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ABSTRACT: The functional significance of newly formed granule neurons in the adult mammalian hippocampus remains a mystery. Recently, it was demonstrated that wheel running increases new neuron survival and c-Fos expression in new and pre-existing granule cells in an activity-dependent manner. It is currently unknown whether other immediate early genes (IEGs) become expressed in granule neurons from running. Further, it is unknown whether locomotor activity in home cages without wheels can influence neurogenesis and IEG expression similar to running. The purpose of this study was three-fold: (1) to determine if Arc and Zif268 expression are also induced from wheel running in both pre-existing and newly formed neurons (2) to determine if neurogenesis and IEG induction is related to horizontal distance traveled in home cages without wheels, and (3) to determine whether IEG induction is related to acute bouts of running or chronic effects. Adult C57BL/6J female mice were placed in cages with or without running wheels for 31 days. The first 10 days, mice received daily injections of 5-Bromo-2'-deoxyuridine (BrdU) to label dividing cells. On day 1, running and non-running animals were euthanized either 2 h after peak activity, or during a period of relative inactivity. Immunohistochemistry was performed on hippocampal sections with antibodies against BrdU, mature neuron marker NeuN, c-Fos, Arc, and Zif268. Results demonstrate that Arc, Zif268, and c-Fos are induced from wheel running but not movement in cages without wheels. All IEGs were expressed in new neurons from running. Further, IEGs were induced acutely by running, as increased expression did not continue into the light cycle, a period of relative inactivity. The results suggest that robust movements, like running, are necessary to stimulate IEG expression and neurogenesis. Moreover, results suggest new neurons from running may be processing information about running behavior itself.
Neuroscience 06/2011; 184:16-27. · 3.38 Impact Factor
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ABSTRACT: New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into preexisting circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large vs. small increases in neurogenesis in response to wheel running so that the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. During the first 10 days mice received daily injections of 5-bromo-2'-deoxyuridine (BrdU) to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Furthermore, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline vs. exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise.
Genes Brain and Behavior 01/2011; 10(3):345-53. · 3.48 Impact Factor
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ABSTRACT: Growing evidence suggests that adolescent mice display differential sensitivity to the acute locomotor activating effects of cocaine as compared to adults, but the direction of the difference varies across studies and the reasons are not clear. Few studies have directly examined genetic contributions to age differences in locomotor stimulation from cocaine. The goal of this study was to determine the extent to which reduced stimulation in C57BL/6J adolescents as compared to adults generalizes to other strains. Therefore, we examined male and female mice from four genetically divergent inbred stains (BALB/cByJ, C57BL/6J, DBA/2J and FVB/NJ) at two ages, postnatal day 30 and postnatal day 65. Mice received either saline or cocaine (15 or 30 mg/kg), and then immediately were placed back into their home cages. Locomotor activity was recorded continuously in the home cage by video tracking. Adolescents displayed reduced stimulation as compared to adults for C57BL/6J, BALB/cByJ and female FVB/NJ mice. No age differences were observed for DBA/2J or male FVB/NJ. No main effects of sex were observed. Strain differences in pharmacokinetics, neural development or physiology could contribute to the observed differences between ages across strains. Future comparative studies could discover biological differences between strains that explain age differences in cocaine sensitivity.
Genes Brain and Behavior 11/2010; 9(8):892-8. · 3.48 Impact Factor
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ABSTRACT: The mammalian hippocampus continues to generate new neurons throughout life. Experiences such as exercise, anti-depressants, and stress regulate levels of neurogenesis. Exercise increases adult hippocampal neurogenesis and enhances behavioral performance on rotarod, contextual fear and water maze in rodents. To directly test whether intact neurogenesis is required for gains in behavioral performance from exercise in C57BL/6J mice, neurogenesis was reduced using focal gamma irradiation (3 sessions of 5 Gy). Two months after treatment, mice (total n=42 males and 42 females) (Irradiated or Sham), were placed with or without running wheels (Runner or Sedentary) for 54 days. The first 10 days mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. The last 14 days mice were tested on water maze (two trials per day for 5 days, then 1 h later probe test), rotarod (four trials per day for 3 days), and contextual fear conditioning (2 days), then measured for neurogenesis using immunohistochemical detection of BrdU and neuronal nuclear protein (NeuN) mature neuronal marker. Consistent with previous studies, in Sham animals, running increased neurogenesis fourfold and gains in performance were observed for the water maze (spatial learning and memory), rotarod (motor performance), and contextual fear (conditioning). These positive results provided the reference to determine whether gains in performance were blocked by irradiation. Irradiation reduced neurogenesis by 50% in both groups, Runner and Sedentary. Irradiation did not affect running or baseline performance on any task. Minimal changes in microglia associated with inflammation (using immunohistochemical detection of cd68) were detected at the time of behavioral testing. Irradiation did not reduce gains in performance on rotarod or contextual fear, however it eliminated gain in performance on the water maze. Results support the hypothesis that intact exercise-induced hippocampal neurogenesis is required for improved spatial memory, but not motor performance or contextual fear in C57BL/6J mice.
Neuroscience 10/2008; 155(4):1048-58. · 3.38 Impact Factor
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ABSTRACT: Recently, a simple procedure was described, drinking in the dark (DID), in which C57BL/6J mice self-administer ethanol to the point of intoxication. The test consists of replacing the water with 20% ethanol in the home cage for 2 or 4 h early during the dark phase of the light/dark cycle.
To determine whether the model displays predictive validity with naltrexone, and whether opioid or dopaminergic mechanisms mediate excessive drinking in the model.
Naltrexone or GBR 12909 were administered via intraperitoneal injections immediately before offering ethanol solutions, plain tap water, or 10% sugar water to male C57BL/6J mice, and consumption was monitored over a 2- or 4-h period using the DID procedure.
Naltrexone (0.5, 1, or 2 mg/kg) dose dependently decreased ethanol drinking but these same doses had no significant effect on the consumption of plain water or 10% sugar water. GBR 12909 (5, 10, and 20 mg/kg) dose dependently reduced the consumption of ethanol and sugar water but had no effect on plain water drinking.
The DID model demonstrates predictive validity. Both opioid and dopamine signaling are involved in ethanol drinking to intoxication. Different physiological pathways mediate high ethanol drinking as compared to water or sugar water drinking in DID. DID may be a useful screening tool to find new alcoholism medications and to discover genetic and neurobiological mechanisms relevant to the human disorder.
Psychopharmacologia 07/2007; 192(2):207-17. · 4.08 Impact Factor
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ABSTRACT: Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice.
Genes Brain and Behavior 03/2007; 6(1):1-18. · 3.48 Impact Factor
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ABSTRACT: The evolution of behavior has been notoriously difficult to study at the molecular level, but mouse genetic technology offers new promise. We applied selective breeding to increase voluntary wheel running in four replicate lines of Mus domesticus (S mice) while maintaining four additional lines through random breeding to serve as controls (C mice). The goal of the study was to identify the gene expression profile of the hippocampus that may have evolved to facilitate the increased voluntary running. The hippocampus was of interest because it is known to display marked physiological responses in association with wheel running itself. We used high-density oligonucleotide arrays representing 11,904 genes. To control for the confounding influence of physical activity itself on gene expression, animals were housed individually without access to running wheels, and were sampled during the day when they are normally inactive. Two-month-old female mice in estrus were used (n = 16 total; two per line; 8 S and 8 C). After correcting for an acceptable false discovery rate (10%), 30 genes, primarily involved in transcription and translation, significantly increased expression whereas 23 genes, distributed among many categories including immune function and neuronal signaling, decreased expression in S versus C mice. These changes were relatively small in magnitude relative to the changes in gene expression that occur in the hippocampus in response to wheel running itself. A priori tests of dopamine receptor expression levels demonstrated an increase of approximately 20% in the expression of D2 and D4 receptors. These results suggest that relatively small changes in the expression patterns of hippocampal genes underlie large changes in phenotypic response to selection, and that the genetic architecture of running motivation likely involves the dopaminergic system as well as CNS signaling machinery.
Evolution 10/2004; 58(9):2079-86. · 5.15 Impact Factor
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ABSTRACT: Mice from 8 to 21 inbred strains were tested for sensitivity to ethanol intoxication using a range of doses and three different measures: the screen test, the dowel test and a test of grip strength. Strains differed under nearly all conditions. For the dowel test, two dowel widths were employed, and mice were tested immediately or 30 min after ethanol. For the dowel and screen tests, low doses failed to affect some strains, and the highest doses failed to discriminate among mice, maximally affecting nearly all. For grip strength, a single ethanol dose was used, and mice of all strains were affected. Pharmacokinetic differences among strains were significant, but these could not account for strain differences in intoxication. For doses and test conditions in the middle range, there were only modest correlations among strain means within a test. In addition, genotypic correlations across tests were modest to quite low. These results suggest that different specific versions of a test reflect the influence of different genes, and that genetic influences on different tests were also distinct.
Genes Brain and Behavior 09/2003; 2(4):201-13. · 3.48 Impact Factor
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ABSTRACT: Previous studies of mice ( Mus domesticus) selectively bred for high voluntary wheel running have suggested that the hyperactivity is associated with dysfunction in the dopaminergic neuromodulatory system and that high-running mice may represent a useful genetic model for attention deficit hyperactivity disorder (ADHD).
We tested the hypothesis that mice from the four replicate hyperactive lines would respond differently to methylphenidate (Ritalin), apomorphine (non-selective dopamine agonist), SCH 23390 (selective D1-like dopamine antagonist), and raclopride (selective D2-like dopamine antagonist) than individuals from the four replicate, randomly bred, control lines.
After animals were habituated (3 weeks) to their cages with attached wheels, drugs were administered via intraperitoneal injections, at night, during peak wheel-running activity. Revolutions on wheels 10-70 min post-injection were used to quantify drug responses.
Ritalin (15 mg/kg and 30 mg/kg) increased wheel running in control lines but decreased running in selected lines. A low-dose (0.125 mg/kg) of apomorphine reduced wheel running by a similar amount in control and selected lines; however, higher doses of apomorphine (0.25 mg/kg and 0.5 mg/kg) produced greater reductions in wheel running in the control lines. SCH 23390 (0.025, 0.05, and 0.1 mg/kg) caused greater reductions in wheel running in control than in selected lines. Raclopride (0.5, 1, and 2 mg/kg) reduced wheel running by a similar amount in control and selected lines.
These results support the interpretation that genetically determined hyperactive wheel-running behavior is associated with altered dopaminergic function in this mouse model. More specifically, results suggest that D1-like (D1 or D5), but not D2-like (D2, D3, or D4), dopamine receptors have reduced function in the high-running mice. The fact that Ritalin decreased wheel running in selected lines further supports their use as an animal model of ADHD.
Psychopharmacologia 06/2003; 167(3):242-50. · 4.08 Impact Factor
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ABSTRACT: Voluntary wheel running in rats increases hippocampal brain-derived neurotrophic factor (BDNF) expression, a neurochemical important for neuronal survival, differentiation, connectivity and synaptic plasticity. Here, we report the effects of wheel running on BDNF and neurotrophin-3 (NT-3) protein levels in normal control mice, and in mice selectively bred (25 generations) for increased voluntary wheel running. We hypothesized that increased voluntary wheel running in selected (S) mice would increase CNS BDNF and NT-3 protein levels more than in control (C) mice. Baseline hippocampal BDNF levels (mice housed without running wheels) were similar in S and C mice. Following seven nights of running, hippocampal BDNF increased significantly more in S versus C mice, and levels were correlated with distance run (considering C and S mice together). Spinal and cerebellar BDNF and hippocampal NT-3 levels were not significantly affected by wheel running in any group, but there was a small, positive correlation between spinal C3-C6 BDNF levels and distance run (considering C and S mice together). This is the first study to demonstrate that mice which choose to run more have greater elevations in hippocampal BDNF, suggesting enhanced potential for exercise-induced hippocampal neuroplasticity.
Neuroscience 02/2003; 121(1):1-7. · 3.38 Impact Factor
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ABSTRACT: In nature, many animals use intermittent rather than continuous locomotion. In laboratory studies, intermittent exercise regimens have been shown to increase endurance compared with continuous exercise. We hypothesized that increased intermittency has evolved in lines of house mice (Mus domesticus) that have been selectively bred for high voluntary wheel-running (wheel diameter 1.12 m) activity. After 23 generations, female mice from four replicate selection lines ran 2.7 times more revolutions per day than individuals from four random-bred control lines. To measure instantaneous running speeds and to quantify intermittency, we videotaped mice (N=41) during a 5-min period of peak activity on night 6 of a 6-day exposure to wheels. Compared with controls (20 revs min(-1) while actually running), selection-line females (41 revs min(-1)) ran significantly faster. These instantaneous speeds closely matched the computer-recorded speeds over the same 5-min period. Selection-line females also ran more intermittently, with shorter (10.0 s bout(-1)) and more frequent (7.8 bouts min(-1)) bouts than controls (16.8 s bout(-1), 3.4 bouts min(-1)). Inter-bout pauses were also significantly shorter in selection-line (2.7 s) than in control-line (7.4 s) females. We hypothesize that intermittency of locomotion is a key feature allowing the increased wheel-running performance at high running speeds in selection-line mice.
Journal of Experimental Biology 01/2002; 204(Pt 24):4311-20. · 3.00 Impact Factor
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ABSTRACT: To study the neural basis of genetic hyperactivity, we measured acute drug responses of mice (Mus domesticus) from four replicate lines that had been selectively bred (23-24 generations) for increased running-wheel activity.
We tested the hypothesis that the high-running lines would respond differently to cocaine, GBR 12909, and fluoxetine (Prozac) compared with four replicate, random-bred, control lines. We also tested the hypothesis that the high-running lines would display hyperactivity in cages without wheels.
Drug trials were conducted at night, during peak activity, after animals were habituated (3 weeks) to their cages with attached wheels. Revolutions on wheels 10-40 min post-injection were used to quantify drug responses. In a separate study, total photobeam breaks (produced on the first and second 24-h period of exposure) were used to quantify basal activity in animals deprived of wheels.
Cocaine and GBR 12909 decreased wheel running in selected lines by reducing the average speed but not the duration of running, but these drugs had little effect in control lines. Fluoxetine reduced running speed and duration in both selected and control animals, and the magnitude of the reduction was proportional to baseline activity. Basal activity in animals deprived of wheels (quantified using photobeam breaks) was significantly higher in selected than control lines on the second day of testing.
These results suggest an association between genetically determined hyperactive wheel-running behavior and dysfunction in the dopaminergic neuromodulatory system. Our selected lines may prove to be a useful genetic model for attention deficit hyperactivity disorder.
Psychopharmacologia 12/2001; 158(2):120-31. · 4.08 Impact Factor
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ABSTRACT: Effects of genetic selection for high wheel-running activity (17th generation) and access to running wheels on skeletal muscle glucose uptake were studied in mice with the following treatments for 8 wk: 1) access to unlocked wheels; 2) same as 1, but wheels locked 48 h before glucose uptake measurement; or 3) wheels always locked. Selected mice ran more than random-bred (nonselected) mice (8-wk mean +/- SE = 8,243 +/- 711 vs. 3,719 +/- 233 revolutions/day). Body weight was 5-13% lower for selected vs. nonselected groups. Fat pad/body weight was ~40% lower for selected vs. nonselected and unlocked vs. locked groups. Insulin-stimulated glucose uptake and fat pad/body weight were inversely correlated for isolated soleus (r = -0.333; P < 0.005) but not extensor digitorum longus (EDL) or epitrochlearis muscles. Insulin-stimulated glucose uptake was higher in EDL (P < 0.02) for selected vs. nonselected mice. Glucose uptake did not differ by wheel group, and amount of running did not correlate with glucose uptake for any muscle. Wheel running by mice did not enhance subsequent glucose uptake by isolated muscles.
Journal of Applied Physiology 09/2001; 91(3):1289-97. · 3.75 Impact Factor
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ABSTRACT: Open-field behavioral assays are commonly used to test both locomotor activity and emotionality in rodents. We performed open-field tests on house mice (Mus domesticus) from four replicate lines genetically selected for high voluntary wheel-running for 22 generations and from four replicate random-bred control lines. Individual mice were recorded by video camera for 3 min in a 1-m2 open-field arena on 2 consecutive days. Mice from selected lines showed no statistical differences from control mice with respect to distance traveled, defecation, time spent in the interior, or average distance from the center of the arena during the trial. Thus, we found little evidence that open-field behavior, as traditionally defined, is genetically correlated with wheel-running behavior. This result is a useful converse test of classical studies that report no increased wheel-running in mice selected for increased open-field activity. However, mice from selected lines turned less in their travel paths than did control-line mice, and females from selected lines had slower travel times (longer latencies) to reach the wall. We discuss these results in the context of the historical open-field test and newly defined measures of open-field activity.
Behavior Genetics 06/2001; 31(3):309-16. · 2.52 Impact Factor
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ABSTRACT: We studied rectal body temperatures of house mice (Mus domesticus) that had been artificially selected for high voluntary wheel running.1. At generation 17, mice from the four replicate selected lines ran, on average, 2.5-times as many revolutions/day as did mice from the four random-bred control lines.2. During the day, repeatability of individual differences in body temperature measured 4 days apart was low; at night, repeatability was statistically significant across three time scales (1 day, 1 week, 2 weeks).3. During the day, body temperatures of selected and control animals did not differ; at night, mice from selected lines had higher body temperatures. However, when amount of wheel running immediately prior to measurement was included as a covariate, the difference was no longer statistically significant.Higher body temperatures, associated with increased activity, might enhance locomotor abilities through Q10 effects, increase metabolic rate and food requirements, affect sleep patterns, and alter expression of heat-shock proteins.
Journal of Thermal Biology 11/2000; · 1.37 Impact Factor
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ABSTRACT: Adolescence is a time period when major changes occur in the brain with long-term consequences for behavior. One ramification is altered responses to drugs of abuse, but the specific brain mechanisms and implications for mental health are poorly understood. Here, we used a mouse model in which adolescents display dramatically reduced sensitivity to the acute locomotor stimulating effects of cocaine and methamphetamine. The goal was to identify key brain regions or circuits involved in the differential behavior. Male adolescent (postnatal day (PN), 30–35) and young adult (PN, 69–74) C57BL/6J mice were administered an i.p. injection of cocaine (0, 15, 30 mg/kg) or methamphetamine (0, 2, 4 mg/kg) and euthanized 90 min later. Locomotor activity was monitored continuously in the home cage by video tracking. Immunohistochemical detection of Fos protein was used to quantify neuronal activation in 16 different brain regions. As expected, adolescents were less sensitive to the locomotor stimulating effects of cocaine and methamphetamine as indicated by a rightward shift in the dose response relationship. After a saline injection, adolescents showed similar levels of Fos as adults in all regions except the dorsal caudate (CPuD) and lateral caudate (CPuL) where levels were lower in adolescents. Cocaine and methamphetamine dose dependently increased Fos in all brain regions sampled in both adolescents and adults, but Fos levels were similar in both age groups for a majority of regions and doses. Locomotor activity was correlated with Fos in several brain areas within adolescent and adult groups, and adolescents had a significantly greater induction of Fos for a given amount of locomotor activity in key brain regions including the caudate where they showed reduced Fos under baseline conditions. Future research will identify the molecular and cellular events that are responsible for the differential psychostimulant-induced patterns of brain activation and behavior observed in adolescent versus adult mice.
Neuroscience.
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ABSTRACT: The mammalian hippocampus continues to generate new neurons throughout life. Experiences such as exercise, anti-depressants, and stress regulate levels of neurogenesis. Exercise increases adult hippocampal neurogenesis and enhances behavioral performance on rotarod, contextual fear and water maze in rodents. To directly test whether intact neurogenesis is required for gains in behavioral performance from exercise in C57BL/6J mice, neurogenesis was reduced using focal gamma irradiation (3 sessions of 5 Gy). Two months after treatment, mice (total n=42 males and 42 females) (Irradiated or Sham), were placed with or without running wheels (Runner or Sedentary) for 54 days. The first 10 days mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. The last 14 days mice were tested on water maze (two trials per day for 5 days, then 1 h later probe test), rotarod (four trials per day for 3 days), and contextual fear conditioning (2 days), then measured for neurogenesis using immunohistochemical detection of BrdU and neuronal nuclear protein (NeuN) mature neuronal marker. Consistent with previous studies, in Sham animals, running increased neurogenesis fourfold and gains in performance were observed for the water maze (spatial learning and memory), rotarod (motor performance), and contextual fear (conditioning). These positive results provided the reference to determine whether gains in performance were blocked by irradiation. Irradiation reduced neurogenesis by 50% in both groups, Runner and Sedentary. Irradiation did not affect running or baseline performance on any task. Minimal changes in microglia associated with inflammation (using immunohistochemical detection of cd68) were detected at the time of behavioral testing. Irradiation did not reduce gains in performance on rotarod or contextual fear, however it eliminated gain in performance on the water maze. Results support the hypothesis that intact exercise-induced hippocampal neurogenesis is required for improved spatial memory, but not motor performance or contextual fear in C57BL/6J mice.
Neuroscience.
