Papers by Steven W Levison
Frontiers in stem cell and regenerative medicine research, Oct 12, 2017
Journal of Biological Chemistry, Mar 1, 2014
Developmental Neuroscience
Hypoxic-ischemic (HI) brain injury in neonatal encephalopathy triggers a wave of neuroinflammator... more 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-β) 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 CD1 mice of both sexes were exposed to 35–40 min of HI. Beginning 3 days later, SB505124, the ALK5 receptor antagonist, was administered systemically through intraperitoneal injections performed every 12 h for 5 days. When evaluated 23 days late...
Glia
The precise timing of neural progenitor development and the correct balance between proliferation... more 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 ...
ASN Neuro
At the turn of the 21st century studies of the cells that resided in the adult mammalian subventr... more 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 appropri...
Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain ... more Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury
Brain, Behavior, and Immunity, 2022
Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of off... more 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 ∼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 ∼30% less time socially engaging with sexually receptive females and produced ∼50% fewer ultrasonic vocalizations during mating. They also engaged ∼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.
STAR Protocols, 2022
Summary This protocol describes an ex vivo approach to identify and quantify the proportions of p... more Summary 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).
Investigative Ophthalmology & Visual Science, 2003
bioRxiv, 2021
Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of off... more 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 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...
Investigative Ophthalmology & Visual Science, 2006
ASN Neuro, 2020
The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including prolife... more 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...
Developmental neuroscience, Jan 20, 2017
Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflamm... more Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5 ), TGF-β receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-β receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 v...
Neural regeneration research, 2016
There is great interest in the regenerative potential of the neural stem cells and progenitors th... more There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone (SVZ). However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury.
Growth Hormone & IGF Research, 2014
OBM Neurobiology, 2019
A number of studies have highlighted the connection between infections during pregnancy in mother... more A number of studies have highlighted the connection between infections during pregnancy in mothers and increased risk for neuropsychiatric disorders later in life leading to the view that maternal immune activation is a significant contributor to psychiatric illnesses. Metaanalyses have revealed associations between the incidence of premature birth and perinatal inflammation with smaller total brain volumes, cognitive, motor and behavioral deficits in childhood and adolescents. In animal studies where inflammation has been induced during the perinatal period, parallel changes in cognition and behavior have been seen reminiscent of those observed in human clinical studies. Several cytokines and in particular IL-1ß and IL-6 that are produced maternally can cross the placenta as well as the blood-brain-barrier to affect the developing brain, and they may positively or negatively regulate the stem cells and progenitors that reside in the brain's germinal matrices. Therefore, here we will review the literature towards the goal of highlighting how IL-1 and IL-6 affect the proliferation and differentiation of the stem cells and progenitors of the major germinal zones of the developing brain, and discuss how changes in the progenitor cell population can contribute to psychiatric disorders such as autism and schizophrenia.
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Papers by Steven W Levison