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Developmental biology - Brain

In Brain Injury Every Cell Tells A Story

Specific cells and genes may become potential treatment targets in brain injuries...


Traumatic brain injury (TBI) threatens widespread brain damage. But now scientists can look in real time at how thousands of individual cells and genes are affected. Studies in mice could lead to precise treatments for TBI, as reported in Nature Communications, and supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
"Instead of clustering responses according to categories of cells, we can now see how individual cells in each group reacts to head injury."

Patrick Bellgowan PhD, Program Director, Repair and Plasticity, National Institute of Neurological Disorders (NINDS).

University of California, Los Angeles professors Fernando Gomez-Pinilla PhD and Xia Yang PhD, along with their colleagues, used a novel method known as Drop-seq to closely look at individual brain cells in the hippocampus following TBI. The hippocampus is a brain region involved in learning and memory. Drop-seq allows thousands of cells and genes to be analyzed simultaneously, its creation in part funded by the NIH's Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative.
"These tools provide us with unprecedented precision to pinpoint exactly which cells and genes to target with new therapies."

Xia Yang PhD, Department of Integrative Biology and Physiology; Bioinformatics Interdepartmental Program, University of California; Institute for Quantitative and Computational Biosciences; and Molecular Biology Institute, University of California, Los Angeles, California, USA.

In one set of experiments, a team of researchers watched as genes in individual cells upregulated or downregulated across numerous brain cell types, suggesting which genes are important in TBIs. Drs. Yang and Gomez-Pinilla's groups, for example, saw altered activity in genes involved in regulating amyloid proteins that build in Alzheimer's.

In particular, gene analysis revealed how the Ttr gene - involved in both thyroid hormone transport and scavenging of amyloid proteins - increases following TBI. This suggests the thyroid hormone pathway as a potential target for therapy. Both Fernando Gomez-Pinilla PhD and Yang's teams then treated TBI animals with thyroxine (T4) thyroid hormone, 1 and 6 hours after brain injury. Those TBI mice performed much better on learning and memory tasks as compared to TBI animals receiving a placebo.
The teams identified 15 clusters of cells based on gene activity. Two clusters, named Unknown1 and Unknown2, had never previously been identified in the hippocampus. Analysis revealed cells in Unknown1 are involved in growth and migration, while cells in Unknown2 differentiate as though still in embryonic development. Although these two cell types have similar structure and shape, their functions are entirely different.

Future studies on cells in other brain areas besides the hippocampus are needed. More analysis of those individual brain cells and genes may identify more potential therapies for the devastating affects of TBI.

Abstract
The complex neuropathology of traumatic brain injury (TBI) is difficult to dissect, given the convoluted cytoarchitecture of affected brain regions such as the hippocampus. Hippocampal dysfunction during TBI results in cognitive decline that may escalate to other neurological disorders, the molecular basis of which is hidden in the genomic programs of individual cells. Using the unbiased single cell sequencing method Drop-seq, we report that concussive TBI affects previously undefined cell populations, in addition to classical hippocampal cell types. TBI also impacts cell type-specific genes and pathways and alters gene co-expression across cell types, suggesting hidden pathogenic mechanisms and therapeutic target pathways. Modulating the thyroid hormone pathway as informed by the T4 transporter transthyretin Ttr mitigates TBI-associated genomic and behavioral abnormalities. Thus, single cell genomics provides unique information about how TBI impacts diverse hippocampal cell types, adding new insights into the pathogenic pathways amenable to therapeutics in TBI and related disorders.

Authors
Douglas Arneson, Guanglin Zhang, Zhe Ying, Yumei Zhuang, Hyae Ran Byun, In Sook Ahn, Fernando Gomez-Pinilla and Xia Yang.


Acknowledgements
This study was supported by the National Institute of Neurological Disorders and Stroke or NINDS (NS103088, NS50465) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK104363).

The NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Oct 11, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




These images show high magnification details of a few types of brain cells. Lower magnification
photos indicate regions magnified. Credit: National Institute of Neurological Disorders and Stroke.


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