Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience. This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies. Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training. Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility. These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.

The well-organized cerebellar structures and neuronal networks are likely crucial for their functions in motor coordination, motor learning, cognition, and emotion. Such cerebellar structures and neuronal networks are formed during developmental periods through orchestrated mechanisms, which include not only cell-autonomous programs but also interactions between the same or different types of neurons. Cerebellar granule cells (GCs) are the most numerous neurons in the brain and are generated through intensive cell division of GC precursors (GCPs) during postnatal developmental periods. While GCs go through their own developmental processes of proliferation, differentiation, migration, and maturation, they also play a crucial role in cerebellar development. One of the best-characterized contributions is the enlargement and foliation of the cerebellum through massive proliferation of GCPs. In addition to this contribution, studies have shown that immature GCs and GCPs regulate multiple factors in the developing cerebellum, such as the development of other types of cerebellar neurons or the establishment of afferent innervations. These studies have often found impairments of cerebellar development in animals lacking expression of certain molecules in GCs, suggesting that the regulations are mediated by molecules that are secreted from or present in GCs. Given the growing recognition of GCs as regulators of cerebellar development, this review will summarize our current understanding of cerebellar development regulated by GCs and molecules in GCs, based on accumulated studies and recent findings, and will discuss their potential further contributions.

UNASSIGNED: Glass coverslips are used as a substrate since Harrison\'s initial nerve cell culture experiments in 1910. In 1974, the first study of brain cells seeded onto polylysine (PL) coated substrate was published. Usually, neurons adhere quickly to PL coating. However, maintaining cortical neurons in culture on PL coating for a prolonged time is challenging.
UNASSIGNED: A collaborative study between chemical engineers and neurobiologists was conducted to find a simple method to enhance neuronal maturation on poly-D-lysine (PDL). In this work, a simple protocol to coat PDL efficiently on coverslips is presented, characterized, and compared to a conventional adsorption method. We studied the adhesion and maturation of primary cortical neurons with various morphological and functional approaches, including phase contrast microscopy, immunocytochemistry, scanning electron microscopy, patch clamp recordings, and calcium imaging.
UNASSIGNED: We observed that several parameters of neuronal maturation are influenced by the substrate: neurons develop more dense and extended networks and synaptic activity is enhanced, when seeded on covalently bound PDL compared to adsorbed PDL.
UNASSIGNED: Hence, we established reproducible and optimal conditions enhancing maturation of primary cortical neurons in vitro. Our method allows higher reliability and yield of results and could also be profitable for laboratories using PL with other cell types.

DNA methylation in neurons is directly linked to neuronal genome regulation and maturation. Unlike other tissues, vertebrate neurons accumulate high levels of atypical DNA methylation in the CH sequence context (mCH) during early postnatal brain development. Here, we investigate to what extent neurons derived in vitro from both mouse and human pluripotent stem cells recapitulate in vivo DNA methylation patterns. While human ESC-derived neurons did not accumulate mCH in either 2D culture or 3D organoid models even after prolonged culture, cortical neurons derived from mouse ESCs acquired in vivo levels of mCH over a similar time period in both primary neuron cultures and in vivo development. mESC-derived neuron mCH deposition was coincident with a transient increase in Dnmt3a, preceded by the postmitotic marker Rbfox3 (NeuN), was enriched at the nuclear lamina, and negatively correlated with gene expression. We further found that methylation patterning subtly differed between in vitro mES-derived and in vivo neurons, suggesting the involvement of additional noncell autonomous processes. Our findings show that mouse ESC-derived neurons, in contrast to those of humans, can recapitulate the unique DNA methylation landscape of adult neurons in vitro over experimentally tractable timeframes, which allows their use as a model system to study epigenome maturation over development.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with polymodal sensory function. TRPV1 links to fever, while, according to previous studies on TRPV1 knock-out (KO) mice, the role of the channel in the generation of febrile seizure is debated. In the hippocampal formation, functional TRPV1 channels are expressed by Cajal-Retzius cells, which have a role in guidance of migrating neurons during development. Despite the developmental aspects of febrile seizure as well as of Cajal-Retzius cells, no information is available about the hippocampal development in TRPV1 KO mouse. Therefore, in the present work postnatal development of the hippocampal formation was studied in TRPV1 KO mice. Several morphological characteristics including neuronal positioning and maturation, synaptogenesis and myelination were examined with light microscopy following immunohistochemical detection of protein markers of various neurons, synapses, and myelination. Regarding the cytoarchitectonics, neuronal migration, morphological, and neurochemical maturation, no substantial difference could be detected between TRPV1 KO and wild-type control mice. Our data indicate that synapse formation and myelination occur similarly in TRPV1 KO and in control animals. We have found slightly, but not significantly larger numbers of persisting Cajal-Retzius cells in the KO mice than in controls. Our result strengthens previous suggestion concerning the role of TRPV1 channel in the postnatal apoptotic cell death of Cajal-Retzius cells. However, the fact that the hippocampus of KO mice lacks major developmental abnormalities supports the use of TRPV1 KO in various animal models of diseases and pathological conditions.

Exposure to adversities in early life appears to affect the development of white matter, especially oligodendrocytes. Furthermore, altered myelination is present in regions subjected to maturation during the developmental time when early adversities are experienced. In this review, studies applying two well-established animal models of early life adversity, namely maternal separation and maternal immune activation, focusing on oligodendrocyte alterations and resulting implications for psychiatric disorders are discussed. Studies revealed that myelination is reduced as a result of altered oligodendrocyte expression. Furthermore, early adversity is associated with increased cell death, a simpler morphology, and inhibited oligodendrocyte maturation. However, these effects seem to be region- specific as some brain regions show increased expression while others show decreased expression of oligodendroglia-related genes, and they occur especially in regions of ongoing development. Some studies furthermore suggest that early adversity leads to premature differentiation of oligodendrocytes. Importantly, especially early exposure results in stronger oligodendrocyte-related impairments. However, resulting alterations are not restricted to exposure during the early pre- and postnatal days as social isolation after weaning leads to fewer internodes and branches and shorter processes of oligodendrocytes in adulthood. Eventually, the found alterations may lead to dysfunction and long-lasting alterations in structural brain development associated with psychiatric disorders. To date, only few preclinical studies have focused on the effects of early adversity on oligodendrocytes. More studies including several developmental stages are needed to further disentangle the role of oligodendrocytes in the development of psychiatric disorders.

The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.

Exercise supports brain health in part by enhancing hippocampal function. The leading hypothesis is that muscles release factors when they contract (e.g., lactate, myokines, growth factors) that enter circulation and reach the brain where they enhance plasticity (e.g., increase neurogenesis and synaptogenesis). However, it remains unknown how the muscle signals are transduced by the hippocampal cells to modulate network activity and synaptic development. Thus, we established an in vitro model in which the media from contracting primary muscle cells (CM) is applied to developing primary hippocampal cell cultures on a microelectrode array. We found that the hippocampal neuronal network matures more rapidly (as indicated by synapse development and synchronous neuronal activity) when exposed to CM than regular media (RM). This was accompanied by a 4.4- and 1.4-fold increase in the proliferation of astrocytes and neurons, respectively. Further, experiments established that factors released by astrocytes inhibit neuronal hyper-excitability induced by muscle media, and facilitate network development. Results provide new insight into how exercise may support hippocampal function by regulating astrocyte proliferation and subsequent taming of neuronal activity into an integrated network.

UNASSIGNED: Neurological diseases, including Alzheimer\'s, Parkinson\'s diseases, and brain cancers, are reportedly caused by genetic aberration and cellular malfunction. Herbs with bioactive compounds that have anti-oxidant effects such as cordyceps and turmeric, are of interest to clinical applications due to their minimal adverse effects. The aim of study is to develop the nanoencapsulated cordyceps and turmeric extracts and investigate their capability to enhance the biological activity and improve neuronal function.
UNASSIGNED: Human neuroblastoma SH-SY5Y cells were utilized as a neuronal model to investigate the properties of nanoencapsulated cordyceps or turmeric extracts, called CMP and TEP, respectively. SH-SY5Y cells were treated with either CMP or TEP and examined the biological consequences, including neuronal maturation and neuronal function.
UNASSIGNED: The results showed that both CMP and TEP improved cellular uptake efficiency within 6 h by 2.3 and 2.8 times, respectively. Besides, they were able to inhibit cellular proliferation of SH-SY5Y cells up to 153- and 218-fold changes, and increase the expression of mature neuronal markers (TUJ1, PAX6, and NESTIN). Upon the treatment of CMP and TEP, the expression of dopaminergic-specific genes (LMX1B, FOXA2, EN1, and NURR1), and the secretion level of dopamine were significantly improved up to 3.3-fold and 3.0-fold, respectively, while the expression of Alzheimer genes (PSEN1, PSEN2, and APP), and the secretion of amyloid precursor protein were significantly reduced by 32-fold and 108-fold, respectively. Importantly, the autophagy activity was upregulated by CMP and TEP at 6.3- and 5.5-fold changes, respectively.
UNASSIGNED: This finding suggested that the nanoencapsulated cordyceps and turmeric extracts accelerated neuronal maturation and alleviated neuronal pathology in human neural cells. This paves the way for nanotechnology-driven drug delivery systems that could potentially be used as an alternative medicine in the future for neurological diseases.

Human induced pluripotent stem cell (hiPSC) technologies offer a unique resource for modeling neurological diseases. However, iPSC models are fraught with technical limitations including abnormal aggregation and inefficient maturation of differentiated neurons. These problems are in part due to the absence of synergistic cues of the native extracellular matrix (ECM). We report on the use of three artificial ECMs based on peptide amphiphile (PA) supramolecular nanofibers. All nanofibers display the laminin-derived IKVAV signal on their surface but differ in the nature of their non-bioactive domains. We find that nanofibers with greater intensity of internal supramolecular motion have enhanced bioactivity toward hiPSC-derived motor and cortical neurons. Proteomic, biochemical, and functional assays reveal that highly mobile PA scaffolds caused enhanced β1-integrin pathway activation, reduced aggregation, increased arborization, and matured electrophysiological activity of neurons. Our work highlights the importance of designing biomimetic ECMs to study the development, function, and dysfunction of human neurons.