Regeneration and repair in the developing and aging brain

The Back Lab develops novel strategies to promote regeneration and repair after injury to the developing and adult brain. Our work spans from premature infants to adults with dementia and focuses on the fundamental biological processes that govern white and gray matter development, injury and recovery.

One major focus of the lab is neurological disorders that cause cerebral white matter injury (WMI) and disturbances in myelination. We study cerebral palsy in survivors of premature birth, multiple sclerosis and vascular dementias. All these disorders share mechanisms in which aberrant glial responses and extracellular matrix signaling arrest oligodendrocyte maturation and prevent effective remyelination. By integrating human pathology with advanced experimental models, we develop novel molecular strategies to restore myelin and improve motor and cognitive function.

We also study how hypoxia disrupts gray matter maturation in disorders like maternal sleep apnea or apnea of prematurity. We are finding that gray matter is markedly more resistant to injury than white matter but is very sensitive to low oxygen exposures. Hypoxia alone can trigger profound disturbances in neuronal maturation and synaptic development that persist into adulthood. Our goal is to define novel causes of chronic neurobehavioral disabilities in survivors of premature birth as they become adults. Our findings guide new preventive and therapeutic approaches in maternal and neonatal care.

On this page you can:

• Learn about our research projects
• Find links to our publications
• Meet our team

Accomplishments

The Back Lab has made foundational discoveries that redefine how white and gray matter vulnerability and repair are understood from prematurity to aging. We have long-standing funding from the NIH (NINDS and NHLBI) including recent support from NIA for our dementia studies. Our accomplishments include:

• Defining the role of maturation dependent vulnerability of the oligodendrocyte lineage to oxidative stress and hypoxia-ischemia
• Discovering that white matter injury in the developing and aging brain sustains myelination failure due to maturation arrest of oligodendrocyte progenitors.
• Identifying that white matter lesions generate specific sizes of hyaluronic acid and disrupt the maturation of oligodendrocyte progenitors
• Identifying that mild to moderate low oxygen exposure to the preterm gray matter can permanently disrupt the maturation of key neuronal populations in diverse gray matter regions
• Defining a novel role for microglial ferroptosis in white matter lesions in Alzheimer’s disease and vascular dementia

News

• Study implicates enzyme in neurodegenerative conditions
• JNeurosci Spotlight: Useful Genetic Mouse Lines
• Dr. Philip Adeniyi joins African Brain Journal editorial board
• OHSU scientists discover new cause of Alzheimer’s, vascular dementia
• OHSU physician-scientist pioneers research to better understand maternal sleep apnea

Research Projects

At the Back Lab, our approach is multidisciplinary and technology-forward. We integrate cellular and molecular biology, electrophysiology, physiology, pharmacology, neuropathology, quantitative morphometry and stereology, advanced microscopy and high-field MRI. We use human tissues and unique animal models to link basic science with human disease.

As part of the OHSU neuroscience community, one of the most highly NIH-funded programs in the United States, we benefit from a deeply collaborative and translational research environment. By combining rigorous human pathology with innovative experimental platforms, we aim to redefine how white and gray matter injury is understood and treated across the lifespan.

Cerebral gray matter dysmaturation in preterm brain injury

We are defining how hypoxia disrupts molecular pathways and increases the risk for neurodevelopmental disorders like autism and mental illness. For former preterm infants, this could lead to improved neurobehavioral outcomes. Read about our 2019 study that showed lack of oxygen doesn't kill infant brain cells.

Preterm infants with white matter injury (WMI) often show diffuse reductions in cortical and subcortical gray matter growth. Our work challenged the longstanding assumption that this impairment results from widespread neuronal death. Instead, we demonstrated that transient hypoxia alone, even without significant oxidative damage or neurodegeneration, can chronically disrupt neuronal maturation.

In small and large animal models, neurons in the cerebral cortex, subplate and hippocampus survive hypoxia but develop persistent structural and functional abnormalities. After as little as 30 minutes of moderate hypoxia, immature neurons show abnormal dendritic arborization and impaired synaptic activity. After one month, CA1 hippocampal neurons show long-lasting disturbances in synaptic activity and cellular mechanisms essential for learning and memory. Our findings redefine preterm gray matter injury as a disorder of neuronal dysmaturation rather than degeneration.

This suggests that we can treat preterm brain injury, that is assumed to be untreatable, after the early phase of injury. Therapies that promote dendritic maturation may restore circuit development and improve long-term neurological outcomes.

Supported by NHLBI, we developed a novel preclinical model of repetitive fetal hypoxia in preterm sheep that mimics maternal sleep apnea. Funded by NINDS, we use preterm-equivalent mouse models to define novel molecular pathways that may explain neuronal dysmaturation. This work is also supported by the Sharma family.

These studies are led by Art Riddle, M.D., Ph.D., and James Maylie, Ph.D., working with Zsolt Bagi, M.D., Ph.D., at the Medical College of Georgia.

Molecular mechanisms of myelination failure

Most cerebral white matter injury (WMI) can’t be seen during its acute phase, so early intervention is often not possible. Our lab focuses on therapies that promote regeneration and remyelination in chronic white matter lesions. Therapeutic strategies suggested by our work could help treat preterm WMI, multiple sclerosis and vascular dementias.

We identified the extracellular matrix as a central regulator of myelination failure. In chronic human WMI, hyaluronic acid (HA) and its receptor CD44 are highly enriched. Working with Larry Sherman, Ph.D., we showed that reactive astrocytes generate high–molecular weight forms of HA that blocks maturation of late oligodendrocyte progenitors (preOLs).

We also discovered that white matter lesions process HA into bioactive fragments, including a 210 kDa fragment that selectively blocks remyelination. This fragment signals through a non-canonical TLR4–TRIF pathway and activates the transcription factor FoxO3. This blocks oligodendrocyte maturation even in the presence of pro-myelination signals. These findings suggest novel strategies to promote myelination.

These ongoing NINDS-funded studies are led by Taasin Srivastava, Ph.D. We are studying maturation-dependent responses to hypoxia-ischemia and the roles of TSG-6 in myelination disorders. In related studies, we are working with OHSU’s Larry Sherman, Ph.D., and Justin Dean, Ph.D., at the University of Auckland to test the effects of novel hyaluronidase inhibitors to promote repair of preterm brain injury.

This work is also supported by the Huebner family.

White matter injury in Alzheimer’s disease and vascular dementia

The Back Lab has extensive expertise in collecting and preserving human brain tissue. Working with C. Dirk Keene, M.D., Ph.D., at the University of Washington, we maintain a large collection of brain samples from autopsies of people with Alzheimer’s disease and vascular dementia. We also have brain tissue from autopsies of premature and term infants.

Over decades, we have developed immunohistochemical protocols that detect human molecules in specific cell types in both white and gray matter. These resources let us anchor research findings in human pathology.

Current studies focus on mechanisms of chronic white matter injury. We study changes in the extracellular matrix that cause myelination failure and regulation of cell death mediated by ferroptosis. Our findings could lead to new approaches to treat Alzheimer’s disease and vascular dementia.

Publications

Below are some of the Back Lab’s significant publications. Find the most recent publications by Dr. Stephen Back on PubMed.

TSG-6-mediated extracellular matrix modifications regulate hypoxic-ischemic brain injury
Journal of Neuroscience 2024 
Srivastava T, Nguyen H, Haden G, Diba P, Sowa S, LaNguyen N, Reed-Dustin W, Zhu W, Gong X, Harris EN, Baltan S, Back SA.

A TLR-AKT-FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors
Journal of Clinical Investigation 2018
Srivastava T, Diba P, Dean JM, Banine F, Shaver D, Hagen M, Gong X, Su W, Emery B, Marks DL, Harris EN, Baggenstoss B, Weigel PH, Sherman LS, Back SA.

Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure via disturbances in neuronal arborization
Science Translational Medicine 2013
Dean JM, McClendon E, Hansen K, Azimi-Zonooz A, Chen K, Riddle A, Gong X, Sharifnia E, Hagen M, Ahmad T, Leigland LA, Hohimer AR, Kroenke CD, Back SA.

Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants
Annals of Neurology 2012
Buser JS, Maire J, Riddle A, Nelson K, Gong X, Luo NL, Ren J, Nguyen T, Struve J, Sherman LS, Miller SP, Chau V, Hendson G, Ballabh P, Grafe MR, Back SA.

Histopathological correlates of MRI-defined chronic perinatal white matter injury
Annals of Neurology 2011
Riddle A, Dean JM, Buser JR, Gong X, Maire J, Chen K, Ahmad T, Cai V, Nguyen T, Kroenke CD, Hohimer AR, Back SA.

People

The Back Lab is a close-knit team of scientists and clinicians who work across projects and disciplines. We have been nicknamed the “dogma busters” for challenging assumptions in brain injury research.

We collaborate widely, publish rigorously quantitative work and support our trainees’ career development.

Principal investigator Stephen Back, M.D., Ph.D.

Dr. Stephen Back is a professor of pediatrics, neurology and anesthesiology-critical care medicine. A pioneer in developmental brain injury research, Dr. Back has been funded by the NIH since 1997. He was one of the first people at OHSU to receive a Javits Award from NINDS, in recognition of his studies in preterm brain injury.

Affiliated faculty

Art Riddle, M.D., Ph,D., is an assistant professor of pediatrics and neurology. He earned his doctoral degrees through the OHSU Neuroscience Graduate Program and completed his residency at Cincinnati Children’s Hospital. Dr. Riddle joined OHSU in 2019 as a postdoctoral scholar in neurophysiology, working with Dr. James Maylie. His research focus is the susceptibility of the preterm brain to hippocampal dysmaturation mediated by intermittent hypoxia.

Taasin Srivastava, Ph.D., is a research assistant professor in the department of pediatrics. He earned his Ph.D. in neurobiology at the University of Arkansas and worked with OHSU’s Dr. Tom Soderling before he joined the Back Lab. As a postdoctoral scholar in the Back Lab, he identified novel forms of hyaluronan that block oligodendrocyte progenitor maturation in the newborn and adult brain. His research focus is to define signaling mechanisms mediated by the proteoglycan TSG-6 that regulate susceptibility to stroke in preterm neonates and adults.