Ph.D. in Zoology, December 2002

The neural basis of hyperactive wheel running in mice

iv + 170 pp.

(Assistant Professor Stephen C. Gammie served as Justin's major professor during the final semester, as Ted Garland had moved to U.C., Riverside)

Abstract

    The neural basis of genetic hyperactivity was studied in four replicate lines of mice selectively bred for increased voluntary wheel running (S mice) along with four randombred control lines (C mice).  S mice ran approximately 10 km/day compared to 4 km/day in C mice, and were hyperactive in photobeam cages without wheels, suggesting they may represent a useful model of attention deficit hyperactivity disorder (ADHD).  Dopamine reuptake blockers Ritalin, cocaine, and GBR 12909 reduced wheel running in S mice, whereas they had either no effect or increased running in C mice.  The non-specific dopamine receptor agonist apomorphine and the specific D1-like receptor antagonist SCH 23390 reduced wheel running more in C than S mice.  The specific D2-like receptor antagonist raclopride and the serotonin reuptake blocker Prozac reduced running to a similar extent in S and C mice.  S and C mice did not differ in tissue concentrations of dopamine, serotonin or catabolites (as measured by high performance liquid chromatography) in the nucleus accumbens or at rest or after 20 min of treadmill running at 0.5, 1.0 or 1.5 km/hr.  Taken together, these results suggest that dopamine function is altered in S mice via a D1-like receptor.  To identify brain regions implicated in the hyperactive wheel running, neuronal activity (as measured by Fos immunohistochemistry) was compared between S and C mice allowed to run or blocked from running to induce craving.  Fos activity in the lateral hypothalamus, nucleus accumbens, prefrontal cortex, and striatum was associated with craving to run, whereas Fos activity in the hippocampus and entorhinal cortex reflected actual locomotion.  To test the hypothesis that exercise, hippocampal neurogenesis (as measured by the BrdU technique), and spatial learning (Morris water maze) are positively associated, S and C mice housed with and without running wheels were compared.  C mice showed a positive correlation between running distance and new cell number, as well as improved learning.  In S mice, wheel running increased neurogenesis to maximal levels but no improvement in learning occurred.  Exercise-induced hippocampal neurogenesis may contribute to motor programming and thus the newly generated cells may not be expected to improve learning.