Effects of physical exercise and exercise-induced adult hippocampal neurogenesis on conditioned place preference for cocaine in mice

Mustroph, Martina

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https://hdl.handle.net/2142/72960 Copy

Description

Title

Effects of physical exercise and exercise-induced adult hippocampal neurogenesis on conditioned place preference for cocaine in mice

Author(s)

Mustroph, Martina

Issue Date

2015-01-21

Director of Research (if dissertation) or Advisor (if thesis)

Rhodes, Justin S.

Doctoral Committee Chair(s)

Rhodes, Justin S.

Committee Member(s)

• Sweedler, Jonathan V.
• Ceman, Stephanie S.
• Gulley, Joshua M.

Department of Study

School of Molecular & Cell Bio

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• cocaine
• conditioned place preference
• exercise
• hippocampal neurogenesis

Abstract

Treatments for drug abuse and addiction remain largely ineffective. Recent studies in both the human and rodent literature suggest that exercise-based interventions for drug addiction have positive outcomes. Exercise has many effects in the brain. The mechanism by which exercise achieves positive outcomes relevant to drug abuse and addiction is not known. One idea is that exercise extends plasticity to the brain that helps to weaken drug-context associations underlying drug abuse and addiction. It is known that exercise increases hippocampal neurogenesis. However, recently, conflicting reports have been published showing hippocampal neurogenesis to either be involved in or not contributory to learning and memory, and so the role of hippocampal neurogenesis in weakening learned drug-context associations remains unclear. The goal of my dissertation is to identify and evaluate select potential mechanisms causally related to accelerated extinction of conditioned place preference (CPP) for cocaine from exercise in male C57BL/6J mice. Since the conditioned place preference paradigm represents the major behavioral assay I employ in the proposed experiments, Chapter 1 presents a review of the relevant conditioned place preference literature. Chapter 2 examines the hypothesis that timing of exercise relative to conditioning has opposing effects on cocaine CPP in male C57BL/6J mice, and that exercise induces hippocampal neurogenesis. The main findings were that wheel running accelerated extinction of CPP when running occurred entirely after drug conditioning, whereas running delayed extinction when administered before conditioning, and that running approximately doubled adult hippocampal neurogenesis. Chapter 3 assesses the relative contribution of running versus enrichment to the neurogenic and pro-cognitive effects of an enriched environment in male C57BL/6J mice. The main finding was that an enriched environment devoid of running wheels did not significantly up-regulate hippocampal neurogenesis or improve behavioral performance on a spatial learning task, although running approximately doubled adult hippocampal neurogenesis. The finding that only running bestowed significant neurogenic and behavioral effects leaves open the possibility environmental enrichment promotes other types of neural plasticity that may make it a suitable substitute for running as an intervention in other domains. Therefore, Chapter 4 investigates the possibility that environmental enrichment, like running, can accelerate extinction of CPP. Results suggest that environmental enrichment does not effectively accelerate extinction of CPP, nor does it significantly increase hippocampal neurogenesis. Chapter 5 directly tests the hypothesis that new neurons from running are necessary for accelerated extinction of cocaine CPP from running. Chapter 6 attempts to answer the question of whether there are neuropeptides that are differentially induced in runners versus sedentary C57BL/6J mice in the amygdala and hippocampus after exposure to a drug-associated context that could underlie the accelerated extinction of CPP from exercise. Neuropeptidomic profiles in the hippocampus suggest differences between sedentary and runner animals, but not in response to the contextual cues. Chapter 7 discusses future projects and directions, including an experiment to test the hypothesis that increased locomotor activity in the testing apparatus disrupts CPP, an experiment that will identify key temporal parameters that influence the effect of running on cocaine CPP by testing both whether one week of running wheel exposure followed by three weeks of sedentary housing or three weeks of sedentary housing followed by one week of running wheel exposure before testing can accelerate extinction of CPP for cocaine, an optogenetics experiment testing the role of new neurons in exercise-induced extinction of CPP for cocaine by hyperpolarizing new hippocampal neurons immediately prior to CPP testing, and the need to house mice in an empty “holding cage” for several hours prior to testing them for CPP to avoid the possible confound of extraneous stress impacting CPP test performance in future experiments involving complex housing conditions. Results of my dissertation further our knowledge of how wheel running may accelerate extinction of CPP by demonstrating that the effect is likely related to plasticity induced in the brain, independent of neurogenesis, and likely caused by the exercise as opposed to environmental enrichment component of running.

Graduation Semester

2014-12

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http://hdl.handle.net/2142/72960

Copyright and License Information

Copyright 2014 Martina Mustroph. Portions of this dissertation have been published elsewhere: Licensee: Martina L Mustroph License Date: May 19, 2014 License Number: 3392651150474 Publication: European Journal of Neuroscience Title: Wheel running can accelerate or delay extinction of conditioned place preference for cocaine in male C57BL/6J mice, depending on timing of wheel access; Licensee: Martina L Mustroph License Date: May 19, 2014 License Number: 3392660912286 Publication: Neuroscience Title: Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice

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