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illustration of brain showing cerebellum

Focusing on the “little brain” to rescue cognition

illustration of brain showing cerebellum

Research faculty at Children’s National in Washington, D.C., with colleagues recently published a review article in Nature Reviews Neuroscience that covers the latest research about how abnormal development of the cerebellum leads to a variety of neurodevelopmental disorders.

Cerebellum translates as “little brain” in Latin. This piece of anatomy – that appears almost separate from the rest of the brain, tucked under the two cerebral hemispheres – long has been known to play a pivotal role in voluntary motor functions, such as walking or reaching for objects, as well as involuntary ones, such as maintaining posture.

But more recently, says Aaron Sathyanesan, Ph.D., a postdoctoral research fellow at the Children’s Research Institute, the research arm of Children’s National  in Washington, D.C., researchers have discovered that the cerebellum is also critically important for a variety of non-motor functions, including cognition and emotion.

Sathyanesan, who studies this brain region in the laboratory of Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and scientific director of the Children’s Research Institute, recently published a review article with colleagues in Nature Reviews Neuroscience covering the latest research about how altered development of the cerebellum contributes to a variety of neurodevelopmental disorders.

These disorders, he explains, are marked by problems in the nervous system that arise while it’s maturing, leading to effects on emotion, learning ability, self-control, or memory, or any combination of these. They include diagnoses as diverse as intellectual disability, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder and Down syndrome.

“One reason why the cerebellum might be critically involved in each of these disorders,” Sathyanesan says, “is because its developmental trajectory takes so long.”

Unlike other brain structures, which have relatively short windows of development spanning weeks or months, the principal cells of the cerebellum – known as Purkinje cells – start to differentiate from stem cell precursors at the beginning of the seventh gestational week, with new cells continuing to appear until babies are nearly one year old.  In contrast, cells in the neocortex, a part of the brain involved in higher-order brain functions such as cognition, sensory perception and language is mostly finished forming while fetuses are still gestating in the womb.

This long window for maturation allows the cerebellum to make connections with other regions throughout the brain, such as extensive connections with the cerebral cortex, the outer layer of the cerebrum that plays a key role in perception, attention, awareness, thought, memory, language and consciousness. It also allows ample time for things to go wrong.

“Together,” Sathyanesan says, “these two characteristics are at the root of the cerebellum’s involvement in a host of neurodevelopmental disorders.”

For example, the review article notes, researchers have discovered both structural and functional abnormalities in the cerebellums of patients with ASD. Functional magnetic resonance imaging (MRI), an imaging technique that measures activity in different parts of the brain, suggests that significant differences exist between connectivity between the cerebellum and cortex in people with ASD compared with neurotypical individuals. Differences in cerebellar connectivity are also evident in resting-state functional connectivity MRI, an imaging technique that measures brain activity in subjects when they are not performing a specific task. Some of these differences appear to involve patterns of overconnectivity to different brain regions, explains Sathyanesan; other differences suggest that the cerebellums of patients with ASD don’t have enough connections to other brain regions.

These findings could clarify research from Children’s National and elsewhere that has shown that babies born prematurely often sustain cerebellar injuries due to multiple hits, including a lack of oxygen supplied by infants’ immature lungs, he adds. Besides having a sibling with ASD, premature birth is the most prevalent risk factor for an ASD diagnosis.

The review also notes that researchers have discovered structural changes in the cerebellums of patients with Down syndrome, who tend to have smaller cerebellar volumes than neurotypical individuals. Experimental models of this trisomy recapitulate this difference, along with abnormal connectivity to the cerebral cortex and other brain regions.

Although the cerebellum is a pivotal contributor toward these conditions, Sathyanesan says, learning more about this brain region helps make it an important target for treating these neurodevelopmental disorders. For example, he says, researchers are investigating whether problems with the cerebellum and abnormal connectivity could be lessened through a non-invasive form of brain stimulation called transcranial direct current stimulation or an invasive one known as deep brain stimulation. Similarly, a variety of existing pharmaceuticals or new ones in development could modify the cerebellum’s biochemistry and, consequently, its function.

“If we can rescue the cerebellum’s normal activity in these disorders, we may be able to alleviate the problems with cognition that pervade them all,” he says.

In addition to Sathyanesan and Senior Author Gallo, Children’s National study co-authors include Joseph Scafidi, D.O., neonatal neurologist; Joy Zhou and Roy V. Sillitoe, Baylor College of Medicine; and Detlef H. Heck, of University of Tennessee Health Science Center.

Financial support for research described in this post was provided by the National Institute of Neurological Disorders and Stroke under grant numbers 5R01NS099461, R01NS089664, R01NS100874, R01NS105138 and R37NS109478; the Hamill Foundation; the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center under grant number U54HD083092; the University of Tennessee Health Science Center (UTHSC) Neuroscience Institute; the UTHSC Cornet Award; the National Institute of Mental Health under grant number R01MH112143; and the District of Columbia Intellectual and Developmental Disabilities Research Center under grant number U54 HD090257.

Study authors Aaron Sathyanesan, Ph.D., Joseph Abbah, B.Pharm., Ph.D., Srikanya Kundu, Ph.D. and Vittorio Gallo, Ph.D.

Children’s perinatal hypoxia research lauded

Study authors Aaron Sathyanesan, Ph.D., Joseph Abbah, B.Pharm., Ph.D., Srikanya Kundu, Ph.D. and Vittorio Gallo, Ph.D.

Study authors Aaron Sathyanesan, Ph.D., Joseph Abbah, B.Pharm., Ph.D., Srikanya Kundu, Ph.D. and Vittorio Gallo, Ph.D.

Chronic sublethal hypoxia is associated with locomotor miscoordination and long-term cerebellar learning deficits in a clinically relevant model of neonatal brain injury, according to a study led by Children’s National Health System researchers published by Nature Communications. Using high-tech optical and physiological methods that allow researchers to turn neurons on and off and an advanced behavioral tool, the research team found that Purkinje cells fire significantly less often after injury due to perinatal hypoxia.

The research team leveraged a fully automated, computerized apparatus – an Erasmus Ladder – to test experimental models’ adaptive cerebellar locomotor learning skills, tracking their missteps as well as how long it took the models to learn the course.

The research project, led by Aaron Sathyanesan, Ph.D., a Children’s postdoctoral research fellow, was honored with a F1000 primevery good rating.” The Children’s research team used both quantitative behavior tests and electrophysiological assays, “a valuable and objective platform for functional assessment of targeted therapeutics in neurological disorders,” according to the recommendation on a digital forum in which the world’s leading scientists and clinicians highlight the best articles published in the field.

Calling the Erasmus Ladder an “elegant” behavioral system, Richard Lu, Ph.D., and Kalen Berry write that the Children’s National Health System research team “revealed locomotor behavior and cerebellar learning deficits, and further utilized multielectrode recording/optogenetics approaches to define critical pathophysiological features, such as defects in Purkinje cell firing after neonatal brain injury.”

Lu, Beatrice C. Lampkin Endowed Chair in Cancer Epigenetics, and Berry, an associate faculty member in the Cancer and Blood Diseases Institute, both at Cincinnati Children’s, note that the Children’s results “suggest that GABA signaling may represent a potential therapeutic target for hypoxia-related neonatal brain injury that, if provided at the correct time during development post-injury, could offer lifelong improvements.”

In addition to Sathyanesan, Children’s co-authors include Co-Lead Author, Srikanya Kundu, Ph.D., and Joseph Abbah, both of Children’s Center for Neuroscience Research, and Vittorio Gallo, Ph.D., Children’s Chief Research Officer and the study’s senior author.

Research covered in this story was supported by the Intellectual and Developmental Disability Research Center under award number U54HD090257.

toddler on a playground

Perinatal hypoxia associated with long-term cerebellar learning deficits and Purkinje cell misfiring

toddler on a playground

The type of hypoxia that occurs with preterm birth is associated with locomotor miscoordination and long-term cerebellar learning deficits but can be partially alleviated with an off-the-shelf medicine, according to a study using a preclinical model.

Oxygen deprivation associated with preterm birth leaves telltale signs on the brains of newborns in the form of alterations to cerebellar white matter at the cellular and the physiological levels. Now, an experimental model of this chronic hypoxia reveals that those cellular alterations have behavioral consequences.

Chronic sublethal hypoxia is associated with locomotor miscoordination and long-term cerebellar learning deficits in a clinically relevant model of neonatal brain injury, according to a study led by Children’s National Health System researchers published online Aug. 13, 2018, by Nature Communications. Using high-tech optical and physiological methods that allow researchers to turn neurons on and off and an advanced behavioral tool, the research team finds that Purkinje cells fire significantly less often after injury due to perinatal hypoxia. However, an off-the-shelf medicine now used to treat epilepsy enables those specialized brain cells to regain their ability to fire, improving locomotor performance.

Step out of the car onto the pavement, hop up to the level of the curb, stride to the entrance, and climb a flight of stairs. Or, play a round of tennis. The cerebellum coordinates such locomotor performance and muscle memory, guiding people of all ages as they adapt to a changing environment.

“Most of us successfully coordinate our movements to navigate the three-dimensional spaces we encounter daily,” says Vittorio Gallo, Ph.D., Children’s Chief Research Officer and the study’s senior author. “After children start walking, they also have to learn how to navigate the environment and the spaces around them.”

These essential tasks, Gallo says, are coordinated by Purkinje cells, large neurons located in the cerebellum that are elaborately branched like interlocking tree limbs and represent the only source of output for the entire cerebellar cortex. The rate of development of the fetal cerebellum dramatically increases at a time during pregnancy that often coincides with preterm birth, which can delay or disrupt normal brain development.

“It’s almost like a short circuit. Purkinje cells play a very crucial role, and when the frequency of their firing is diminished by injury the whole output of this brain region is impaired,” Gallo says. “For a family of a child who has this type of impaired neural development, if we understand the nature of this disrupted circuitry and can better quantify it, in terms of locomotor performance, then we can develop new therapeutic approaches.”

Study authors Aaron Sathyanesan, Ph.D., Joseph Abbah, B.Pharm., Ph.D., Srikanya Kundu, Ph.D. and Vittorio Gallo, Ph.D.

The research team leveraged a fully automated, computerized apparatus that looks like a ladder placed on a flat surface, encased in glass, with a darkened box at either end. Both the hypoxic and control groups had training sessions during which they learned how to traverse the horizontal ladder, coaxed out of the darkened room by a gentle puff of air and a light cue. Challenge sessions tested their adaptive cerebellar locomotor learning skills. The pads they strode across were pressure-sensitive and analyzed individual stepping patterns to predict how long it should take each to complete the course.

During challenge sessions, obstacles were presented in the course, announced by an audible tone. If learning was normal, then the response to the tone paired with the obstacle would be a quick adjustment of movement, without breaking stride, says Aaron Sathyanesan, Ph.D., co-lead author. Experimental models exposed to perinatal hypoxia showed significant deficits in associating that tone with the obstacle.

“With the control group, we saw fewer missteps during any given trial,” Sathyanesan says. “And, when they got really comfortable, they took longer steps. With the hypoxic group, it took them longer to learn the course. They made a significantly higher number of missteps from day one. By the end of the training period, they could walk along all of the default rungs, but it took them longer to learn how to do so.”

Purkinje cells fire two different kinds of spikes. Simple spikes are a form of constant activity as rhythmic and automatic as a heartbeat. Complex spikes, by contrast, occur less frequently. Sathyanesan and co-authors say that some of the deficits that they observed were due to a reduction in the frequency of simple spiking.

Two weeks after experiencing hypoxia, the hypoxic group’s locomotor performance remained significantly worse than the control group, and delays in learning could still be seen five weeks after hypoxia.

Gamma-aminobutyric acid (GABA), a neurotransmitter, excites immature neurons before and shortly after birth but soon afterward switches to having an inhibitory effect within in the cerebellum, Sathyanesan says. The research team hypothesizes that reduced levels of excitatory GABA during early development leads to long-term motor problems. Using an off-the-shelf drug to increase GABA levels immediately after hypoxia dramatically improved locomotor performance.

“Treating experimental models with tiagabine after hypoxic injury elevates GABA levels, partially restoring Purkinje cells’ ability to fire,” Gallo says. “We now know that restoring GABA levels during this specific window of time has a beneficial effect. However, our approach was not specifically targeted to Purkinje cells. We elevated GABA everywhere in the brain. With more targeted and selective administration to Purkinje cells, we want to gauge whether tiagabine has a more powerful effect on normalizing firing frequency.”

In addition to Gallo and Sathyanesan, Children’s co-authors include Co-Lead Author, Srikanya Kundu, Ph.D., and Joseph Abbah, B.Pharm., Ph.D., both of Children’s Center for Neuroscience Research.

Research covered in this story was supported by the Intellectual and Developmental Disability Research Center under award number U54HD090257.