CI patient care, and informs the selection of materials for cochlear implant electrode materials in the future.

Slight and hidden hearing loss in young rats is associated with impaired recognition memory and reduced myelination in the corpus callosum.

Slight and hidden hearing loss in children have been linked to cognitive and social difficulties, and yet the neurobiological mechanisms behind these issues remain poorly understood. Most animal models focus on severe hearing loss, leaving the effects of hidden or slight hearing loss largely unexplored. To uncover the neural mechanisms connecting slight/hidden hearing loss to cognitive and social challenges, we induced hearing loss in young (4-week-old) Wistar rats through noise exposure. We then examined cognitive function (object recognition test) and social behavior (juvenile play behavior and social interaction). Changes in brain anatomy were assessed using cortical thickness and hippocampal size measurements, while (immuno)histochemical staining investigated neuronal circuitry maturation (myelin basic protein, parvalbumin, and perineuronal nets) and neurogenesis (doublecortin). Noise-exposed rats displayed slight high-frequency hearing loss (around 20 dB) and hidden hearing loss at other tested frequencies. This slight/hidden hearing loss was associated with impaired object recognition but did not alter social behavior. Slight/hidden hearing loss was associated with reduced myelin basic protein expression in the corpus callosum but no other alterations in cortical thickness, hippocampal size, or other markers of maturation and neurogenesis were found. These findings show that even slight/hidden hearing loss can lead to subtle brain alterations tied to cognitive deficits. This study emphasizes the need for further research to fully understand the brain changes associated with slight/hidden hearing loss and to pinpoint the mechanisms connecting these changes to behavioral deficits. This information is crucial to develop interventions to prevent the cognitive and social consequences of hearing loss. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exaggerated postnatal surge of orexin neurons and the effects of elimination of excess orexin on blood pressure and exaggerated chemoreflex in spontaneously hypertensive rats.

An overactive orexin (OX) system is associated with neurogenic hypertension and an exaggerated chemoreflex in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of this association is unclear. We hypothesized that increased postnatal neurogenesis of OX neurons in SHRs precedes and contributes to the aberrant increase in mean arterial blood pressure (MAP) and the exaggerated response to hypercapnia during postnatal development. Using immunohistochemical methods and bromodeoxyuridine, we mapped the timeline of orexin neuron neurogenesis and maturation during early postnatal development. We then used whole-body plethysmography with EEG and EMG to map the development of mean arterial pressure (MAP) and state regulation. Finally, we used OX-targeted saporin toxin to determine the effects of eliminating excess OX neurons on the elevated MAP and exaggerated chemoreflex in adult SHRs. We found that both SHRs and Wistar-Kyoto (WKY) rats experienced postnatal increases in OX neurons. However, SHRs experienced a greater increase than WKY rats before P15, which led to significantly more OX neurons in SHRs than age-matched WKY controls by P15-16 (3,720 ± 780 vs. 2,406 ± 363, p = 0.005). We found that neurogenesis, as evidenced by BrdU staining in OX-positive neurons, was the primary contributor to the excess OX neurons in SHRs during early postnatal development. While SHRs develop more OX neurons by P15-16, SHRs and normotensive WKY control rats have similar MAP during postnatal development until P25 in wakefulness (81.6 ± 6.6 vs. 67.5 ± 6.8mmHg, p = 0.006) and sleep (79.3 ± 6.1 vs. 66.6 ± 6.5, p = 0.009), about 10 days after the surge of OX neurons. By selectively eliminating excess (∼30%) OX neurons in SHRs, we saw a significantly lowered MAP and hypercapnic ventilatory chemoreflex compared to non-lesioned SHRs at P40. Additionally, we found unique signatures in state indicative of the attention defecit phenotype commonly associated with this model. We suggest that the postnatal increase of OX neurons, primarily attributed to exaggerated postnatal OX neurogenesis, may be necessary for the development of higher MAP and exaggerated chemoreflex in SHRs, and modulation of the overactive OX system may have a potential therapeutic effect during the pre-hypertensive period.

APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.

Apolipoprotein E4 ( APOE4 ) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, imaging, and cognitive assessments reveal that APOE4 influences brain structure and function as early as infancy. Here, we examined human-relevant cellular phenotypes across neurodevelopment using induced pluripotent stem cell (iPSC) derived cortical and ganglionic eminence organoids (COs and GEOs). In COs, we showed that APOE4 decreased BRN2+ and SATB2+ cortical neurons, increased astrocytes and outer radial glia, and was associated with increased cell death and dysregulated GABA-related gene expression. In GEOs, APOE4 accelerated maturation of neural progenitors and neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupted network formation and altered response to GABA, resulting in heightened excitability and synchronicity. Together, our data provides new insights into how APOE4 may influence cortical neurodevelopmental processes and network formation in the human brain.