Oligodendrocyte progenitor development from the postnatal rat subventricular zone is regulated by the p75 neurotrophin receptor.

The precise timing of neural progenitor development and the correct balance between proliferation and differentiation are crucial to generating a functional brain. The number, survival, and differentiation of neural progenitors during postnatal neurogenesis and gliogenesis is a highly regulated process. Postnatally, the majority of brain oligodendrocytes are generated from progenitors residing in the subventricular zone (SVZ), the germinal niche surrounding the lateral ventricles. In this study, we demonstrate that the p75 neurotrophin receptor (p75NTR) is highly expressed by OPCs in the postnatal male and female rat SVZ. Whereas the p75NTR is known to initiate apoptotic signaling after brain injury, it is highly expressed by proliferating progenitors in the SVZ, suggesting that it may have a different function during development. Lack of p75NTR reduced progenitor proliferation and caused premature oligodendrocyte differentiation and maturation both in vitro and in vivo, leading to aberrant early myelin formation. Our data reveal a novel role for p75NTR as a rheostat for oligodendrocyte production and maturation during myelin formation in the postnatal rat brain.

Neuroprotective Effects of Delayed TGF-ß1 Receptor Antagonist Administration On Perinatal Hypoxic-Ischemic Brain Injury.

Hypoxic-ischemic (HI) brain injury in neonatal encephalopathy triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the primary damage. The cellular processes mediating this prolonged neurodegeneration in HI injury are not sufficiently understood. Consequently, current therapies are not fully protective. In a recent study, we found significant improvements in neurologic outcomes when a small molecule antagonist for Activin-Like Kinase 5 (ALK5), a transforming growth factor beta (TGF-ß) receptor was used as a therapeutic in a rat model of moderate term HI. Here, we have extended those studies to a mouse preterm pup model of HI. For these studies, postnatal day 7 (P7) CD1 mice of both sexes were exposed to 35-40 minutes of HI. Beginning 3 days later, SB505124, the ALK5 receptor antagonist, was administered systemically through intraperitoneal injections performed every 12 hours for 5 days. When evaluated 23 days later, SB505124-treated mice had ~2.5-fold more hippocampal area and ~2-fold more thalamic tissue. Approximately ~90% of the ipsilateral hemisphere (ILH) was preserved in the SB505124-treated HI mice compared to the vehicle-treated HI mice, where the ILH was ~60% of its normal size. SB505124 also preserved the subcortical white matter. SB505124 treatment preserved levels of aquaporin-4 and n-cadherin, key proteins associated with blood-brain-barrier function. Importantly, SB505124 administration improved sensorimotor function as assessed by a battery of behavioral tests. Altogether these data lend additional support to the conclusion that SB505124 is a candidate neuroprotective molecule that could be an effective treatment for HI-related encephalopathy in moderately injured preterm infants.

Intranasal Leukemia Inhibitory Factor Attenuates Gliosis and Axonal Injury and Improves Sensorimotor Function After a Mild Pediatric Traumatic Brain Injury.

Leukemia inhibitory factor (LIF) is a neuroprotective cytokine that is essential for appropriate glial responses, remyelination, and preservation of neuronal conductance after injury. The intranasal route for delivery of therapeutics to the central nervous system is of particular interest given that it bypasses the blood-brain barrier and peripheral clearance systems. We explored the possibility that LIF might improve neurological function when administered intranasally during the acute phase in a pediatric model of mild traumatic brain injury (mTBI). We tested two doses of LIF and evaluated behavioral outcomes. Here, we show that acute 40-ng intranasal LIF treatment twice a day for 3 days attenuates astrogliosis and microgliosis, protects against axonal damage, significantly improves sensorimotor function, and is well tolerated without detrimental effects on growth. Altogether, our studies provide pre-clinical evidence for the use of acute intranasal LIF treatment as a viable therapeutic for pediatric cases of mTBIs.

Neuroprotective effect of lipopolysaccharides in a dual-hit rat pup model of preterm hypoxia-ischemia.

The combination of lipopolysaccharide (LPS) and hypoxia-ischemia (HI) has been used to model the brain injury sustained by sick pre-term infants in order to study the pathological conditions of diffuse white matter injury, which is a major cause of preterm morbidity. Prior studies have shown that the timing and dose of LPS administration will determine whether the injury is reduced or exacerbated. Here we show that administering a single injection of LPS (0.1 mg/kg) to postnatal-day-2 rat pups 14 h before inducing HI effectively protects the brain from HI-associated damage. We show that the LPS-treated HI rat pups have significantly less histopathology compared to the saline-treated HI rat pups. Apoptotic deaths were dramatically curtailed in both the neocortex and white matter when evaluated at 2 days of recovery. Microglial activation was reduced when the percentage of CD68+/Iba1+ cells was quantified in the neocortex of the LPS-treated vs the saline-treated HI rat pups. One mechanism through which LPS pre-treatment appears to be preventing injury is through the AKT-endothelial nitric oxide synthase (eNOS) pathway as LPS induced an increase in both the expression and phosphorylation of eNOS. Altogether these data show that the neocortex, as well as the white matter sustain damage after HI at this timepoint in forebrain development and that acutely activating the immune system can protect the brain from brain injury.

Neural Stem Cells in Adult Mammals are not Astrocytes.

At the turn of the 21st century studies of the cells that resided in the adult mammalian subventricular zone (SVZ) characterized the neural stem cells (NSCs) as a subtype of astrocyte. Over the ensuing years, numerous studies have further characterized the properties of these NSCs and compared them to parenchymal astrocytes. Here we have evaluated the evidence collected to date to establish whether classifying the NSCs as astrocytes is appropriate and useful. We also performed a meta-analysis with 4 previously published datasets that used cell sorting and unbiased single-cell RNAseq to highlight the distinct gene expression profiles of adult murine NSCs and niche astrocytes. On the basis of our understanding of the properties and functions of astrocytes versus the properties and functions of NSCs, and from our comparative transcriptomic analyses we conclude that classifying the adult mammalian NSC as an astrocyte is potentially misleading. From our vantage point, it is more appropriate to refer to the cells in the adult mammalian SVZ that retain the capacity to produce new neurons and macroglia as NSCs without attaching the term "astrocyte-like."

Subventricular zone adult mouse neural stem cells require insulin receptor for self-renewal.

The insulin receptor (INSR) is an evolutionarily conserved signaling protein that regulates development and cellular metabolism. INSR signaling promotes neurogenesis in Drosophila; however, a specific role for the INSR in maintaining adult neural stem cells (NSCs) in mammals has not been investigated. We show that conditionally deleting the Insr gene in adult mouse NSCs reduces subventricular zone NSCs by ∼70% accompanied by a corresponding increase in progenitors. Insr deletion also produced hyposmia caused by aberrant olfactory bulb neurogenesis. Interestingly, hippocampal neurogenesis and hippocampal-dependent behaviors were unperturbed. Highly aggressive proneural and mesenchymal glioblastomas had high INSR/insulin-like growth factor (IGF) pathway gene expression, and isolated glioma stem cells had an aberrantly high ratio of INSR:IGF type 1 receptor. Moreover, INSR knockdown inhibited GBM tumorsphere growth. Altogether, these data demonstrate that the INSR is essential for a subset of normal NSCs, as well as for brain tumor stem cell self-renewal.

Analyzing mouse neural stem cell and progenitor cell proliferation using EdU incorporation and multicolor flow cytometry.

This protocol describes an ex vivo approach to identify and quantify the proportions of proliferating neural stem cells and progenitors of the mouse subventricular zone. It uses ethynyl deoxyuridine (EdU) incorporation to identify dividing cells, combined with multicolor flow cytometry for 4 cell surface antigens to distinguish between 8 phenotypically distinct mouse neural progenitors and stem cells. It has been optimized for wild-type neonatal mice but can be used on mice of any postnatal age. For complete details on the use and execution of this profile, please refer to Kumari et al. (2020).

Modestly increasing systemic interleukin-6 perinatally disturbs secondary germinal zone neurogenesis and gliogenesis and produces sociability deficits.

Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with the developmental origins of psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3-6 when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by âˆ¼ 50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent âˆ¼ 30% less time socially engaging with sexually receptive females and produced âˆ¼ 50% fewer ultrasonic vocalizations during mating. They also engaged âˆ¼ 50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in leukemia inhibitory factor heterozygous mice.

Traumatic brain injury (TBI) is a significant problem that affects over 800,000 children each year. As cell proliferation is disturbed by injury and required for normal brain development, we investigated how a pediatric closed head injury (CHI) would affect the progenitors of the subventricular zone (SVZ). Additionally, we evaluated the contribution of leukemia inhibitory factor (LIF) using germline LIF heterozygous mice (LIF Het), as LIF is an injury-induced cytokine, known to influence neurogenesis and gliogenesis. CHIs were performed on P20 LIF Het and wild-type (WT) mice. Ki-67 immunostaining and stereology revealed that cell proliferation increased ~250% in injured LIF Het mice compared to the 30% increase observed in injured WT mice at 48-hr post-CHI. OLIG2+ cell proliferation increased in the SVZ and white matter of LIF Het injured mice at 48-hr recovery. Using an 8-color flow cytometry panel, the proliferation of three distinct multipotential progenitors and early oligodendrocyte progenitor cell proliferation was significantly increased in LIF Het injured mice compared to WT injured mice. Supporting its cytostatic function, LIF decreased neurosphere progenitor and oligodendrocyte progenitor cell proliferation compared to controls. In highly enriched mouse oligodendrocyte progenitor cell cultures, LIF increased phospho-protein kinase B after 20 min and increased phospho-S6 ribosomal protein at 20 and 40 min of exposure, which are downstream targets of the mammalian target of rapamycin pathway. Altogether, our data provide new insights into the regulatory role of LIF in suppressing neural progenitor cell proliferation and, in particular, oligodendrocyte progenitor cell proliferation after a mild TBI.

Mechanisms of Tertiary Neurodegeneration after Neonatal Hypoxic-Ischemic Brain Damage.

Neonatal encephalopathy linked to hypoxia-ischemia (H-I) which is regarded as the most important neurological problem of the newborn, can lead to a spectrum of adverse neurodevelopmental outcomes such as cerebral palsy, epilepsy, hyperactivity, cognitive impairment and learning difficulties. There have been numerous reviews that have focused on the epidemiology, diagnosis and treatment of neonatal H-I; however, a topic that is less often considered is the extent to which the injury might worsen over time, which is the focus of this review. Similarly, there have been numerous reviews that have focused on mechanisms that contribute to the acute or subacute injury; however, there is a tertiary phase of recovery that can be defined by cellular and molecular changes that occur many weeks and months after brain injury and this topic has not been the focus of any review for over a decade. Therefore, in this article we review both the clinical and pre-clinical data that show that tertiary neurodegeneration is a significant contributor to the final outcome, especially after mild to moderate injuries. We discuss the contributing roles of apoptosis, necroptosis, autophagy, protein homeostasis, inflammation, microgliosis and astrogliosis. We also review the limited number of studies that have shown that significant neuroprotection and preservation of neurological function can be achieved administering drugs during the period of tertiary neurodegeneration. As the tertiary phase of neurodegeneration is a stage when interventions are eminently feasible, it is our hope that this review will stimulate a new focus on this stage of recovery towards the goal of producing new treatment options for neonatal hypoxic-ischemic encephalopathy.

Leukemia Inhibitory Factor Is Required for Subventricular Zone Astrocyte Progenitor Proliferation and for Prokineticin-2 Production after a Closed Head Injury in Mice.

Astrogliosis is one of the hallmarks of brain injury, and after a mild injury activated astrocytes subserve neuroprotective and pro-regenerative functions. We previously found that the astroglial response to closed head injury (CHI) was blunted in mice that were haplodeficient in leukemia inhibitory factor (LIF); therefore, the goal of these studies was to determine if the delayed astrogliosis was due to decreased recruitment of subventricular zone (SVZ) progenitors. CHI's were performed on post-natal day 20 on LIF heterozygous (Het) and wild-type (WT) mice. At 48 h post-CHI, astrocyte progenitor proliferation within the SVZ increased ∼250% in WT mice but was reduced by ∼200% in LIF Het mice compared with sham controls. Using neurospheres to model the SVZ, LIF increased the percentage of proliferating astrocyte progenitors by 2-fold compared with controls but had no effect on neural stem cell proliferation. To rule out the involvement of other cytokines, 105 cytokines were analyzed using a multi-plex array and with targeted validation on injured LIF Het versus WT neocortex. Of the cytokines analyzed, only prokineticin-2 (ProK2) required LIF signaling. Correspondingly, LIF-treated neurospheres expressed higher levels of ProK2, the ProK1 and ProK2 receptors (ProKR1 and ProKR2). Using in situ hybridization, ProK2 messenger RNA (mRNA) was most abundant in neocortical neurons and highly expressed within the SVZ. However, in contrast to LIF, ProK2 decreased astrocyte progenitor proliferation 2-fold. Altogether, these data demonstrate that LIF is necessary for astrocyte progenitor proliferation after injury and reveal a new role for LIF as an essential regulator of the neurotrophic factor ProK2.

Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia.

Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)ß1 is highly elevated following HI and that delivering an antagonist for TGFß receptor activin-like kinase 5 (ALK5)-SB505124-three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.

Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice.

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

Neuroregenerative and protective functions of Leukemia Inhibitory Factor in perinatal hypoxic-ischemic brain injury.

Neonatal hypoxic-ischemic encephalopathy remains the most important neurological problem of the newborn. Delays in diagnosing perinatal brain injuries are common, preventing access to acute therapies. Therefore, there is a critical need for therapeutic strategies that are beneficial when delivered beyond 24 h after birth. Here we show that Leukemia Inhibitory Factor (LIF) functions as an essential injury-induced neurotrophic cytokine in the CNS and that non-invasively administering LIF as late as 3 days after a hypoxic-ischemic insult improves neurological function. Using a mouse model of late preterm brain injury we show that astroglial and microglial/macrophage reactivity to hypoxia-ischemia was diminished at 3 days of recovery, but then exacerbated at 2 weeks of recovery in LIF haplodeficient mice. There also were significantly more CD68+/Iba-1+ cells in the ipsilateral striatum in LIF-Het mice compared to WT mice at 2 weeks of recovery. This desynchronized glial response was accompanied by increased neuronal cell death in the striatum and neocortex (Fluorojade C), hypomyelination (reduced MBP staining and thinner external capsule), increased extent of brain damage (Nissl) and diminished neurological function on sensorimotor tests. To our surprise, injured LIF-Het mice had ~7-fold higher IGF-1 levels than injured WT mice at 3 days after HI injury. Intranasally administered LIF activated the Jak-Stat-3 pathway both within the subventricular zone and the neocortex at 30 min after administration. When delivered with a delay of 3 days after the insult, intranasal LIF reduced the extent of brain injury by ~60%, attenuated astrogliosis and microgliosis in striatum, improved subcortical white matter thickness, increased numbers of Olig2+ cells in corpus callosum and improved performance on sensorimotor tests at 2 weeks of recovery. These studies provide key pre-clinical data recommending LIF administration as a neuroprotectant and regenerative cytokine and they highlight the feasibility of pursuing new therapeutics targeting the tertiary phase of neurodegeneration for hypoxic-ischemic encephalopathies.

Developmental IL-6 Exposure Favors Production of PDGF-Responsive Multipotential Progenitors at the Expense of Neural Stem Cells and Other Progenitors.

Interleukin-6 (IL-6) is increased in maternal serum and amniotic fluid of children subsequently diagnosed with autism spectrum disorders. However, it is not clear how increased IL-6 alters brain development. Here, we show that IL-6 increases the prevalence of a specific platelet-derived growth factor (PDGF)-responsive multipotent progenitor, with opposite effects on neural stem cells and on subsets of bipotential glial progenitors. Acutely, increasing circulating IL-6 levels 2-fold above baseline in neonatal mice specifically stimulated the proliferation of a PDGF-responsive multipotential progenitor accompanied by increased phosphorylated STAT3, increased Fbxo15 expression, and decreased Dnmt1 and Tlx expression. Fate mapping studies using a Nestin-CreERT2 driver revealed decreased astrogliogenesis in the frontal cortex. IL-6-treated mice were hyposmic; however, olfactory bulb neuronogenesis was unaffected. Altogether, these studies provide important insights into how inflammation alters neural stem cells and progenitors and provide new insights into the molecular and cellular underpinnings of neurodevelopmental disorders associated with maternal infections.

Perinatal IL-1ß-induced inflammation suppresses Tbr2+ intermediate progenitor cell proliferation in the developing hippocampus accompanied by long-term behavioral deficits.

Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1 ß (IL-1ß) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 â€‹ng/g IL-1ß was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1α and acutely reduced the proliferation of Tbr2+ neural progenitors in the DG. In vitro, both IL-1α and IL-1ß produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1ß treatment increased neural stem cell frequency. Upon terminating IL-1ß treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1ß as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1ß as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus by producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants.

Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury.

There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration. In this study, we have compared neural progenitors (NPs) from the fetal ventricular zone (VZ), the postnatal subventricular zone, and an immortalized radial glia (RG) cell line engineered to conditionally secrete the trophic factor insulin-like growth factor 1 (IGF-1). Upon differentiation in vitro, the VZ cells were able to generate a greater number of neurons than subventricular zone cells. Furthermore, differentiated VZ cells generated pyramidal neurons . In vitro, doxycycline-driven secretion of IGF-1 strongly promoted neuronal differentiation of cells with hippocampal, interneuron and cortical specificity. Accordingly, VZ and engineered RG-IGF-1-hemagglutinin (HA) cells were selected for subsequent in vivo experiments. To increase cell survival, we delivered the NPs attached to a multifunctional chitosan-based scaffold. The microspheres containing adherent NPs were injected subacutely into the lesion cavity of adult rat brains that had sustained controlled cortical impact injury. At 2 weeks posttransplantation, the exogenously introduced cells showed a reduction in stem cell or progenitor markers and acquired mature neuronal and glial markers. In beam walking tests assessing sensorimotor recovery, transplanted RG cells secreting IGF-1 contributed significantly to functional improvement while native VZ or RG cells did not promote significant recovery. Altogether, these results support the therapeutic potential of chitosan-based multifunctional microsphere scaffolds seeded with genetically modified NPs expressing IGF-1 to promote repair and functional recovery after traumatic brain injuries.

Insulin-like Growth Factor II: An Essential Adult Stem Cell Niche Constituent in Brain and Intestine.

Tissue-specific stem cells have unique properties and growth requirements, but a small set of juxtacrine and paracrine signals have been identified that are required across multiple niches. Whereas insulin-like growth factor II (IGF-II) is necessary for prenatal growth, its role in adult stem cell physiology is largely unknown. We show that loss of Igf2 in adult mice resulted in a ∼50% reduction in slowly dividing, label-retaining cells in the two regions of the brain that harbor neural stem cells. Concordantly, induced Igf2 deletion increased newly generated neurons in the olfactory bulb accompanied by hyposmia, and caused impairments in learning and memory and increased anxiety. Induced Igf2 deletion also resulted in rapid loss of stem and progenitor cells in the crypts of Lieberkühn, leading to body-weight loss and lethality and the inability to produce organoids in vitro. These data demonstrate that IGF-II is critical for multiple adult stem cell niches.

TGFß1: Friend or Foe During Recovery in Encephalopathy.

The cytokine transforming growth factor (TGF)-ß1 is highly induced after encephalopathic brain injury, with data showing that it can both contribute to the pathophysiology and aid in disease resolution. In the immature brain, sustained TGFß-signaling after injury may prolong inflammation to both exacerbate acute stage damage and perturb the normal course of development. Yet in adult encephalopathy, elevated TGFß1 may promote a reparative state. In this review, we highlight the context-dependent actions of TGFß-signaling in the brain during resolution of encephalopathy and focus on neuronal survival mechanisms that are affected by TGFß1. We discuss the mechanisms that contribute to the disparate actions of TGFß1 toward elucidating the long-term neurological and neuropsychiatric consequences that follow encephalopathic injury.