Posts

glial cells

Dr. Nathan A. Smith receives $600,000 DOD ARO grant to study the role of glial cells in neural excitability and cognition

glial cells

Microglia are the resident immune cells of the central nervous system that have highly dynamic processes that continuously survey the brain’s microenvironment, making contact with both neurons and astrocytes.

In his pursuit to understand the function of neural circuits within the brain, Nathan A. Smith, M.S., Ph.D., principal investigator at Children’s National Hospital, is examining how specialized glial cells, known as astrocytes and microglia, work together to influence neural networks and potentially enhance neuro-cognition.

Dr. Smith has just secured a new $600,000 grant from the Department of Defense Army Research Laboratory to pursue cutting-edge experimental approaches to examine the role of astrocytes in Ca2+-dependent microglia modulation of synaptic activity. This project will enhance our understanding of neuronal excitability and cognition, and define a new role for microglia in these processes.

“Glia cells play an important role in modulating synaptic function via Ca2+-dependent mechanisms,” says Dr. Smith. “It’s time for these cells to receive recognition as active participants, rather than passive contributors, in fundamental neural processes.”

Dr. Smith and his laboratory at Children’s National Research Institute are using novel experimental models to study the dynamics underlying Ca2+-mediated microglia process extension and retraction to further our understanding of how microglia, astrocytes and neurons interact in the healthy brain.

“Completion of the proposed studies has the potential to redefine the role(s) of microglia in higher brain functions and highlight the significant contribution of these cells,” Dr. Smith says. “Most importantly, elucidating the mechanisms that underlie glial cell modulation of neural circuits will not only further our understanding of normal brain function but also open new avenues to developing more accurate computational models of neural circuits.”

Dr. Nathan Smith

Dr. Smith and his laboratory at Children’s National Research Institute are using novel experimental models to study the dynamics underlying Ca2+-mediated microglia process extension and retraction to further our understanding of how microglia, astrocytes and neurons interact in the healthy brain.

Microglia are the resident immune cells of the central nervous system that have highly dynamic processes that continuously survey the brain’s microenvironment, making contact with both neurons and astrocytes. However, because of our inability to directly monitor Ca2+ activity in microglia, very little is known about the intracellular Ca2+ dynamics in resting microglia and their role in surveillance and modulation of synaptic activity.

Dr. Smith’s research team and his use of cutting-edge technology are a perfect match with the Army’s new modernization priorities. Dr. Smith’s research program and the new Army’s initiatives will greatly benefit from each other and ultimately contribute to a better understanding of the human brain.

“This research will help address a major gap in our understanding of the roles that glial cells play in regulating the computations of the nervous system through their interactions with neurons, which could also inspire a new class of artificial neural network architectures,” said Dr. Frederick Gregory, program manager, Army Research Office, an element of the U.S. Army Combat Capabilities Development Command’s Army Research Laboratory.

The grant will begin on July 1, 2020, and will last over three years. Dr. Smith’s research is also supported by other grants, including awards from the NIH and the National Science Foundation.

“As Dr. Smith’s mentor, the ultimate joy for a mentor is to see his mentees follow their dreams and be recognized for their accomplishments,” said Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National Hospital. “I couldn’t be prouder of Nathan, and I am fully confident that this new research grant will help him continue to grow an exceptional research program.”

Presidnet's Award for Innovation in Research

President’s Award highlights innovative work by early-career researchers

Presidnet's Award for Innovation in Research

As part of Research and Education Week 2018, two Presidential awardees were recognized for their research contributions, Catherine “Katie” Forster, M.D., M.S., and Nathan Anthony Smith, Ph.D.

Catherine “Katie” Forster, M.D., M.S., and Nathan Anthony Smith, Ph.D., received the President’s Award for Innovation in Research honoring their respective research efforts to explore an understudied part of the microbiome and to shed light on an underappreciated player in nerve cell communication.

Drs. Forster and Smith received their awards April 19, 2018, the penultimate day of Research and Education Week 2018, an annual celebration of the excellence in research, education, innovation and scholarship that takes place at Children’s National Health System. This year marks the fifth time the President’s Award honor has been bestowed to Children’s faculty.

Dr. Forster’s work focuses on preventing pediatric urinary tract infections (UTIs). Frequently, children diagnosed with illnesses like spina bifida have difficulty urinating on their own, and they often develop UTIs. These repeated infections are frequently treated with antibiotics which, in turn, can lead to the child developing antibiotic-resistant organisms.

“The majority of the time if you culture these children, you’ll grow something. In a healthy child, that culture would indicate a UTI,” Dr. Forster says. “Children with neurogenic bladder, however, may test positive for bacteria that simply look suspect but are not causing infection. Ultimately, we’re looking for better ways to diagnose UTI at the point of care to better personalize antibiotic treatment and limit prescriptions for children who do not truly need them.”

Powered by new sequencing techniques, a research group that includes Dr. Forster discovered that the human bladder hosts a significant microbiome, a diverse bacterial community unique to the bladder. Dr. Forster’s research will continue to characterize that microbiome to determine how that bacterial community evolves over time and whether those changes are predictable enough to intervene and prevent UTIs.

“Which genes are upregulated in Escherichia coli and the epithelium, and which genes are upregulated by both in response to each other? That can help us understand whether genes being upregulated are pathogenic,” she adds. “It’s a novel and exciting research area with significant public health implications.”

Smith’s work focuses on the role of astrocytes, specialized star-shaped glial cells, in modulating synaptic plasticity via norepinephrine. Conventional thinking describes astrocytes as support cells but, according to Smith, astrocytes are turning out to be more instrumental.

Norepinephrine, a neurotransmitter that plays an essential role in attention and focus, is released by a process known as volume transmission, which is a widespread release of a neurotransmitter at once, says Smith, a principal investigator in Children’s Center for Neuroscience Research. Astrocytes, which outnumber neurons in the brain, are strategically and anatomically located to receive this diffuse input and translate it into action to modulate neural networks.

“We hypothesize that astrocytes are integral, functional partners with norepinephrine in modulating cortical networks,” Smith adds. “Since astrocytes and norepinephrine have been implicated in many central nervous system functions, including learning and attention, it is critical to define mechanistically how astrocytes and norepinephrine work together to influence neural networks. This knowledge also will be important for the development of novel therapeutics to treat diseases such as attention deficit hyperactivity disorder and epilepsy.”

Harnessing progenitor cells in neonatal white matter repair

The sirtuin protein Sirt1 plays a crucial role in the proliferation and regeneration of glial cells from an existing pool of progenitor cells — a process that rebuilds vital white matter following neonatal hypoxic brain injury. Although scientists do not fully understand Sirt1’s role in controlling cellular proliferation, this pre-clinical model of neonatal brain injury outlines for the first time how Sirt1 contributes to development of additional progenitor cells and maturation of fully functional oligodendrocytes.

The findings, published December 19 in Nature Communications, suggest that modulation of this protein could enhance progenitor cell regeneration, spurring additional white matter growth and repair following neonatal brain injury.

“It is not a cure. But, in order to regenerate the white matter that is lost or damaged, the first steps are to identify endogenous cells capable of regenerating lost cells and then to expand their pool. The glial progenitor cells represent 4 to 5 percent of total brain cells,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and senior author of the study. “It’s a sizable pool, considering that the brain is made up of billions of cells. The advantage is that these progenitor cells are already there, with no requirement to slip them through the blood-brain barrier. Eventually they will differentiate into oligodendrocyte cells in white matter, mature glia, and that’s exactly what we want them to do.”

The study team identified Sirt1 as a novel, major regulator of basal oligodendrocyte progenitor cell (OPC) proliferation and regeneration in response to hypoxia in neonatal white matter, Gallo and co-authors write. “We demonstrate that Sirt1 deacetylates and activates Cdk2, a kinase which controls OPC expansion. We also elucidate the mechanism by which Sirt1 targets other individual members of the Cdk2 signaling pathway, by regulating their deacetylation, complex formation and E2F1 release, molecular events which drive Cdk2-mediated OPC proliferation,” says Li-Jin Chew, Ph.D., research associate professor at Children’s Center for Neuroscience Research and a study co-author.

Hypoxia-induced brain injury in neonates initiates spontaneous amplification of progenitor cells but also causes a deficiency of mature oligodendrocytes. Inhibiting Sirt1 expression in vitro and in vivo showed that loss of its deacetylase activity prevents OPC proliferation in hypoxia while promoting oligodendrocyte maturation – which underscores the importance of Sirt1 activity in maintaining the delicate balance between these two processes.

The tantalizing findings – the result of four years of research work in mouse models of neonatal hypoxia – hint at the prospect of lessening the severity of developmental delays experienced by the majority of preemies, Gallo adds. About 1 in 10 infants born in the United States are delivered preterm, prior to the 37th gestational week of pregnancy, according to the Centers for Disease Control and Prevention.  Brain injury associated with preterm birth – including white matter injury – can have long-term cognitive and behavioral consequences, with more than 50 percent of infants who survive prematurity needing special education, behavioral intervention and pharmacological treatment, Gallo says.

Time is of the essence, since Sirt1 plays a beneficial role at a certain place (white matter) and at a specific time (while the immature brain continues to develop). “We see maximal Sirt1 expression and activity within the first week after neonatal brain injury. There is a very narrow window in which to harness the stimulus that amplifies the progenitor cell population and target this particular molecule for repair,” he says.

Sirt1, a nicotinamide adenine dinucleotide-dependent class III histone deacetylase, is known to be involved in normal cell development, aging, inflammatory responses, energy metabolism and calorie restriction, the study team reports. Its activity can be modulated by sirtinol, an off-the-shelf drug that inhibits sirtuin proteins. The finding points to the potential for therapeutic interventions for diffuse white matter injury in neonates.

Next, the research team aims to study these processes in a large animal model whose brains are structurally, anatomically and metabolically similar to the human brain.

“Ideally, we want to be able to promote the timely regeneration of cells that are lost by designing strategies for interventions that synchronize these cellular events to a common and successful end,” Gallo says.