MDPV (3,4-methylenedioxypyrovalerone) administered to mice during development of the central nervous system produces persistent learning and memory impairments.

BACKGROUND: Synthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice. METHODS: All experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11-20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot. RESULTS: Exposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent. CONCLUSIONS: MDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.

From signalling to form: the coordination of neural tube patterning.

The development of the vertebrate spinal cord involves the formation of the neural tube and the generation of multiple distinct cell types. The process starts during gastrulation, combining axial elongation with specification of neural cells and the formation of the neuroepithelium. Tissue movements produce the neural tube which is then exposed to signals that provide patterning information to neural progenitors. The intracellular response to these signals, via a gene regulatory network, governs the spatial and temporal differentiation of progenitors into specific cell types, facilitating the assembly of functional neuronal circuits. The interplay between the gene regulatory network, cell movement, and tissue mechanics generates the conserved neural tube pattern observed across species. In this review we offer an overview of the molecular and cellular processes governing the formation and patterning of the neural tube, highlighting how the remarkable complexity and precision of vertebrate nervous system arises. We argue that a multidisciplinary and multiscale understanding of the neural tube development, paired with the study of species-specific strategies, will be crucial to tackle the open questions.

Unfolding the ventral nerve center of chaetognaths.

BACKGROUND: Chaetognaths are a clade of marine worm-like invertebrates with a heavily debated phylogenetic position. Their nervous system superficially resembles the protostome type, however, knowledge regarding the molecular processes involved in neurogenesis is lacking. To better understand these processes, we examined the expression profiles of marker genes involved in bilaterian neurogenesis during post-embryonic stages of Spadella cephaloptera. We also investigated whether the transcription factor encoding genes involved in neural patterning are regionally expressed in a staggered fashion along the mediolateral axis of the nerve cord as it has been previously demonstrated in selected vertebrate, insect, and annelid models. METHODS: The expression patterns of genes involved in neural differentiation (elav), neural patterning (foxA, nkx2.2, pax6, pax3/7, and msx), and neuronal function (ChAT and VAChT) were examined in S. cephaloptera hatchlings and early juveniles using whole-mount fluorescent in situ hybridization and confocal microscopy. RESULTS: The Sce-elav + profile of S. cephaloptera hatchlings reveals that, within 24 h of post-embryonic development, the developing neural territories are not limited to the regions previously ascribed to the cerebral ganglion, the ventral nerve center (VNC), and the sensory organs, but also extend to previously unreported CNS domains that likely contribute to the ventral cephalic ganglia. In general, the neural patterning genes are expressed in distinct neural subpopulations of the cerebral ganglion and the VNC in hatchlings, eventually becoming broadly expressed with reduced intensity throughout the CNS in early juveniles. Neural patterning gene expression domains are also present outside the CNS, including the digestive tract and sensory organs. ChAT and VAChT domains within the CNS are predominantly observed in specific subpopulations of the VNC territory adjacent to the ventral longitudinal muscles in hatchlings. CONCLUSIONS: The observed spatial expression domains of bilaterian neural marker gene homologs in S. cephaloptera suggest evolutionarily conserved roles in neurogenesis for these genes among bilaterians. Patterning genes expressed in distinct regions of the VNC do not show a staggered medial-to-lateral expression profile directly superimposable to other bilaterian models. Only when the VNC is conceptually laterally unfolded from the longitudinal muscle into a flat structure, an expression pattern bearing resemblance to the proposed conserved bilaterian mediolateral regionalization becomes noticeable. This finding supports the idea of an ancestral mediolateral patterning of the trunk nervous system in bilaterians.

Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus.

Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination, which is closely associated with cognitive decline. However, the mechanisms underlying this phenomenon remain unclear. Chitinase-3-like (CHI3L1), secreted by activated astrocytes, has been identified as a biomarker for MS progression. Our study investigates CHI3L1's function within the demyelinating hippocampus and demonstrates a correlation between CHI3L1 expression and cognitive impairment in patients with MS. Activated astrocytes release CHI3L1 in reaction to induced demyelination, which adversely affects the proliferation and differentiation of neural stem cells and impairs dendritic growth, complexity, and spine formation in neurons. Our findings indicate that the astrocytic deletion of CHI3L1 can mitigate neurogenic deficits and cognitive dysfunction. We showed that CHI3L1 interacts with CRTH2/receptor for advanced glycation end (RAGE) by attenuating ß-catenin signaling. The reactivation of ß-catenin signaling can revitalize neurogenesis, which holds promise for therapy of inflammatory demyelination.

Effects of unilateral hippocampal surgical procedures needed for calcium imaging on mouse behavior and adult hippocampal neurogenesis.

Hippocampus is essential for episodic memory formation, lesion studies demonstrating its role especially in processing spatial and temporal information. Further, adult hippocampal neurogenesis (AHN) in the dentate gyrus (DG) has also been linked to learning. To study hippocampal neuronal activity during events like learning, in vivo calcium imaging has become increasingly popular. It relies on the use of adeno-associated viral (AAV) vectors, which seem to lead to a decrease in AHN when applied on the DG. More notably, imaging requires the implantation of a relatively large lens into the tissue. Here, we examined how injection of an AAV vector and implantation of a 1-mm-diameter lens into the dorsal DG routinely used to image calcium activity impact the behavior of adult male C57BL/6 mice. To this aim, we conducted open-field, object-recognition and object-location tasks at baseline, after AAV vector injection, and after lens implantation. Finally, we determined AHN from hippocampal slices using a doublecortin-antibody. According to our results, the operations needed for in vivo imaging of the dorsal DG did not have adverse effects on behavior, although we noticed a decrease in AHN ipsilaterally to the operations. Thus, our results suggest that in vivo imaging can be safely used to, for example, correlate patterns of calcium activity with learned behavior. One should still keep in mind that the defects on the operated side might be functionally compensated by the (hippocampus in the) contralateral hemisphere.

Neurorestorative approaches for ischemic stroke.

Despite recent advances in acute stroke management, most patients experiencing a stroke will suffer from residual brain damage and functional impairment. Addressing those residual deficits would require neurorestoration, i.e., rebuilding brain tissue to repair the structural brain damage caused by stroke. However, there are major pathobiological, anatomical and technological hurdles making neurorestorative approaches remarkably challenging, and true neurorestoration after larger ischemic lesions could not yet be achieved. On the other hand, there has been steady advancement in our understanding of the limits of tissue regeneration in the adult mammalian brain as well as of the fundamental organization of brain tissue growth during embryo- and ontogenesis. This has been paralleled by the development of novel animal models to study stroke, advancement of biomaterials that can be used to support neurorestoration, and in stem cell technologies. This review gives a detailed explanation of the major hurdles so far preventing the achievement of neurorestoration after stroke. It will also describe novel concepts and advancements in biomaterial science, brain organoid culturing, and animal modeling that may enable the investigation of post-stroke neurorestorative approaches in translationally relevant setups. Finally, there will be a review of recent achievements in experimental studies that have the potential to be the starting point of research and development activities that may eventually bring post-stroke neurorestoration within reach.

Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.

Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as it inhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.

Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age.

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research.

Oscillatory control of embryonic development.

Proper embryonic development depends on the timely progression of a genetic program. One of the key mechanisms for achieving precise control of developmental timing is to use gene expression oscillations. In this Review, we examine how gene expression oscillations encode temporal information during vertebrate embryonic development by discussing the gene expression oscillations occurring during somitogenesis, neurogenesis, myogenesis and pancreas development. These oscillations play important but varied physiological functions in different contexts. Oscillations control the period of somite formation during somitogenesis, whereas they regulate the proliferation-to-differentiation switch of stem cells and progenitor cells during neurogenesis, myogenesis and pancreas development. We describe the similarities and differences of the expression pattern in space (i.e. whether oscillations are synchronous or asynchronous across neighboring cells) and in time (i.e. different time scales) of mammalian Hes/zebrafish Her genes and their targets in different tissues. We further summarize experimental evidence for the functional role of their oscillations. Finally, we discuss the outstanding questions for future research.

Advances in Engineered Nanoparticles for the Treatment of Ischemic Stroke by Enhancing Angiogenesis.

Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment.

Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy.

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1ß, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.

Cannabidiol improves nonmotor symptoms, attenuates neuroinflammation and favors hippocampal newborn neuronal maturation in a rat model of Parkinsonism.

OBJECTIVE: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. METHODS: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioral paradigms to evaluate nonmotor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. RESULTS: 6-hydroxydopamine-lesioned rats exhibited memory impairments and despair-like behavior in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. Cannabidiol decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behavior that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favored the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. CONCLUSION: The present findings suggest a potential beneficial effect of CBD on nonmotor symptoms induced by intra-nigral 6-OHDA infusion in rats.

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Adult Hippocampal Neurogenesis in the Human Brain: Updates, Challenges, and Perspectives.

The existence of neurogenesis in the adult human hippocampus has been under considerable debate within the past three decades due to the diverging conclusions originating mostly from immunohistochemistry studies. While some of these reports conclude that hippocampal neurogenesis in humans occurs throughout physiologic aging, others indicate that this phenomenon ends by early childhood. More recently, some groups have adopted next-generation sequencing technologies to characterize with more acuity the extent of this phenomenon in humans. Here, we review the current state of research on adult hippocampal neurogenesis in the human brain with an emphasis on the challenges and limitations of using immunohistochemistry and next-generation sequencing technologies for its study.

Association of dietary and nutritional factors with cognitive decline, dementia, and depressive symptomatology in older individuals according to a neurogenesis-centred biological susceptibility to brain ageing.

Hippocampal neurogenesis (HN) occurs throughout the life course and is important for memory and mood. Declining with age, HN plays a pivotal role in cognitive decline (CD), dementia, and late-life depression, such that altered HN could represent a neurobiological susceptibility to these conditions. Pertinently, dietary patterns (e.g., Mediterranean diet) and/or individual nutrients (e.g., vitamin D, omega 3) can modify HN, but also modify risk for CD, dementia, and depression. Therefore, the interaction between diet/nutrition and HN may alter risk trajectories for these ageing-related brain conditions. Using a subsample (n = 371) of the Three-City cohort-where older adults provided information on diet and blood biobanking at baseline and were assessed for CD, dementia, and depressive symptomatology across 12 years-we tested for interactions between food consumption, nutrient intake, and nutritional biomarker concentrations and neurogenesis-centred susceptibility status (defined by baseline readouts of hippocampal progenitor cell integrity, cell death, and differentiation) on CD, Alzheimer's disease (AD), vascular and other dementias (VoD), and depressive symptomatology, using multivariable-adjusted logistic regression models. Increased plasma lycopene concentrations (OR [95% CI] = 1.07 [1.01, 1.14]), higher red meat (OR [95% CI] = 1.10 [1.03, 1.19]), and lower poultry consumption (OR [95% CI] = 0.93 [0.87, 0.99]) were associated with an increased risk for AD in individuals with a neurogenesis-centred susceptibility. Increased vitamin D consumption (OR [95% CI] = 1.05 [1.01, 1.11]) and plasma γ-tocopherol concentrations (OR [95% CI] = 1.08 [1.01, 1.18]) were associated with increased risk for VoD and depressive symptomatology, respectively, but only in susceptible individuals. This research highlights an important role for diet/nutrition in modifying dementia and depression risk in individuals with a neurogenesis-centred susceptibility.

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Stem Cell Therapy and Thiamine Deficiency-Induced Brain Damage.

Wernicke's encephalopathy (WE) is a major central nervous system disorder resulting from thiamine deficiency (TD) in which a number of brain regions can develop serious damage including the thalamus and inferior colliculus. Despite decades of research into the pathophysiology of TD and potential therapeutic interventions, little progress has been made regarding effective treatment following the development of brain lesions and its associated cognitive issues. Recent developments in our understanding of stem cells suggest they are capable of repairing damage and improving function in different maladys. This article puts forward the case for the potential use of stem cell treatment as a therapeutic strategy in WE by first examining the effects of TD on brain functional integrity and its consequences. The second half of the paper will address the future benefits of treating TD with these cells by focusing on their nature and their potential to effectively treat neurodegenerative diseases that share some overlapping pathophysiological features with TD. At the same time, some of the obstacles these cells will have to overcome in order to become a viable therapeutic strategy for treating this potentially life-threatening illness in humans will be highlighted.

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size.

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

Leptin combined with withaferin A boost posthemorrhagic neurogenesis via activation of STAT3/SOCS3 pathway.

Neurogenesis as a potential strategy to improve the consequences of intracerebral hemorrhage (ICH). The current study investigates the effects of withaferin A (WFA) in combination with leptin (LEP) on ICH and neurogenesis mechanisms. LEP levels were dramatically reduced on days 7 and 14 following ICH insults in mice, but continuous WFA therapy significantly improved the potency of intrinsic LEP on day 14 after ICH. Furthermore, WFA combined with LEP enhances intrinsic neurogenesis and lessen motor deficits and long-term cognitive outcomes after ICH. In parallel, leptin deficiency in ob/ob mice limits enhancement of neurogenesis following ICH in response to WFA combined with LEP treatment. Importantly, the functional recovery conferred by WFA combined with LEP after ICH was inhibited by neurogenesis suppression. Mechanistically, this study unveiled that the signal transducer and activator of transcription-3 (STAT3) / suppressor of cytokine signaling-3 (SOCS3) pathway is a critical signaling pathway through which WFA combined with LEP treatment promotes intrinsic neurogenesis after ICH. Collectively, the results of this study elucidate the neuroprotective effects of WFA and LEP in ICH, and highlight a potential approach for ICH cell therapy.

DNA origami scaffold promoting nerve guidance and regeneration.

Self-assembly of biological elements into biomimetic cargo carriers for targeting and delivery is a promising approach. However, it still holds practical challenges. We developed a functionalization approach of DNA origami (DO) nanostructures with neuronal growth factor (NGF) for manipulating neuronal systems. NGF bioactivity and its interactions with the neuronal system were demonstrated in vitro and in vivo models. The DO elements fabricated by molecular self-assembly have manipulated the surrounding environment through static spatially and temporally controlled presentation of ligands to the cell surface receptors. Our data showed effective bioactivity in differentiating PC12 cells in vitro. Furthermore, the DNA origami NGF (DON) affected the growth directionality and spatial capabilities of dorsal root ganglion neurons in culture by introducing a chemotaxis effect along a gradient of functionalized DO structures. Finally, we showed that these elements provide enhanced axonal regeneration in a rat sciatic nerve injury model in vivo. This study is a proof of principle for the functionality of DO in neuronal manipulation and regeneration. The approach proposed here, of an engineered platform formed out of programmable nanoscale elements constructed of DO, could be extended beyond the nervous system and revolutionize the fields of regenerative medicine, tissue engineering, and cell biology.