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Neurons migrate throughout infancy

A previously unrecognized stage of brain development has just been recognized to continue long after birth. Neurons in the cerebral cortex, the outer layer of the brain, migrate into the cortex continuing growth throughout infancy.

Researchers at the University of California San Francisco (UCSF) have discovered a previously unknown mass migration of inhibitory neurons — neurons that release the GABA neurotransmitter and hyperpolarize or change a cell's membrane to make it more negative — and harder to fire. This 'inhibition' in the brain's frontal cortex during the first few months of life, may help establish cognitive abilities. Its disruption may also contribute to neurodevelopmental disorders.

Most neurons of the cerebral cortex, the outermost layer of the brain responsible for advanced cognition, migrate from their birthplace deep in the brain to take up positions within the cortex. Developmental neuroscientists have long believed most neural migration ends well before an infant is born. But the new research, published October 6, 2016 in Science, for the first time suggests many neurons continue to migrate and integrate into neural circuits well into infancy.

"The dogma among developmental neuroscientists was that after birth all that is left is fine wiring and pruning. These results suggest there's a whole new phase of human brain development we had never noticed before."

Mercedes Paredes MD, PhD, Assistant Professor, Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, USA and study leader.

Several recent studies, including work by her collaborators Arturo Alvarez-Buylla PhD and Eric J. Huang MD, had identified small populations of immature neurons deep in the front of the brain that migrate after birth into the orbito-frontal cortex — a small region of the frontal cortex just above the eyes. Given that the entire frontal cortex continues to expand massively after birth, researchers wanted to discover whether neural migration continues after birth in the rest of the frontal cortex.

The team examined brain tissue histological samples from the Pediatric Brain Tissue Bank. These revealed clusters of immature, migratory neurons widely distributed and deep within the frontal lobe of the newborn brain, just above the fluid-filled lateral ventricles.

MRI imaging of the three-dimensional structure of these clusters showed a long arc of migratory neurons sitting like a cap in front of and on top of the ventricles — stretching from deep behind the eyebrows, all the way to the top of the head.

"Several labs had observed there seemed to be many young neurons around birth and along the ventricles. But, no one knew what they were doing there," said Paredes. "As soon as we looked closely, we were shocked to discover how massive this population was and to find that they were actively migrating for weeks and weeks after birth."

Histological studies of the cingulate cortex, a portion of the brain's frontal lobe, showed that Arc neurons migrate outward from the ventricles into the cortex primarily within the first three months of life, where they differentiate into multiple different subtypes of inhibitory neurons.

"It is impressive that these cells can find their way to precise positions within the cortex. Earlier in fetal development the brain is much smaller and the tissue far less complicated, but at this later stage it is quite a long and treacherous journey."

Arturo Alvarez-Buylla PhD, Professor, Neurological Surgery, University of California San Francisco; formerly postdoctoral researcher when in the Paredes laboratory.

Inhibitory neurons, which use the neurotransmitter GABA, make up about 20 percent of the neurons in the cerebral cortex and play a vital role in balancing the brain's need for stability with its ability to learn and change. Imbalanced excitation and inhibition — particularly in circuits of the frontal lobe of the brain, which are involved in executive control — have been implicated in many neurological disorders, from autism to schizophrenia.

The new research suggests that inhibitory circuits in humans develop significantly later than previously realized. This postnatal migration is much larger than what is seen in mice and other mammals, the authors believe, suggesting that it may be an important developmental factor behind the uniqueness of the human brain.

The first months of life, when an infant first begins to interact with its environment, is crucial in brain development, Huang adds.

"The timing of this migration corresponds very well with the development of more complex cognitive functions in infants. It suggests that the arrival of these cells could play a role in setting up the basis for complex human cognition."

Eric J. Huang PhD, Department of Radiology and Biomedical Imaging, Department of Pathology, Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, USA.

Researchers plan to follow up their study by exploring whether this migration of inhibitory neurons from the Arc to the cortex might be affected in brains of children with neurological disorders such as autism, previously associated exclusively with abnormal inhibitory circuitry in the frontal cortex.

"Trying to understand what makes human brain development so unique is what drove me to tackle this research. If we don't understand how our brains are built, we won't understand what is going wrong when people suffer from neurological disease."

Mercedes Paredes MD, PhD

The unique cognitive abilities of humans have long captured the imagination of philosophers and neuroscientists alike. But which features of the human brain set us apart from other mammals? Most likely, our intellectual advantages result from a relative expansion of cortical regions responsible for associative and executive function (1). However, the question of how this cortical expansion is achieved during human development has remained unresolved. A major clue came from the elucidation of neurogenic events taking place during the later phases of embryonic human brain development. This began with the recognition that the human cortical subventricular zone is greatly expanded relative to that of lower mammals. This evolutionary innovation allowed for the marked expansion of associative cortex, especially the frontal lobes. Subsequently, a thorough investigation of the fetal human cortex revealed the existence of a number of distinct excitatory neuronal progenitor types (e.g., outer radial glia) that were identified as key to driving a remarkable burst of late neurogenesis (2). However, the cortex is able to function only when excitatory and inhibitory activities in the brain are balanced. On page 81 of this issue, Paredes et al. (3) identify a population of interneurons that migrate to the cortex during infancy to establish inhibitory circuits.

Paredes et al. Extensive migration of young neurons into the human infant frontal lobe. Science. Vol. 354, October 7, 2016, p.81. doi:10.1126/science.aaf7073.

Other UCSF authors on the paper are David James, Hosung Kim, PhD, Jennifer A. Cotter, MD, Carissa Ng, PhD, Kadellyn Sandoval, David Rowitch, MD, PhD, and Patrick S. McQuillen, MD, PhD.M.

This work was sponsored by a generous gift from the John G. Bowes Research Fund. Alvarez-Buylla is the Heather and Melanie Muss Endowed Chair of Neurological Surgery at UCSF. Additional research funds were provided by the National Institutes of Health research grants (RO1 HD032116-21, PO1 NS083513-02, R01EB009756, R01HD072074, 2R01 NS060896) and training grants from the NIH (MBRS-RISE R25-GM059298, K08NS091537-01A1) and from the California Institute of Regenerative Medicine (TG-01153 and TB1-01194), the Spanish Institute of Health Carlos III (ISCIII2012-RD19-016), a Rio Hortega fellowship (CM12/00014), Banting and FRS Canadian fellowships, the Economics and Competitivity Ministry of Spain (BFU2015-64207-P) and a Generalitat Valenciana grant (PrometeoII 2014-075).

Alvarez-Buylla is on the scientific advisory board and is co-founder of Neurona Therapeutics, which is developing stem cell technology for human clinical trials.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.
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Oct 10, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Arc neurons migrate into the cortex in the first three months, where they differentiate into
inhibitory neurons to b
alance excitation and inhibition — particularly in the frontal lobe.
The frontal lobe is involved in working memory, mental flexibility, and self-control. Errors in
its executive control are implicated in neurological disorders from autism to schizophrenia.
Image Credit:
Mercedes Paredes MD PhD, artist: Kenneth X. Probst for Science.com


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