This project explores continuing post-developmental neurogenesis and non-neuronal cytogenesis as processes that could be harnessed to aid in rehabilitation of the fetal alcohol-damaged brain. We have found that the capacity for post-weaning cytogenesis in adolescence and young adulthood is present, even enhanced, in the motor cortex of rats given binge-like alcohol exposure during the neonatal period of rapid brain growth, compared to unexposed controls. However, the alcohol-exposed rats fall behind their controls in preserving these newly-generated cells as they grow older. In the dentate gyrus of the hippocampus, a region known to generate new neurons post-developmentally and into adulthood, the number of adult-generated cells was similar in alcohol-exposed and control rats, but the alcohol-exposed rats again failed to preserve these new cells in the long term, falling behind their unexposed control counterparts. Overall, early alcohol exposure did not prevent genesis of new cells, but affected neurogenesis in dentate gyrus, and fewer of these cells survived. In contrast, increased voluntary physical exercise in adolescent rats (under social housing conditions) in a running wheel did increase cytogenesis and neurogenesis both in alcohol-exposed and control animals, but these new cells persisted less well in the alcohol-exposed rats than in controls. The goal of the proposed work is to determine whether and, if so, how combinations of experience, including physical exercise and learning in a physically stimulating toy-equipped environment, can be used to drive cell genesis and promote survival of newly-generated cells in a manner that positively influences brain function. The effects of these manipulations will be assessed both histologically in terms of the relative numbers of neurons and non- neuronal cells, and functionally in terms of performance on a set of behavioral tasks that depend on functional or structural plasticity in the hippocampus. Histological measures will use homologs to BrdU that are independently immuno-detectable, allowing populations of cells generated at different times to be independently assessed. Behavioral tests appropriate to the assessment of hippocampal function will be assessed in independent sets of animals, including trace eyeblink conditioning, trace fear conditioning (both contextual and CS-elicited fear), and spatial working memory in a water maze task. By combining age-specific markers of neurogenesis during the post-weaning intervention period with assessment of subsequent behavioral performance on hippocampal-dependent tasks, it will be possible to identify potential links between experience-dependent promotion of neurogenesis in the dentate gyrus and improved outcomes in cognitive behavior relevant to fetal alcohol spectrum disorders.

Public Health Relevance

Fetal alcohol spectrum disorders is a leading cause of developmental disability and mental retardation both in the US and in many other countries. Effective rehabilitative strategies directed at the damaged brain are at present not known. This project, using a rodent model of fetal alcohol damage, focuses on the capacity of some post-developmental brain regions to generate new neurons or other cell types and searches for ways to harness this capacity as a route to effective rehabilitative intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA009838-14
Application #
7528203
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hereld, Dale
Project Start
1994-08-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
14
Fiscal Year
2009
Total Cost
$387,718
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
Organized Research Units
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Gursky, Zachary H; Klintsova, Anna Y (2017) Wheel Running and Environmental Complexity as a Therapeutic Intervention in an Animal Model of FASD. J Vis Exp :
Hamilton, G F; Criss, K J; Klintsova, A Y (2015) Voluntary exercise partially reverses neonatal alcohol-induced deficits in mPFC layer II/III dendritic morphology of male adolescent rats. Synapse 69:405-15
Boschen, K E; Criss, K J; Palamarchouk, V et al. (2015) Effects of developmental alcohol exposure vs. intubation stress on BDNF and TrkB expression in the hippocampus and frontal cortex of neonatal rats. Int J Dev Neurosci 43:16-24
Hamilton, G F; Jablonski, S A; Schiffino, F L et al. (2014) Exercise and environment as an intervention for neonatal alcohol effects on hippocampal adult neurogenesis and learning. Neuroscience 265:274-90
Boschen, Karen E; Hamilton, Gillian F; Delorme, James E et al. (2014) Activity and social behavior in a complex environment in rats neonatally exposed to alcohol. Alcohol 48:533-41
Wagner, Jennifer L; Klintsova, Anna Y; Greenough, William T et al. (2013) Rehabilitation training using complex motor learning rescues deficits in eyeblink classical conditioning in female rats induced by binge-like neonatal alcohol exposure. Alcohol Clin Exp Res 37:1561-70
Schreiber, W B; St Cyr, S A; Jablonski, S A et al. (2013) Effects of exercise and environmental complexity on deficits in trace and contextual fear conditioning produced by neonatal alcohol exposure in rats. Dev Psychobiol 55:483-95
Dokovna, Lisa B; Jablonski, Sarah A; Stanton, Mark E (2013) Neonatal alcohol exposure impairs contextual fear conditioning in juvenile rats by disrupting cholinergic function. Behav Brain Res 248:114-20
Murawski, N J; Klintsova, A Y; Stanton, M E (2012) Neonatal alcohol exposure and the hippocampus in developing male rats: effects on behaviorally induced CA1 c-Fos expression, CA1 pyramidal cell number, and contextual fear conditioning. Neuroscience 206:89-99
Jablonski, Sarah A; Schiffino, Felipe L; Stanton, Mark E (2012) Role of age, post-training consolidation, and conjunctive associations in the ontogeny of the context preexposure facilitation effect. Dev Psychobiol 54:714-22

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