Brain Injury and Neurogenesis

Principal Investigator

Lab members

Antiño Allen, PhD
Barrett Allen, AS
Jennifer Baure, BS
Ayanabha Chakraborti, PhD

Mission Statement

Establish how neurogenesis is affected by ionizing irradiation and/or traumatic brain injury, and to identify approaches that will enable us to ameliorate the adverse effects of those injuries.

General overview and areas of focus

Individuals who undergo cranial radiotherapy for treatment of primary or metastatic brain tumors, or who suffer from traumatic brain injury (TBI), are at risk of developing debilitating brain damage, including severe and persistent cognitive impairments. Because irradiation and TBI often impact hippocampal function, and because the hippocampal dentate gyrus is a site of active neurogenesis throughout life, we contend that altered neurogenesis may play an important role in the development of long-term side effects of these injuries.

Using genetic models and pharmacologic approaches, we are focusing on how specific microenvironmental factors (e.g. inflammation, oxidative stress) affect neurogenesis and cognitive function after exposure to ionizing irradiation and/or TBI. Our studies of the molecular, cellular and behavioral mechanisms associated with these injuries will improve our understanding of the dentate gyrus, and will hopefully lead to new strategies to combat clinically-significant problems.

Accomplishments

The first lab to show that neural stem/precursor cells in the mammalian forebrain died via apoptosis after clinically relevant doses of x-rays;
The first lab to show that changes in neurogenesis after x-irradiation or heavy ion irradiation was dose dependent;
Showed that altered neurogenesis after irradiation was associated with hippocampal-dependent cognitive function;
Showed that decreased neurogenesis after irradiation or TBI was associated with increased indications of neuroinflammation (activated microglia, increased expression of chemokine receptor-2 (CCR2));
Showed that an environment deficient in CCR2 rescued neurogenesis after irradiation;
Showed that decreased neurogenesis after irradiation was associated with increased indications of oxidative stress;
The first lab to show that an environment deficient in extracellular superoxide dismutase provided a survival advantage to neurogenic cells after irradiation;
Showed that the behavioral induced early immediate gene Arc was reduced by x-irradiation;
Showed how irradiation combined with TBI affected neurogenesis.

Objectives

Determine how deficiencies in the superoxide dismutase isoforms affect neurogenesis after radiation treatment;
Determine how specific factors associated with neuroinflammation affect neurogenesis after radiation and/or TBI;
Determine the effects of combined injury (radiation and TBI) on neurogenesis;
Determine the possible role of inflammation and/or oxidative stress on neurogenesis after combined injury;
Determine how the expression of the behaviorally induced gene Arc is impacted by x-rays, heavy ion irradiation or TBI, either alone or in combination

Future Outlook

Address the cellular and molecular mechanisms associated with altered neurogenesis after single or combined injury (i.e. radiation and TBI);
Establish the relationship between altered neurogenesis and microenvironmental factors like inflammation and oxidative stress;
Assess the functional integration (i.e. expression of Arc protein) of newly born neurons into the hippocampal circuitry;
Correlate changes in neurogenesis and Arc expression with cognitive function;
Determine how combined injury develops when there is time between the insults.

Funding and Contributors

NIH R01 NS046051 (Fike, PI); Radiation and Oxidative Stress: Effects on Neurogenesis
NASA NNJ05HE33G (Fike, PI): Inflammation in the Brain after Particulate Irradiation Predisposes the Hippocampus to a Heightened Vulnerability after a Secondary Insult
NASA NNJ04HC90G (Fike, PI): Progressive Alterations of Central Nervous System Structure and Function Are Caused by Charged Particle Radiation
NASA NNA06CB39G (Fike, Co-I): High LET Radiation and Neurogenesis: Implications and Mechanisms Underlying Cognitive Impairment
NASA NNA06CB37G (Fike, Co-I): Mechanisms of High LET Radiation Induced Genomic Instability in the CNS;
ACS RSG 00-036-04 (Fike, Co-I): Genomic Instability and Redox: Radioresponse of Brain Tumor Precursor Cells;
NASA NNJ05HE63G (Fike, Co-I): Neurogenesis and cognition in human apoE transgenic mice following 56Fe radiation

Current Lab Members

Marta Andres-Mach, PhD
Kelly Fishman, BS
Jennifer Baure, BS

Collaborators

Susanna Rosi, Ph.D. UCSF, BASIC

Charles L. Limoli, Ph.D., University of California, Irvine

Jacob Raber, Ph.D., Oregon Health and Sciences University

Ting-Ting Huang, Ph.D. Stanford University

Selected Publications

Mizumatsu S, Monje M, Morhardt D, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of x-irradiation. Can. Res. 63: 4021-4027, 2003.

Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp. Neurol. 188: 316-330, 2004.

Raber J, Rola R, LeFevour A, Morhardt DR, Curley J, Mizumatsu S, Fike JR. Radiation-induced cognitive impairments are associated with changes in hippocampal neurogenesis. Radiat. Res. 162: 39-47, 2004.

Limoli CL, Rola R, Giedzinski E, Mantha S, Huang T-T, Fike JR. Cell density dependent regulation of neural precursor cell function. PNAS 2004; 101:16052-7.

Rola R, Mizumatsu S, Otsuka S, Morhardt DR, Noble-Haeusslein, Fishman K, Potts, MB, Fike JR. Alterations in hippocampal neurogenesis following traumatic brain injury in mice. Exp. Neurol. 202: 189-199, 2006.

Fike JR, Rola R, Limoli CL. Radiation Response of Neural Precursor Cells. Neurosurg. Clin. N. Amer. 18: 115-127, 2007.

Rola R, Zou Y, Huang T-T, Fishman K, Baure J, Rosi S, Milliken H, Limoli CL, Fike JR. Lack of EC-SOD in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radicals in Biol. Med. 42: 1133-1145, 2007.