The interaction between aerobic exercise and drug abuse is relatively unexplored. It deserves attention because recent data suggest neuroadaptations from exercise promote learning in circuits that overlap with drug abuse. The hippocampus is an important point of intersection because it is a major locus for change from aerobic exercise and it plays a central role in contextual conditioning. Specifically, contextual cues paired with drugs trigger emotional responses related to craving and relapse. The long-term goal of this research program is to identify molecular and physiological mechanisms underlying the influence of exercise on drug-related behaviors in mice. The overall objective of this application is to develop a mouse model to study the effects of wheel running exercise on extinction of cocaine conditioned place preference, and to test one hypothesized mechanism for how exercise can influence Pavlovian drug associations. The central hypothesis is that new neurons from exercise can cause drug associations to persist if the drug is administered at a critical period in the development of the new neurons when they are preferentially recruited into learning networks. This is supported by the Preliminary Studies that show resistance to extinction of conditioned place preference for cocaine in runners as compared to sedentary animals after re-exposure to cocaine in context. The objective of this application will be accomplished by pursuing two specific aims.
Aim 1 is to identify the impact of aerobic exercise on extinction of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that exercise will either facilitate or delay extinction of conditioned place preference depending on whether drug exposure occurs before or after exercise training, in parallel with increased adult hippocampal neurogenesis in the dentate gyrus. To accomplish this aim, the order of conditioning and exercise treatments will be manipulated, and then conditioned place preference will be measured repeatedly until extinction. Animals will be injected with BrdU to label dividing cells, and the number of BrdU cells co-labeled with neuronal nuclear marker, NeuN, in the granule layer of the dentate gyrus will be used to measure neurogenesis.
Aim 2 is to determine the extent to which new neurons from exercise causally contribute to persistence of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that new neurons from exercise will function to enhance Pavlovian conditioning. This hypothesis will be directly tested by reducing neurogenesis using 2 separate methods, a transgenic mouse model and focal gamma irradiation, to determine whether new neurons are required for exercise to delay extinction of place preference. The extent to which new neurons are preferentially recruited into circuits involved in cocaine conditioning will also be determined by measuring the proportion of BrdU positive versus negative cells expressing c-Fos in response to the preference test. The project will discover mechanisms for interactions between exercise and drug abuse. This will be useful for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse.

Public Health Relevance

This proposal will discover the impact of enhanced neuroplasticity from aerobic exercise on extinction of cocaine conditioned behavior in a mouse model. The project will provide useful evidence for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA027487-03
Application #
8132911
Study Section
Special Emphasis Panel (ZDA1-GXM-A (05))
Program Officer
Lin, Geraline
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$258,947
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Sorokina, Anastasia M; Saul, Michael; Goncalves, Tassia M et al. (2018) Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling. PLoS One 13:e0201553
Hamilton, G F; Hernandez, I J; Krebs, C P et al. (2017) Neonatal alcohol exposure reduces number of parvalbumin-positive interneurons in the medial prefrontal cortex and impairs passive avoidance acquisition in mice deficits not rescued from exercise. Neuroscience 352:52-63
Majdak, Petra; Grogan, Elizabeth L; Gogola, Joseph V et al. (2016) The impact of maternal neglect on genetic hyperactivity. Behav Brain Res 313:282-292
Mustroph, M L; Pinardo, H; Merritt, J R et al. (2016) Parameters for abolishing conditioned place preference for cocaine from running and environmental enrichment in male C57BL/6J mice. Behav Brain Res 312:366-73
Hamilton, G F; Bucko, P J; Miller, D S et al. (2016) Behavioral deficits induced by third-trimester equivalent alcohol exposure in male C57BL/6J mice are not associated with reduced adult hippocampal neurogenesis but are still rescued with voluntary exercise. Behav Brain Res 314:96-105
Mustroph, M L; Merritt, J R; Holloway, A L et al. (2015) Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice. Eur J Neurosci 41:216-26
Hamilton, G F; Majdak, P; Miller, D S et al. (2015) Evaluation of a C57BL/6J × 129S1/SvImJ Hybrid Nestin-Thymidine Kinase Transgenic Mouse Model for Studying the Functional Significance of Exercise-Induced Adult Hippocampal Neurogenesis. Brain Plast 1:83-95
Rendeiro, Catarina; Masnik, Ashley M; Mun, Jonathan G et al. (2015) Fructose decreases physical activity and increases body fat without affecting hippocampal neurogenesis and learning relative to an isocaloric glucose diet. Sci Rep 5:9589
Romanova, Elena V; Rubakhin, Stanislav S; Ossyra, John R et al. (2015) Differential peptidomics assessment of strain and age differences in mice in response to acute cocaine administration. J Neurochem 135:1038-48
Merritt, Jennifer R; Rhodes, Justin S (2015) Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze. Behav Brain Res 280:62-71

Showing the most recent 10 out of 31 publications