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Neurons migrate 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.
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.
"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.
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 first months of life, when an infant first begins to interact with its environment, is crucial in brain development, Huang adds.
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.
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.
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.
Arc neurons migrate into the cortex in the first three months, where they differentiate into
inhibitory neurons to balance 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