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Biomolecules Jun 2024Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular...
BACKGROUND
Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs).
METHODS
Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone).
RESULTS
Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment.
CONCLUSIONS
Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.
Topics: Humans; Olanzapine; Risperidone; Neurogenesis; Hippocampus; Haloperidol; Antipsychotic Agents; Induced Pluripotent Stem Cells; Neural Stem Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Neuronal Outgrowth
PubMed: 38927091
DOI: 10.3390/biom14060688 -
Journal of Neural Engineering Jun 2024Current neuronal imaging methods use bulky lenses that either impede animal behavior or prohibit multi-depth imaging. To overcome these limitations, we developed a...
Current neuronal imaging methods use bulky lenses that either impede animal behavior or prohibit multi-depth imaging. To overcome these limitations, we developed a lightweight lensless biophotonic system for neuronal imaging, enabling compact and simultaneous visualization of multiple brain layers. Our developed "CIS-NAIST" device integrates a micro-CMOS image sensor, thin-film fluorescence filter, micro-LEDs, and a needle-shaped flexible printed circuit. With this device, we monitored neuronal calcium dynamics during seizures across the different layers of the hippocampus. The CIS-NAIST device revealed distinct calcium activity patterns across the CA1, molecular interlayer, and dentate gyrus. Our findings indicated an elevated calcium amplitude activity specifically in the dentate gyrus compared to other layers. Then, leveraging the multi-layer data obtained from the device, we employed machine learning techniques for seizure classification and prediction. Using Long-Short Term Memory and Hidden Markov Models, we successfully classified seizure calcium activity and predicted seizure behavior based on the multi-layer imaging data. Taken together, our device can enable a minimally invasive method of seizure monitoring that can help elucidate the mechanisms of temporal lobe epilepsy. .
PubMed: 38925109
DOI: 10.1088/1741-2552/ad5c03 -
Neuron Jun 2024The hippocampus receives sequences of sensory inputs from the cortex during exploration and encodes the sequences with millisecond precision. We developed a predictive...
The hippocampus receives sequences of sensory inputs from the cortex during exploration and encodes the sequences with millisecond precision. We developed a predictive autoencoder model of the hippocampus including the trisynaptic and monosynaptic circuits from the entorhinal cortex (EC). CA3 was trained as a self-supervised recurrent neural network to predict its next input. We confirmed that CA3 is predicting ahead by analyzing the spike coupling between simultaneously recorded neurons in the dentate gyrus, CA3, and CA1 of the mouse hippocampus. In the model, CA1 neurons signal prediction errors by comparing CA3 predictions to the next direct EC input. The model exhibits the rapid appearance and slow fading of CA1 place cells and displays replay and phase precession from CA3. The model could be learned in a biologically plausible way with error-encoding neurons. Similarities between the hippocampal and thalamocortical circuits suggest that such computation motif could also underlie self-supervised sequence learning in the cortex.
PubMed: 38917804
DOI: 10.1016/j.neuron.2024.05.024 -
Brain Structure & Function Jun 2024In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein...
In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment.
PubMed: 38916724
DOI: 10.1007/s00429-024-02816-1 -
International Journal of Nanomedicine 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a...
BACKGROUND
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR TItpr3/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.
METHODS
Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.
RESULTS
Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX and SOX2/GFAP cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.
CONCLUSION
In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.
Topics: Animals; Mice, Inbred C57BL; Mice; Fullerenes; Autism Spectrum Disorder; Cognitive Dysfunction; Disease Models, Animal; Male; Doublecortin Protein; Social Behavior; Behavior, Animal; Hippocampus; Vascular Endothelial Growth Factor A; Neuroprotective Agents; Neurogenesis; Autistic Disorder
PubMed: 38911505
DOI: 10.2147/IJN.S459511 -
Cell Reports Jun 2024The dentate gyrus plays a key role in the discrimination of memories by segregating and storing similar episodes. Whether hilar mossy cells, which constitute a major...
The dentate gyrus plays a key role in the discrimination of memories by segregating and storing similar episodes. Whether hilar mossy cells, which constitute a major excitatory principal cell type in the mammalian hippocampus, contribute to this decorrelation function has remained largely unclear. Using two-photon calcium imaging of head-fixed mice performing a spatial virtual reality task, we show that mossy cell populations robustly discriminate between familiar and novel environments. The degree of discrimination depends on the extent of visual cue differences between contexts. A context decoder revealed that successful environmental classification is explained mainly by activity difference scores of mossy cells. By decoding mouse position, we reveal that in addition to place cells, the coordinated activity among active mossy cells markedly contributes to the encoding of space. Thus, by decorrelating context information according to the degree of environmental differences, mossy cell populations support pattern separation processes within the dentate gyrus.
PubMed: 38909362
DOI: 10.1016/j.celrep.2024.114386 -
Neuroscience Bulletin Jun 2024Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely...
Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
PubMed: 38907786
DOI: 10.1007/s12264-024-01241-y -
NPJ Microgravity Jun 2024Cognitive impairments have been reported in astronauts during spaceflights and documented in ground-based models of simulated microgravity (SMG) in animals. However, the...
Cognitive impairments have been reported in astronauts during spaceflights and documented in ground-based models of simulated microgravity (SMG) in animals. However, the neuronal causes of these behavioral effects remain largely unknown. We explored whether adult neurogenesis, known to be a crucial plasticity mechanism supporting memory processes, is altered by SMG. Adult male Long-Evans rats were submitted to the hindlimb unloading model of SMG. We studied the proliferation, survival and maturation of newborn cells in the following neurogenic niches: the subventricular zone (SVZ)/olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus, at different delays following various periods of SMG. SMG exposure for 7 days, but not shorter periods of 6 or 24 h, resulted in a decrease of newborn cell proliferation restricted to the DG. SMG also induced a decrease in short-term (7 days), but not long-term (21 days), survival of newborn cells in the SVZ/OB and DG. Physical exercise, used as a countermeasure, was able to reverse the decrease in newborn cell survival observed in the SVZ and DG. In addition, depending on the duration of SMG periods, transcriptomic analysis revealed modifications in gene expression involved in neurogenesis. These findings highlight the sensitivity of adult neurogenesis to gravitational environmental factors during a transient period, suggesting that there is a period of adaptation of physiological systems to this new environment.
PubMed: 38906877
DOI: 10.1038/s41526-024-00411-6 -
Neurobiology of Learning and Memory Jun 2024The ability to learning and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as...
The ability to learning and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as abnormal levels of maternal care. The exact mechanisms underlying these effects still remain elusive. This study examined in male mice whether early life stress (ELS) alters memory and brain activation patterns, by studying the expression of the immediate early genes (IEGs) c-Fos and Arc in the dentate gyrus (DG) and basolateral amygdala (BLA) after training and memory retrieval in a fear conditioning task. Furthermore, we examined the potential of RU38486 (RU486), a glucocorticoid receptor antagonist, to mitigate ELS-induced memory deficits by blocking stress signalling during adolescence. Arc::dVenus reporter mice, which allow investigating experience-dependent expression of the immediate early gene Arc also at more remote time points, were exposed to ELS by housing dams and offspring with limited bedding and nesting material (LBN) between postnatal days (PND) 2-9 and trained in a fear conditioning task at adult age. We found that ELS reduced both fear acquisition and contextual memory retrieval. RU486 did not prevent these effects. ELS reduced the number of Arc::dVenus cells in DG and BLA after training, while the number of c-Fos cells were left unaffected. After memory retrieval, ELS decreased c-Fos cells in the ventral DG and BLA. ELS also disrupted the colocalization of c-Fos cells with (training activated) Arc::dVenus cells in the ventral DG, possibly indicating impaired engram allocation in the ventral DG after memory retrieval. Altered correlated activity during training and changes in IEG expression over time were also found in ELS animals. In conclusion, this study shows that ELS alters neuronal activation patterns after fear acquisition and retrieval, which may provide mechanistic insights into enduring impact of early-life stress on the processing of fear memories, possibly via changes in cell (co-) activation and engram cell allocation.
PubMed: 38906243
DOI: 10.1016/j.nlm.2024.107952 -
European Journal of Pharmacology Jun 2024Depression triggered by harmful stress during adolescence is a common problem that can affect mental health. To date, the mechanisms underlying this type of depression...
Apoptosis-induced decline in hippocampal microglia mediates the development of depression-like behaviors in adult mice triggered by unpredictable stress during adolescence.
Depression triggered by harmful stress during adolescence is a common problem that can affect mental health. To date, the mechanisms underlying this type of depression remain unclear. One mechanism for the promotion of depression by chronic stress in adulthood is the loss of hippocampal microglia. Since deleterious stress in adolescence also activates microglia, we investigated the dynamic changes of microglia in the hippocampus in mice exposed to chronic unpredictable stress (CUS) in adolescence. Our results showed that 12 days of CUS stimulation in adolescence induced typical depression-like behaviors in adult mice, which were accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus of the hippocampus. Further analysis showed that this decrease in microglia was mediated by the initial response of microglia to unpredictable stress in the dentate gyrus of the hippocampus and their subsequent apoptosis. Blocking the initial response of microglia to unpredictable stress by pretreatment with minocycline was able to prevent apoptosis and microglial decline as well as the development of depression-like behaviors in adult mice induced by adolescent CUS. Moreover, administration of lipopolysaccharide (LPS) or macrophage-colony stimulatory factor (M-CSF), two drugs that reversed microglia decline in the dentate gyrus, ameliorated the depression-like behaviors induced by CUS stimulation in adolescence. These findings reveal a novel mechanism for the development of depression-like behaviors in animals triggered by deleterious stress in adolescence and suggest that reversing microglial decline in the hippocampus may be a hopeful strategy for the treatment of depression triggered by deleterious stress in adolescence.
PubMed: 38906239
DOI: 10.1016/j.ejphar.2024.176763