Neurogenesis In Subventricular Zone Research Articles

Cerebral stroke-induced neurogenesis: insights and therapeutic implications

Stroke, one of the leading causes of global morbidity and mortality, results from disrupted cerebral blood circulation, leads to cellular damage or death. Ischemic stroke, the predominant subtype, relies mainly on recombinant tissue plasminogen activator (rtPA) and endovascular thrombectomy for the treatment. Neurological impairments following ischemic stroke highlight the importance of understanding the interplay between neuroinflammation and neurogenesis in brain repair. Research reveals a complex relationship, where inflammation both promotes and hinders neurogenesis, impacting post-stroke outcomes. The subventricular zone (SVZ) of striatum and sub granular zone (SGZ) in hippocampus play pivotal roles in adult neurogenesis, with distinct characteristics and functions. SVZ neurogenesis involves neuroblast progenitors migrating to the olfactory bulb, while SGZ facilitates granule cell generation for hippocampal function. Understanding the intricate processes of neuroinflammation, neurogenesis, and angiogenesis is crucial for developing effective stroke therapeutics. Promising avenues include drug therapy, selective serotonin reuptake inhibitors, antibody therapy, angiogenesis stimulation, growth factor therapy, hormone therapy, miRNAs, extracellular vesicles, and neuroprotective agents. Stem cell therapy, exploring various cell types, holds potential for neuronal replacement and recovery. In conclusion, deciphering the roles of SVZ and SGZ in neurogenesis, unraveling the complexity of neuroinflammation’s impact on repair, and exploring diverse therapeutic approaches highlight the need for comprehensive investigations to enhance stroke outcomes. The multifaceted landscape of stroke therapeutics presents challenges, but ongoing research offers promising avenues for bridging the gap between preclinical findings and clinical treatments.

6-Shogaol attenuates natural aging-induced locomotive and cognitive declines through suppression of p75 neurotrophin receptor in vivo

The present study aimed to investigate the effect of 6-shogaol (6S) treatment on brain senescence. Mice were naturally aged until 25-month-old and treated with 10 mg/kg of 6S for a month. Behavioral tests were performed to measure locomotion and cognitive function. Neuronal damage, synaptic plasticity, neuroinflammation, neurogenesis and p75 neurotrophin receptor (p75NTR) expression were examined by immunohistochemistry or immunofluorescence. 6S treatment improved locomotion during open field test in the aged mice and spontaneous alternation in Y-maze. These data are in line with that 6S administration improved dopaminergic neuronal loss and dopamine signaling and attenuated hippocampal synaptic plasticity in the aged brain. Additionally, 6S treatment reduced striatal and hippocampal microgliosis and astrocytosis but promoted neurogenesis in subventricular zone. Furthermore, 6S treatment reversed the p75NTR expression in the senescent brain. The current findings suggest that 6S can be a functional food for successful aging through brain rejuvenation at the molecular level.

Adipose transplantation improves olfactory function and neurogenesis via PKCα-involved lipid metabolism in Seipin Knockout mice

BackgroundLipodystrophy-associated metabolic disorders caused by Seipin deficiency lead to not only severe lipodystrophy but also neurological disorders. However, the underlying mechanism of Seipin deficiency-induced neuropathy is not well elucidated, and the possible restorative strategy needs to be explored.MethodsIn the present study, we used Seipin knockout (KO) mice, combined with transcriptome analysis, mass spectrometry imaging, neurobehavior test, and cellular and molecular assay to investigate the systemic lipid metabolic abnormalities in lipodystrophic mice model and their effects on adult neurogenesis in the subventricular zone (SVZ) and olfactory function. After subcutaneous adipose tissue (AT) transplantation, metabolic and neurological function was measured in Seipin KO mice to clarify whether restoring lipid metabolic homeostasis would improve neurobehavior.ResultsIt was found that Seipin KO mice presented the ectopic accumulation of lipids in the lateral ventricle, accompanied by decreased neurogenesis in adult SVZ, diminished new neuron formation in the olfactory bulb, and impaired olfactory-related memory. Transcriptome analysis showed that the differentially expressed genes (DEGs) in SVZ of adult Seipin KO mice were significantly enriched in lipid metabolism. Mass spectrometry imaging showed that the levels of glycerophospholipid and diglyceride (DG) were significantly increased. Furthermore, we found that AT transplantation rescued the abnormality of peripheral metabolism in Seipin KO mice and ameliorated the ectopic lipid accumulation, concomitant with restoration of the SVZ neurogenesis and olfactory function. Mechanistically, PKCα expression was up-regulated in SVZ tissues of Seipin KO mice, which may be a potential mediator between lipid dysregulation and neurological disorder. DG analogue (Dic8) can up-regulate PKCα and inhibit the proliferation and differentiation of neural stem cells (NSCs) in vitro, while PKCα inhibitor can block this effect.ConclusionThis study demonstrates that Seipin deficiency can lead to systemic lipid disorder with concomitant SVZ neurogenesis and impaired olfactory memory. However, AT restores lipid homeostasis and neurogenesis. PKCα is a key mediator mediating Seipin KO-induced abnormal lipid metabolism and impaired neurogenesis in the SVZ, and inhibition of PKCα can restore the impaired neurogenesis. This work reveals the underlying mechanism of Seipin deficiency-induced neurological dysfunction and provides new ideas for the treatment of neurological dysfunction caused by metabolic disorders.

The anti-viral immune response of the adult host robustly modulates neural stem cell activity in spatial, temporal, and sex-specific manners

Viruses induce a wide range of neurological sequelae through the dysfunction and death of infected cells and persistent inflammation in the brain. Neural stem cells (NSCs) are often disturbed during viral infections. Although some viruses directly infect and kill NSCs, the antiviral immune response may also indirectly affect NSCs. To better understand how NSCs are influenced by a productive immune response, where the virus is successfully resolved and the host survives, we used the CD46+ mouse model of neuron-restricted measles virus (MeV) infection. As NSCs are spared from direct infection in this model, they serve as bystanders to the antiviral immune response initiated by selective infection of mature neurons. MeV-infected mice showed distinct regional and temporal changes in NSCs in the primary neurogenic niches of the brain, the hippocampus and subventricular zone (SVZ). Hippocampal NSCs increased throughout the infection (7 and 60 days post-infection; dpi), while mature neurons transiently declined at 7 dpi and then rebounded to basal levels by 60 dpi. In the SVZ, NSC numbers were unchanged, but mature neurons declined even after the infection was controlled at 60 dpi. Further analyses demonstrated sex, temporal, and region-specific changes in NSC proliferation and neurogenesis throughout the infection. A relatively long-term increase in NSC proliferation and neurogenesis was observed in the hippocampus; however, neurogenesis was reduced in the SVZ. This decline in SVZ neurogenesis was associated with increased immature neurons in the olfactory bulb in female, but not male mice, suggesting potential migration of newly-made neurons out of the female SVZ. These sex differences in SVZ neurogenesis were accompanied by higher infiltration of B cells and greater expression of interferon-gamma and interleukin-6 in female mice. Learning, memory, and olfaction tests revealed no overt behavioral changes after the acute infection subsided. These results indicate that antiviral immunity modulates NSC activity in adult mice without inducing gross behavioral deficits among those tested, suggestive of mechanisms to restore neurons and maintain adaptive behavior, but also revealing the potential for robust NSC disruption in subclinical infections.

Serine Racemase mediates subventricular zone neurogenesis via fatty acid metabolism.

The adult subventricular zone (SVZ) is a neurogenic niche that continuously produces newborn neurons. Here we show that serine racemase (SR), an enzyme that catalyzes the racemization of L-serine to D-serine and vice versa, affects neurogenesis in the adult SVZ by controlling de novo fatty acid synthesis. Germline and conditional deletion of SR (nestin precursor cells) leads to diminished neurogenesis in the SVZ. Nestin-cre+ mice showed reduced expression of fatty acid synthase and its substrate malonyl-CoA, which are involved in de novo fatty acid synthesis. Global lipidomic analyses revealed significant alterations in different lipid subclasses in nestin-cre+ mice. Decrease in fatty acid synthesis was mediated by phospho Acetyl-CoA Carboxylase that was AMP-activated protein kinase independent. Both L- and D-serine supplementation rescued defects in SVZ neurogenesis, proliferation, and levels of malonyl-CoA invitro. Our work shows that SR affects adult neurogenesis in the SVZ via lipid metabolism.

Brain Infection by Group B Streptococcus Induces Inflammation and Affects Neurogenesis in the Adult Mouse Hippocampus.

Central nervous system infections caused by pathogens crossing the blood-brain barrier are extremely damaging and trigger cellular alterations and neuroinflammation. Bacterial brain infection, in particular, is a major cause of hippocampal neuronal degeneration. Hippocampal neurogenesis, a continuous multistep process occurring throughout life in the adult brain, could compensate for such neuronal loss. However, the high rates of cognitive and other sequelae from bacterial meningitis/encephalitis suggest that endogenous repair mechanisms might be severely affected. In the current study, we used Group B Streptococcus (GBS) strain NEM316, to establish an adult mouse model of brain infection and determine its impact on adult neurogenesis. Experimental encephalitis elicited neurological deficits and death, induced inflammation, and affected neurogenesis in the dentate gyrus of the adult hippocampus by suppressing the proliferation of progenitor cells and the generation of newborn neurons. These effects were specifically associated with hippocampal neurogenesis while subventricular zone neurogenesis was not affected. Overall, our data provide new insights regarding the effect of GBS infection on adult brain neurogenesis.

Crocetin Regulates Functions of Neural Stem Cells to Generate New Neurons for Cerebral Ischemia Recovery.

Many neurons undergo apoptosis after ischemic stroke. In the brain, neurogenesis has the potential for neuronal replacement and can be activated by external conditions to repair the injury. Crocetin (CRO), naturally extracted from the plant saffron, acts as a neuroprotective agent for ischemic stroke. However, the underlying mechanism remains unknown. In this work, the effect of CRO on neural stem cell (NSC) behaviors and subventricular zone neurogenesis is investigated. Initially, NSCs are incubated with different concentrations of CRO to detect the cell proliferation and differentiation in vitro. Second, ischemic stroke induced rats are treated with CRO using nimodipine (NMDP) as a comparison. The behavioral functions, infarcted volume, and apoptotic Nissl bodies of rats are noticeably improved after CRO-treatment, comparable to those of NMDP. In addition, the increased regional cerebral blood flow and promoted neuronal differentiation are achieved by CRO-treatment. Brain tissue examination shows significantly increased neuronal regeneration in the focal ischemic injury area. Meanwhile, the length of neurites is prolonged, indicating that CRO could potentially promote neurite extension to enhance cell-cell communication. These findings demonstrate that CRO facilitated the neuronal differentiation of NSCs by activating subventricular zone neurogenesis in damaged cortex and striatum sites to repair ischemic stroke.

Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone

The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and invitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders.

Repeated administration of acrylamide for 28 days suppresses adult neurogenesis of the olfactory bulb in young-adult rats

Acrylamide (AA) is a neurotoxicant that inhibits synaptic function in distal axons. We previously found that AA decreased neural cell lineages during late-stage differentiation of adult hippocampal neurogenesis and downregulated genes related to neurotrophic factor, neuronal migration, neurite outgrowth, and synapse formation in the hippocampal dentate gyrus in rats. To investigate whether olfactory bulb (OB)-subventricular zone (SVZ) neurogenesis is similarly affected by AA exposure, AA was administered to 7-week-old male rats via oral gavage at doses of 0, 5, 10, and 20 mg/kg for 28 days. Immunohistochemical analysis revealed that AA decreased the numbers of doublecortin-positive (+) cells and polysialic acid-neural cell adhesion molecule+ cells in the OB. On the other hand, the numbers of doublecortin+ cells and polysialic acid-neural cell adhesion molecule+ cells in the SVZ did not change with AA exposure, suggesting that AA impaired neuroblasts migrating in the rostral migratory stream and OB. Gene expression analysis in the OB revealed that AA downregulated Bdnf and Ncam2, which are related to neuronal differentiation and migration. These results suggest that AA decreased neuroblasts in the OB by suppressing neuronal migration. Thus, AA decreased neuronal cell lineages during late-stage differentiation of adult neurogenesis in the OB-SVZ, similar to the effect on adult hippocampal neurogenesis.

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Relationship between adult subventricular neurogenesis and Alzheimer's disease: Pathologic roles and therapeutic implications.

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by irreversible cognitive declines. Senile plaques formed by amyloid-β (Aβ) peptides and neurofibrillary tangles, consisting of hyperphosphorylated tau protein accumulation, are prominent neuropathological features of AD. Impairment of adult neurogenesis is also a well-known pathology in AD. Adult neurogenesis is the process by which neurons are generated from adult neural stem cells. It is closely related to various functions, including cognition, as it occurs throughout life for continuous repair and development of specific neural pathways. Notably, subventricular zone (SVZ) neurogenesis, which occurs in the lateral ventricles, transports neurons to several brain regions such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. These migrating neurons can affect cognitive function and behavior in different neurodegenerative diseases. Despite several studies indicating the importance of adult SVZ neurogenesis in neurodegenerative disorders, the pathological alterations and therapeutic implications of impaired adult neurogenesis in the SVZ in AD have not yet been fully explained. In this review, we summarize recent progress in understanding the alterations in adult SVZ neurogenesis in AD animal models and patients. Moreover, we discuss the potential therapeutic approaches for restoring impaired adult SVZ neurogenesis. Our goal is to impart to readers the importance of adult SVZ neurogenesis in AD and to provide new insights through the discussion of possible therapeutic approaches.

Topoisomerase IIA in adult NSCs regulates SVZ neurogenesis by transcriptional activation of Usp37.

Topoisomerase IIA (TOP2a) has traditionally been known as an important nuclear enzyme that resolves entanglements and relieves torsional stress of DNA double strands. However, its function in genomic transcriptional regulation remains largely unknown, especially during adult neurogenesis. Here, we show that TOP2a is preferentially expressed in neurogenic niches in the brain of adult mice, such as the subventricular zone (SVZ). Conditional knockout of Top2a in adult neural stem cells (NSCs) of the SVZ significantly inhibits their self-renewal and proliferation, and ultimately reduces neurogenesis. To gain insight into the molecular mechanisms by which TOP2a regulates adult NSCs, we perform RNA-sequencing (RNA-Seq) plus chromatin immunoprecipitation sequencing (ChIP-Seq) and identify ubiquitin-specific protease 37 (Usp37) as a direct TOP2a target gene. Importantly, overexpression of Usp37 is sufficient to rescue the impaired self-renewal ability of adult NSCs caused by Top2a knockdown. Taken together, this proof-of-principle study illustrates a TOP2a/Usp37-mediated novel molecular mechanism in adult neurogenesis, which will significantly expand our understanding of the function of topoisomerase in the adult brain.

Long-Term Intranasal Nerve Growth Factor Treatment Favors Neuron Formation in de novo Brain Tissue.

ObjectiveTo date, no safe and effective pharmacological treatment has been clinically validated for improving post-stroke neurogenesis. Growth factors are good candidates but low safety has limited their application in the clinic. An additional restraint is the delivery route. Intranasal delivery presents many advantages.Materials and MethodsA brain lesion was induced in twenty-four rats. Nerve growth factor (NGF) 5 μg/kg/day or vehicle was given intranasally from day 10 post-lesion for two periods of five weeks, separated by a two-week wash out period with no treatment. Lesion volume and atrophy were identified by magnetic resonance imaging (MRI). Anxiety and sensorimotor recovery were measured by behavior tests. Neurogenesis, angiogenesis and inflammation were evaluated by histology at 12 weeks.ResultsRemarkable neurogenesis occurred and was visible at the second and third months after the insult. Tissue reconstruction was clearly detected by T2 weighted MRI at 8 and 12 weeks post-lesion and confirmed by histology. In the new tissue (8.1% of the lesion in the NGF group vs. 2.4%, in the control group at 12 weeks), NGF significantly increased the percentage of mature neurons (19% vs. 7%). Angiogenesis and inflammation were not different in the two groups. Sensorimotor recovery was neither improved nor hampered by NGF during the first period of treatment, but NGF treatment limited motor recovery in the second period.InterpretationThe first five-week period of treatment was very well tolerated. This study is the first presenting the effects of a long treatment with NGF and has shown an important tissue regeneration rate at 8 and 12 weeks post-injury. NGF may have increased neuronal differentiation and survival and favored neurogenesis and neuron survival through subventricular zone (SVZ) neurogenesis or reprogramming of reactive astrocytes. For the first time, we evidenced a MRI biomarker of neurogenesis and tissue reconstruction with T2 and diffusion weighted imaging.

Synergistic effects of hIAPP and Aβ1–42 impaired the olfactory function associated with the decline of adult neurogenesis in SVZ

According to many in the field，the prevalence of Alzheimer's disease (AD) in type II diabetes (T2DM) populations is considerably higher than that in the normal population. Human islet amyloid polypeptide (hIAPP) is considered to be a common risk factor for T2DM and AD. Preliminary observations around T2DM animal model show that the decrease of adult neural stem cells (NSCs) in the subventricular zone (SVZ) is accompanied by olfactory dysfunction. Furthermore, impaired olfactory function could serve as to an early predictor of neurodegeneration，which is associated with cognitive impairment. However, the synergistic effects between hIAPP and amyloid-beta (Aβ) 1–42 in the brain and the neurodegeneration remains to be further clarified. In this study, olfactory capacity, synaptic density, status of NSC in SVZ, and status of newborn neurons in olfactory bulb (OB) were assessed 6 months after stereotactic injection of oligomer Aβ1–42 into the dens gyrus (DG) of hIAPP−/+ mice or wild-type homogenous mice. Our results set out that Aβ42 and amylin co-localized into OB and raised Aβ42 deposition in hIAPP−/+ mice compared with wild-type brood mice. In addition, 6 months after injection of Aβ1–42 in hIAPP−/+ mice, these mice showed increased olfactory dysfunction, significant loss of synapses, depletion of NSC in SVZ, and impaired cell renewal in OB. Our present study suggested that the synergistic effects between hIAPP and Aβ1–42 impairs olfactory function and was associated with decreased neurogenesis in adults with SVZ.

BMP4 Exerts Anti-Neurogenic Effect via Inducing Id3 during Aging.

Bone morphogenetic protein (BMP) signaling has been shown to be intimately associated with adult neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Adult neurogenesis declines in aging rodents and primates. However, the role of BMP signaling in the age-related neurogenesis decline remains elusive and the effect of BMP4 on adult SVZ neurogenesis remains controversial. Here, the expression of BMP4 and its canonical effector phosphorylated-Smad1/5/8 (p-Smad1/5/8) in the murine SVZ and SGZ were found to be increased markedly with age. We identified Id3 as a major target of BMP4 in neuronal stem cells (NSCs) of both neurogenic regions, which exhibited a similar increase during aging. Intracerebroventricular infusion of BMP4 activated Smad1/5/8 phosphorylation and upregulated Id3 expression, which further restrained NeuroD1, leading to attenuated neurogenesis in both neurogenic regions and defective differentiation in the SGZ. Conversely, noggin, a potent inhibitor of BMP4, demonstrated opposing effects. In support of this, BMP4 treatment or lentiviral overexpression of Id3 resulted in decreased NeuroD1 protein levels in NSCs of both neurogenic regions and significantly inhibited neurogenesis. Thus, our findings revealed that the increased BMP4 signaling with age inhibited adult neurogenesis in both SVZ and SGZ, which may be attributed at least in part, to the changes in the Id3-NeuroD1 axis.

Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3β/β-catenin signaling pathway.

Stroke is the major cause of death and disability worldwide. Most stroke patients who survive in the acute phase of ischemia display various extents of neurological deficits. In order to improve the prognosis of ischemic stroke, promoting endogenous neurogenesis has attracted great attention. Salvianolic acid A (SAA) has shown neuroprotective effects against ischemic diseases. In the present study, we investigated the neurogenesis effects of SAA in ischemic stroke rats, and explored the underlying mechanisms. An autologous thrombus stroke model was established by electrocoagulation. The rats were administered SAA (10 mg/kg, ig) or a positive drug edaravone (5 mg/kg, iv) once a day for 14 days. We showed that SAA administration significantly decreased infarction volume and vascular embolism, and ameliorated pathological injury in the hippocampus and striatum as well as the neurological deficits as compared with the model rats. Furthermore, we found that SAA administration significantly promoted neural stem/progenitor cells (NSPCs) proliferation, migration and differentiation into neurons, enhanced axonal regeneration and diminished neuronal apoptosis around the ipsilateral subventricular zone (SVZ), resulting in restored neural density and reconstructed neural circuits in the ischemic striatum. Moreover, we revealed that SAA-induced neurogenesis was associated to activating Wnt3a/GSK3β/β-catenin signaling pathway and downstream target genes in the hippocampus and striatum. Edaravone exerted equivalent inhibition on neuronal apoptosis in the SVZ, as SAA, but edaravone-induced neurogenesis was weaker than that of SAA. Taken together, our results demonstrate that long-term administration of SAA improves neurological function through enhancing endogenous neurogenesis and inhibiting neuronal apoptosis in ischemic stroke rats via activating Wnt3a/GSK3β/β-catenin signaling pathway. SAA may be a potential therapeutic drug to promote neurogenesis after stroke.

Developmental thyroid disruption permanently affects the neuroglial output in the murine subventricular zone.

SummaryNeural stem cells (NSCs) in the adult brain are a source of neural cells for brain injury repair. We investigated whether their capacity to generate new neurons and glia is determined by thyroid hormone (TH) during development because serum levels peak during postnatal reorganization of the main NSC niche, the subventricular zone (SVZ). Re-analysis of mouse transcriptome data revealed increased expression of TH transporters and deiodinases in postnatal SVZ NSCs, promoting local TH action, concomitant with a burst in neurogenesis. Inducing developmental hypothyroidism reduced NSC proliferation, disrupted expression of genes implicated in NSC determination and TH signaling, and altered the neuron/glia output in newborns. Three-month-old adult mice recovering from developmental hypothyroidism had fewer olfactory interneurons and underperformed on short-memory odor tests, dependent on SVZ neurogenesis. Our data provide readouts permitting comparison with adverse long-term events following thyroid disruptor exposure and ideas regarding the etiology of prevalent neurodegenerative diseases in industrialized countries.

Expression of D5 dopamine receptors in the lateral ventricle walls during post-weaning rat development.

Even before the first synapses appear, neurotransmitters and their receptors are present in the developing brain, regulating the cell fate of neuronal progenitors in neurogenic niches, such as the lateral ventricle. In particular, dopamine appears to play a pivotal role in the neurogenesis of the subventricular zone by controlling the proliferation and differentiation of progenitors through activation of different receptors. Although dopamine receptor 5 (D5R) is expressed prenatally, there is little information regarding its role in either pre- or postnatal forebrain development. To examine the role of D5Rs in neurogenesis in the rat lateral ventricle subventricular zone (V-SVZ), we immunohistochemically defined D5R expression, as well as BrdU incorporation in progenitor cells of various post-weaning stages (Post-natal day (P) 20 until P80). We found that the level of proliferating cells is stable from postnatal day 20 until 50, and then declines sharply on P80. Concomitantly, D5R is expressed in all ages examined, but we detected a progressive decrease in the density of D5R+ cells from P40 until P80. Moreover, double immunostaining for BrdU and D5R revealed that proliferating cells in V-SVZ also express D5R. Collectively, our data suggest that D5R is expressed in the post-weaning V-SVZ of rat at least until P80, and its expression pattern coincides with that of proliferating cells in the V-SVZ, hinting at a possible role of D5Rs in the regulation of neuronal progenitor division/differentiation.

Novel Galectin-3 Roles in Neurogenesis, Inflammation and Neurological Diseases.

Galectin-3 (Gal-3) is an evolutionarily conserved and multifunctional protein that drives inflammation in disease. Gal-3’s role in the central nervous system has been less studied than in the immune system. However, recent studies show it exacerbates Alzheimer’s disease and is upregulated in a large variety of brain injuries, while loss of Gal-3 function can diminish symptoms of neurodegenerative diseases such as Alzheimer’s. Several novel molecular pathways for Gal-3 were recently uncovered. It is a natural ligand for TREM2 (triggering receptor expressed on myeloid cells), TLR4 (Toll-like receptor 4), and IR (insulin receptor). Gal-3 regulates a number of pathways including stimulation of bone morphogenetic protein (BMP) signaling and modulating Wnt signalling in a context-dependent manner. Gal-3 typically acts in pathology but is now known to affect subventricular zone (SVZ) neurogenesis and gliogenesis in the healthy brain. Despite its myriad interactors, Gal-3 has surprisingly specific and important functions in regulating SVZ neurogenesis in disease. Gal-1, a similar lectin often co-expressed with Gal-3, also has profound effects on brain pathology and adult neurogenesis. Remarkably, Gal-3’s carbohydrate recognition domain bears structural similarity to the SARS-CoV-2 virus spike protein necessary for cell entry. Gal-3 can be targeted pharmacologically and is a valid target for several diseases involving brain inflammation. The wealth of molecular pathways now known further suggest its modulation could be therapeutically useful.

Adult Neurogenesis and Stroke: A Tale of Two Neurogenic Niches.

In the aftermath of an acute stroke, numerous signaling cascades that reshape the brain both in the perilesional zone as well as in more distal regions are activated. Despite continuous improvement in the acute treatment of stroke and the sustained research efforts into the pathophysiology of stroke, we critically lag in our integrated understanding of the delayed and chronic responses to ischemic injury. As such, the beneficial or maladaptive effect of some stroke-induced cellular responses is unclear, restricting the advancement of therapeutic strategies to target long-term complications. A prominent delayed effect of stroke is the robust increase in adult neurogenesis, which raises hopes for a regenerative strategy to counter neurological deficits in stroke survivors. In the adult brain, two regions are known to generate new neurons from endogenous stem cells: the subventricular zone (SVZ) and the dentate subgranular zone (SGZ) of the hippocampus. While both niches respond with an increase in neurogenesis post-stroke, there are significant regional differences in the ensuing stages of survival, migration, and maturation, which may differently influence functional outcome. External interventions such as rehabilitative training add a further layer of complexity by independently modulating the process of adult neurogenesis. In this review we summarize the current knowledge regarding the effects of ischemic stroke on neurogenesis in the SVZ and in the SGZ, and the influence of exogenous stimuli such as motor activity or enriched environment (EE). In addition, we discuss the contribution of SVZ or SGZ post-stroke neurogenesis to sensory, motor and cognitive recovery.