Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Dec 7.
Published in final edited form as: Cogn Sci (Hauppauge). 2012;7(2):187–205.

Maternal Exercise and Cognitive Functions of the Offspring

Andrea M Robinson 1, David J Bucci 1
PMCID: PMC4671504  NIHMSID: NIHMS694678  PMID: 26664667

Abstract

Substantial research has established that exercise can improve mental health and cognitive function in both human and non-human animals. Exercise has been shown to improve learning and memory in both adult and juvenile animals, with larger and more durable effects associated with exercising during development. Exercise during the gestational period has also been shown to improve cognition in the offspring. Several recent studies indicate that the offspring of mothers that exercised during pregnancy exhibit improved learning and memory and decreased anxiety-like behaviors. These behavioral changes are accompanied by increased neurogenesis, neurotrophic factor expression, and neuronal activity in the offspring. This review summarizes the current literature regarding the effects of maternal exercise in rodents and presents avenues for future research to reveal the biological mechanism(s) through which maternal exercise changes the brain and behavior of the offspring.

Keywords: memory, learning, pregnancy, BDNF, neurogenesis, anxiety

INTRODUCTION

Numerous studies in humans and laboratory animals have demonstrated that physical exercise can benefit cognitive function. Exercise enhances learning and memory (Fordyce & Wehner, 1993; Kramer et al., 1999; Albeck et al., 2006), facilitates recovery after brain injury (Grealy et al., 1999), and can prevent cognitive decline associated with aging (Laurin et al., 2001). To date, the vast majority of this research has been conducted in adults and has focused particularly on the beneficial effects of exercise on the hippocampus and hippocampal-dependent learning and memory. For example, aerobic exercise has been shown to reverse hippocampal volume loss in late adulthood in humans, as well as improve spatial memory function (Erickson et al., 2011). Similarly, research in rodent models has demonstrated that exercise increases neurogenesis (Lazarov et al., 2010) and brain-derived neurotrphic factor (BDNF) expression (Neeper et al., 1996; Vaynman et al., 2003) in the hippocampus. Indeed, these changes are required for exercise-induced enhancements in spatial learning and memory (Clark et al., 2008; Vaynman et al., 2004).

Although the effects of exercise on the adult brain have been well documented, far less is known about the effects of exercise on the developing brain. Brain development begins in utero and continues throughout adolescence (Rice & Barone, 2000). During this developmental process, the brain can be affected both positively and negatively by internal and external factors. For example, maternal deprivation in early developmental periods has been linked to neuropsychiatric disorders later in life, including anxiety disorders, depression, and drug abuse (Moffett et al., 2007; Marco et al., 2009; Levine et al., 2005). Conversely, exercise and environmental enrichment in juvenile rats can improve learning and memory (Kim et al., 2007; Lou et al., 2008; Rosenzweig & Bennett, 1996; Hopkins et al., 2011) while enhancing growth, development, and plasticity of the brain (Gomes da Silva et al., 2010; Hopkins et al., 2011). Notably, exercise has been found to have more robust and longer-lasting effects on both the brain and behavior when rats exercise as juveniles rather than as adults. For example, rats that exercised during adolescence had greater increases in cell proliferation (Kim et al., 2004), BDNF expression (Adlard et al., 2005; Hopkins et al., 2011), and object recognition memory (Hopkins et al., 2011) than rats that exercised as adults. In addition, in the rats that exercised as adolescents, the exercise-induced improvements in behavior lasted long after exercise stopped, while in adults the effects did not persist after the exercise regimen had ended (Hopkins et al, 2011). These data provide evidence that exercising during critical periods of development can have more robust effects on cognition.

Similarly, several recent studies have reported that regular physical exercise during gestation can affect the offspring. In particular, maternal exercise during pregnancy has been shown to enhance learning and also reduce anxiety-like behavior in the offspring (Aksu et al., 2012, Parnpiansil et al., 2003; Akhavan et al., 2008; Dayi et al., 2012; Kim et al., 2007; Lee et al., 2006; Robinson & Bucci, 2014). These findings have significant implications for a variety of health issues and also demonstrate the need for additional research to determine how maternal behavior affects the brain of the developing fetus. Thus, this chapter will consider the findings to date, focusing primarily on studies of maternal exercise in laboratory rodents and the effects on cognition in the offspring. Particular emphasis will be placed on identifying avenues for future research to identify the biological mechanisms that mediate the effects of maternal exercise on the brain and behavior of the offspring.

RESEARCH TO DATE

In humans, maternal exercise during pregnancy has been suggested to exert beneficial effects on the growth of the fetus and placenta (Ezmerli, 2000; Clapp, 2006). Studies have also reported enhanced cognitive functioning in the offspring of mothers who exercised throughout pregnancy. Continuing regular exercise throughout pregnancy was shown to improve early motor skills in 1 year olds (Clapp, 1998) and improve performance on general intelligence and oral language skills at 5 years of age (Clapp, 1996). In addition, high levels of leisure-time physical activity (e.g., jogging, aerobics, yoga, weight-lifting) during pregnancy were associated with increased vocabulary in the offspring at 15 months of age (Jukic et al., 2013). These studies provide evidence that exercise throughout pregnancy is beneficial for both the mother and child.

Studies using rodent models have also revealed benefits of gestational exercise on the cognitive function of offspring. In rats, exercising during pregnancy has been found to improve spatial learning and memory in the offspring, as tested in the Morris Water Maze (MWM) and T-maze (Parnpiansil et al., 2003; Akhavan et al., 2008; 2013; Dayi et al., 2012). Adult and adolescent offspring of mothers that exercised during pregnancy required less time to find a submerged platform in the MWM, indicating improved spatial learning. These offspring also had improved memory retention and spent more time in the quadrant of the pool that previously contained the platform during a probe trial conducted one day after training (Dayi et al., 2012). In the multiple T-maze, the offspring of exercising mothers exhibited a decrease in the latency to travel from the start box to the target and a decrease in the number of errors during the first four days of training (Parnpiansil et al., 2003). The improvements in spatial learning and memory were accompanied by increased hippocampal BDNF mRNA (Parnpiansil et al., 2003), increased hippocampal neurogenesis (Dayi et al., 2012), and increased hippocampal leptin receptor expression (Dayi et al., 2012) in the offspring.

Exercise also improved fear memory in the offspring of exercising mothers. Fear memory was measured by the latency to step down off a platform onto a grid floor that had been paired with a footshock 7 days earlier. Offspring of mothers that underwent forced treadmill or swimming exercise during pregnancy displayed a longer latency to step down off the platform at postnatal day (PND) 28, indicating improved memory of the floor-shock pairing (Kim et al., 2007; Lee et al., 2006). This effect was associated with enhanced neurogenesis and increased levels of BDNF mRNA in the hippocampus.

Most of the studies described above have examined the effects of maternal exercise on hippocampal-related function in juvenile or adolescent offspring. However, there is evidence to suggest that these effects may persist into adulthood and affect behaviors that rely on structures other than the hippocampus. For example, the adult offspring of mothers that exercised during pregnancy exhibited improvements in a non-hippocampal-dependent object memory task (Robinson & Bucci, 2014). Object recognition is a non-spatial form of memory that depends on the perirhinal cortex (PER; Dere et al., 2007) and is based on the spontaneous tendency of rodents to spend more time exploring a novel object than a familiar one. In this procedure, rats are presented with two identical objects and allowed to explore them during the sample phase. During the subsequent test phase, one of the objects is replaced with a new object. Greater exploration of the novel object is thought to reflect memory for the previously encountered (familiar) object. The adult offspring from exercising mothers explored the novel object more than the familiar object during three different test sessions (spaced two weeks apart) whereas the offspring of non-exercising mothers spent equivalent time with both the old and new objects. After the final test of object recognition, rats were sacrificed and c-FOS expression was measured in the PER cortex. c-FOS is an immediate-early gene that is often used as a marker of neural activation. Indeed, c-FOS expression in PER is a reliable marker of changes in neuronal activity related to recognition memory (Zhu et al., 1995b, 1996; Wan et al., 1999, 2004; Warburton et al., 2003, 2005; Albasser et al., 2010; Seoane et al., 2012). The offspring of exercising mothers exhibited increased c-FOS expression in the PER, suggesting that exercise during the gestational period enhanced brain function of the offspring. In addition, these findings indicate that the cognitive-enhancing effects of maternal exercise on the offspring persist into adulthood and that the effects are durable over time.

LIMITATIONS

Stress

One potential confound in interpreting the effects of maternal exercise on the behavior of offspring is that most of the tasks used in the studies to date assessed cognitive function using tasks that induce a substantial stress response. The MWM and step-down avoidance tasks increase the release of stress hormones by the adrenal gland (Engelmann et al., 2006; Sandi et al., 1997), which can influence cognitive function both positively and negatively depending on the experimental preparation (Sandi et al., 1997). Importantly, exercise has been shown to reduce stress in both exercising animals (Fulk et al., 2004; Hopkins & Bucci, 2010) and in the offspring of exercising animals (Aksu et al., 2012). Thus, the effects of exercise on cognitive function could be secondary to effects on stress and anxiety. For example, Dayi et al., (2012) reported less thigmotaxis in the MWM in offspring whose mothers exercised during pregnancy. Thigmotaxis, or the tendency to remain close to walls, is a stress response and reduced thigmotaxis has been found to improve navigation strategies in the MWM (Beiko et al., 2004). Thus, rather than exercise directly improving cognitive functioning, it may reduce stress, which results in better performance on certain learning and memory tasks.

However, Robinson and Bucci (2014) assessed cognitive functioning using a novel object recognition task that is not stress inducing. Indeed, it has been found previously that there is no relationship between anxiety-like behavior and performance on this task (Hopkins & Bucci, 2010). Maternal exercise improved the performance of the offspring on the object recognition memory task indicating that maternal exercise can improve cognitive function in tasks that are not stress inducing. However, future research is needed to more fully determine how exercise and stress interact to affect performance on tasks that assess learning and memory.

Forced versus voluntary exercise

The majority of studies examining the effects of maternal exercise have employed forced exercise protocols. Forced (i.e., moderate treadmill running) and voluntary exercise (i.e., access to a running wheel) has been shown to have different effects on the brain and behavior (Leasure & Jones, 2008; Liu et al., 2009). Studies using both exercise paradigms show different effects on anxiety-like behaviors (Burghardt et al., 2004, Dishman, 1997; Leasure and Jones, 2008), neurogenesis (Leasure & Jones, 2008), and hippocampal expression of various neurotrophic factors (Dishman, 1997; Ploughman et al., 2005; Liu et al., 2009). In fact, different forms of exercise can induce distinct brain region-dependent neuronal adaptations. Forced and voluntary exercise differentially improve the performance of hippocampus- and amygdala-dependent contextual fear conditioning and amygdala-dependent cued fear conditioning in rats (Lin et al., 2012). Whereas forced exercise induced neuroplasticity changes in both hippocampus and amygdala, voluntary exercise primarily affected the hippocampus. These results support the notion that different forms of exercise induce neuroplastic changes in different brain regions, and thus exert diverse effects on various forms of learning and memory.

Because most of the studies that have examined the effects of maternal exercise on the offspring have employed only forced exercise protocols, it is unclear if different results would be obtained with other types of exercise. However, Akhavan et al. (2008) used both forced (swimming) and voluntary (wheel running) exercise in pregnant mothers and found that both forced and voluntary exercise decreased the latency to find the platform in the MWM, but only forced swimming enhanced memory retention in the offspring during a probe trial. Forced and voluntary exercise are inherently different: voluntary wheel running is typically characterized by rapid pace and short duration, whereas forced exercise involves a slower, more consistent pace for longer periods of time (Leasure & Jones, 2008). This basic difference between the two forms of exercise may be responsible for their differential effects on brain and behavior. In addition, it could be the elevated stress experienced by rodents forced to swim or run may potentially confound results, especially since forced exercise has been found to acutely elevate corticosterone to a greater extent than voluntary exercise (Ploughman et al., 2005; 2007). Future studies are needed to determine the duration, intensity, and type of exercise that produces the greatest cognitive benefits in the offspring.

Sex differences

Most of the studies to date have not tested for potential sex differences in the effects of maternal exercise on the offspring. Indeed, there are sex-specific effects of exercise on both the brain (Titterness et al., 2011) and behavior (Hopkins et al., 2009) in adult rodents. In addition, the prenatal environment has been shown to differentially affect male and female offspring. Prenatal stress produces sex specific alterations in spatial learning, object recognition, delayed alteration, and passive avoidance (Bowman et al., 2004; Szuran et al., 2007; Weinstock, 2001; Koenig, Elmer, Shepard, Lee, Mayo, Joy, et al., 2005) and evidence suggests that males may be more impaired by gestational stress than females (Mueller & Bale, 2007; Szuran et al., 2007; Weinstock, 2001; Koenig et al., 2005; Nishio et al., 2001). Since exercise can be a type of stressor, future research should determine if maternal exercise during pregnancy affects cognition in males and females differently.

MECHANISMS OF ACTION

Studies that have examined the effects of maternal exercise during pregnancy on cognitive function in the offspring have begun to investigate the biological factors that underlie the observed effects on behavior. For example, the offspring of exercising mothers have been found to exhibit increased neurogenesis (Akhvan et al., 2008; Bick-Sander et al., 2006; Lee et al., 2006; Kim et al., 2007), BDNF levels (Parnpiansil et al., 2013; Lee et al., 2006; Kim et al., 2007; Akhavan et al., 2013), expression of basic fibroblast growth factor (FGF2; Bick-Sanders et al., 2006), and c-FOS protein (Robinson & Bucci, 2014). Nonetheless, it remains unclear how these effects are mediated. In the following section we consider several potential mechanisms and encourage future studies to determine whether the biological and behavioral effects observed in the offspring are due to direct transfer of neurochemical across the placental or mammary barrier, epigenetic mechanisms, or through alternations in maternal behavior.

Placental transfer

Exercise in the adult rat improves learning and memory in the MWM and these improvements are associated with an increase in BDNF mRNA levels and receptors (i.e., TrkB receptors), and downstream signaling molecules including synapsin I and CREB (Gomez-Pinilla et al., 2001; Vaynman et al., 2003; 2004). Maternal exercise during pregnancy has also been shown to increase BDNF mRNA in the hippocampus of the offspring. Thus, it is possible that maternal exercise is able to induce similar effects in the offspring through direct transfer of BDNF across the placental barrier. Indeed, maternal BDNF has been found to reach the fetal brain. Administration of exogenous BDNF to pregnant dams increased BDNF protein levels in the fetal brain in a dose-dependent manner (Kodomari et al., 2009). This result supports the notion that maternal BDNF can be transported to the fetus across the utero-placenta barrier, and this may result in improved cognitive functioning. Indeed, inhibiting BDNF expression in the hippocampus of offspring of exercising mothers prevented an exercise-induced enhancement in learning in the MWM, while having no effect on learning in offspring of non-exercising mothers (Akhavan et al., 2013). However, inhibiting BDNF by blocking its TrkB receptor had no effect on memory retention in a probe trial. This study demonstrates that voluntary exercise during pregnancy may act via a TrkB-mediated mechanism to enhance spatial learning, but not memory retention in the offspring. Yet, it remains unclear how blocking TrkB receptors could specifically suppress the enhancing effect of maternal voluntary exercise on learning in the offspring.

To date, only one other published study has attempted to block the cognitive-enhancing effects of exercise during gestation in the offspring. A systemic lesion of the noradrenergic system or serotonergic system eliminated the maternal exercise induced improvement in spatial learning in offspring, whereas such lesions did not alter cognitive function in rat pups from sedentary mothers (Akhavan et al., 2008). Indeed, several studies have revealed the importance of noradrenergic and serotonergic systems in mediating the effects of exercise on learning and memory (Ebrahimi et al., 2010; van Hoomissen et al., 2004) and exercise-induced BDNF expression (Garcia et al., 2003; Ivy et al., 2003; Klempin et al., 2013). This suggests that the noradrenergic and serotonergic systems may play an important role in mediating the effects of maternal exercise on the cognitive function of the offspring.

Epigenetics

Environmental stimuli can induce epigenetic modifications that, in turn, modulate gene expression. Several studies have demonstrated the existence of epigenetic changes after acute and chronic exercise and show that they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (e.g. c-Fos and BDNF; Collins et al., 2009; Gomez-Pinilla et al., 2011). These exercise-induced changes are mediated by DNA methylation and modification of histones H3 and H4. Four weeks of voluntary exercise improved the ability of rats to cope with stressful challenges and also enhanced memory performance, effects that were associated with increased histone H3 phospho-acetylation and increased c-Fos activation in the dentate gyrus granule neurons (Collins et al., 2009). These epigenetic modifications of histone H3 are associated with a relaxed chromatin structure and therefore greater potential for the expression of previously silenced genes. In another study, one week of voluntary exercise was found to increase histone acetylation and decrease DNA methylation specifically on the promotor region of exon IV on the Bdnf gene in the hippocampus. In addition, exercise was found to elevate levels of activated (phosphorylated) CREB and CAMKII protein in the hippocampus. These data demonstrate that exercise promotes remodeling of chromatin structure containing the Bdnf gene specifically at the promotor IV region of the gene, which is known to be particularly responsive to neuronal activity and is the target of epigenetic regulation during task acquisition and memory formation (Gomez-Pinilla et al., 2011).

Certain epigenetic modifications are passed on to subsequent generations and affect gene expression (Wolff et al., 1998; Morgan et al., 1999). Particular environmental factors (e.g., diet) have been shown produce distinct inheritance of epigenetic modifications, which have also been shown to be trans-generationally heritable (Carone et al., 2010; Burdge et al., 2007). For example, a low protein diet throughout pregnancy altered epigenetic regulation of specific genes across the next two generations of rats (Burdge et al., 2007). Notably, physical exercise modulates gene expression and DNA methylation of many of the same metabolic genes affected by diet that have been shown to be trans-generationally heritable (Barres et al., 2012; Nitert et al., 2012). This suggests that exercise may be shaping epigenetic modifications and gene expression of not only the individual performing the physical exercise but also that of their progeny. These epigenetic changes may lead to improved cognitive performance in the offspring, an idea that awaits future research.

Maternal behavior

Another possible mechanism mediating the beneficial effects of maternal exercise on the offspring is the influence of exercise on maternal behavior. Gestational stress can directly alter maternal behavior in the rat leading to poorer outcomes in the offspring (Champagne & Meaney, 2006; Smith et al., 2004). Stress during pregnancy can cause less frequent and less intense mother-pup interactions, which results in an increased endocrine response to stress and increased levels of depression-like behavior in adult offspring (Smith et al., 2004). Maternal care during the first week of life can have long-lasting effects on the offspring’s behavior through changes in the epigenome (Weaver et al., 2004; Fish et al., 2004). In fact, the stress-induced alterations in maternal behavior can be transmitted across generations and can also affect the neural substrates of maternal behavior in the female progeny (Champagne & Meaney, 2006).

If adversity promotes reduced behavioral investment in the offspring, then more favorable environments should have the opposite effect. Exercise has been shown to decrease stress and anxiety-like behavior in rats (Fulk et al., 2004; Hopkins & Bucci, 2010) so exercise during the gestational period may improve subsequent care of the young. Thus, the effects of maternal exercise on the cognitive function of the offspring could be mediated through maternal care rather than a direct transfer of a growth factor (or other substance) across the placental or mammary barrier. Future studies could cross-foster pups from exercising and non-exercising mothers to determine if the beneficial effects on the offspring are mediated by changes in maternal behavior.

CONCLUSION

Maternal exercise during pregnancy can improve cognitive function in the offspring as evidenced by improved learning and memory and decreased anxiety-like behaviors. These behavioral changes are accompanied by increased neurogenesis, neurotrophic factor expression, and neuronal activity. However, the specific mechanism through which maternal exercise is transmitted to the offspring remains unclear. Future studies are needed to investigate whether these cognitive-enhancing effects occur through direct transfer of substances across the placental barrier, epigenetic changes, and/or changes in maternal behavior. The effects of exercise during gestation are obsreved in juvenile, adolescent, and adult offspring, suggesting that exercising during this developmental period leads to long lasting and durable effects on cognitive function. These data encourage further investigations in this direction to determine if the effects are translatable to humans.

Acknowledgments

Supported by NIH Grant R01MH082893.

References

  1. Adlard PA, Perreau VM, Pop V, Cotman CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:4217–4221. doi: 10.1523/JNEUROSCI.0496-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akhavan MM, Emami-Abarghoie M, Safari M, Sadighi-Moghaddam B, Vafaei AA, Bandegi AR, Rashidy-Pour A. Serotonergic and noradrenergic lesions suppress the enhancing effect of maternal exercise during pregnancy on learning and memory in rat pups. Neuroscience. 2008;151(4):1173–1183. doi: 10.1016/j.neuroscience.2007.10.051. [DOI] [PubMed] [Google Scholar]
  3. Akhavan MM, Miladi-Gorji H, Emami-Abarghoie M, Safari M, Sadighi-Moghaddam B, Vafaei AA, Rashidy-Pour A. Maternal Voluntary Exercise during Pregnancy Enhances the Spatial Learning Acquisition but not the Retention of Memory in Rat Pups via a TrkB-mediated Mechanism: The Role of Hippocampal BDNF Expression. Iran J Basic Med Sci. 2013;16(9):955. [PMC free article] [PubMed] [Google Scholar]
  4. Aksu I, Baykara B, Ozbal S, Cetin F, Sisman AR, Dayi A, Uysal N. Maternal treadmill exercise during pregnancy decreases anxiety and increases prefrontal cortex VEGF and BDNF levels of rat pups in early and late periods of life. Neurosci Lett. 2012;516(2):221–225. doi: 10.1016/j.neulet.2012.03.091. [DOI] [PubMed] [Google Scholar]
  5. Albasser MM, Poirier GL, Aggleton JP. Qualitatively different modes of perirhinal–hippocampal engagement when rats explore novel vs. familiar objects as revealed by c-Fos imaging. Eur J Neurosci. 2010;31(1):134–147. doi: 10.1111/j.1460-9568.2009.07042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Albeck DS, Sano K, Prewitt GE, Dalton L. Mild forced treadmill exercise enhances spatial learning in the aged rat. Behav Brain Res. 2006;168(2):345–348. doi: 10.1016/j.bbr.2005.11.008. [DOI] [PubMed] [Google Scholar]
  7. Barres R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, Zierath JR. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15(3):405–411. doi: 10.1016/j.cmet.2012.01.001. [DOI] [PubMed] [Google Scholar]
  8. Beiko J, Lander R, Hampson E, Boon F, Cain DP. Contribution of sex differences in the acute stress response to sex differences in water maze performance in the rat. Behav Brain Res. 2004;151(1):239–253. doi: 10.1016/j.bbr.2003.08.019. [DOI] [PubMed] [Google Scholar]
  9. Bick-Sander A, Steiner B, Wolf SA, Babu H, Kempermann G. Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring. Proc Natl Acad Sci USA. 2006;103(10):3852–3857. doi: 10.1073/pnas.0502644103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bowman RE, MacLusky NJ, Sarmiento Y, Frankfurt M, Gordon M, Luine VN. Sexually dimorphic effects of prenatal stress on cognition, hormonal responses, and central neurotransmitters. Endocrinology. 2004;145(8):3778–3787. doi: 10.1210/en.2003-1759. [DOI] [PubMed] [Google Scholar]
  11. Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA. Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr. 2007;97(03):435–439. doi: 10.1017/S0007114507352392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Burghardt PR, Pasumarthi RK, Wilson MA, Fadel J. Alterations in fear conditioning and amygdalar activation following chronic wheel running in rats. Pharmacol Biochem Be. 2006;84(2):306–312. doi: 10.1016/j.pbb.2006.05.015. [DOI] [PubMed] [Google Scholar]
  13. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Rando OJ. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010;143(7):1084–1096. doi: 10.1016/j.cell.2010.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Champagne FA, Meaney MJ. Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol Psychiatry. 2006;59(12):1227–1235. doi: 10.1016/j.biopsych.2005.10.016. [DOI] [PubMed] [Google Scholar]
  15. Clapp JF., III Morphometric and neurodevelopmental outcome at age five years of the offspring of women who continued to exercise regularly throughout pregnancy. J Pediatr. 1996;129(6):856–863. doi: 10.1016/s0022-3476(96)70029-x. [DOI] [PubMed] [Google Scholar]
  16. Clapp JF, III, Simonian S, Lopez B, Appleby-Wineberg S, Harcar-Sevcik R. The one-year morphometric and neurodevelopmental outcome of the offspring of women who continued to exercise regularly throughout pregnancy. Am J Obstet Gynecol. 1998;178(3):594–599. doi: 10.1016/s0002-9378(98)70444-2. [DOI] [PubMed] [Google Scholar]
  17. Clapp JF. Influence of endurance exercise and diet on human placental development and fetal growth. Placenta. 2006;27(6):527–534. doi: 10.1016/j.placenta.2005.07.010. [DOI] [PubMed] [Google Scholar]
  18. Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS. Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience. 2008;155(4):1048–1058. doi: 10.1016/j.neuroscience.2008.06.051. [DOI] [PubMed] [Google Scholar]
  19. Collins A, Hill LE, Chandramohan Y, Whitcomb D, Droste SK, Reul JM. Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus. PLoS One. 2009;4(1):e4330. doi: 10.1371/journal.pone.0004330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dayi A, Agilkaya S, Ozbal S, Cetin F, Aksu I, Gencoglu C, Uysal N. Maternal aerobic exercise during pregnancy can increase spatial learning by affecting leptin expression on offspring’s early and late period in life depending on gender. Scientific World Journal. 2012 doi: 10.1100/2012/429803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav R. 2007;31(5):673–704. doi: 10.1016/j.neubiorev.2007.01.005. [DOI] [PubMed] [Google Scholar]
  22. Dishman RK. Brain monoamines, exercise, and behavioral stress: animal models. Med Sci Sports Exerc. 1997;29(1):63–74. doi: 10.1097/00005768-199701000-00010. [DOI] [PubMed] [Google Scholar]
  23. Ebrahimi S, Rashidy-Pour A, Vafaei AA, Akhavan MM. Central β-adrenergic receptors play an important role in the enhancing effect of voluntary exercise on learning and memory in rat. Behav Brain Res. 2010;208(1):189–193. doi: 10.1016/j.bbr.2009.11.032. [DOI] [PubMed] [Google Scholar]
  24. Engelmann M, Ebner K, Landgraf R, Wotjak CT. Effects of Morris water maze testing on the neuroendocrine stress response and intrahypothalamic release of vasopressin and oxytocin in the rat. Horm Behav. 2006;50(3):496–501. doi: 10.1016/j.yhbeh.2006.04.009. [DOI] [PubMed] [Google Scholar]
  25. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011;108(7):3017–3022. doi: 10.1073/pnas.1015950108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ezmerli NM. Exercise in pregnancy. Prim Care Update Ob Gyns. 2000;7(6):260–265. doi: 10.1016/s1068-607x(00)00056-1. [DOI] [PubMed] [Google Scholar]
  27. Fish EW, Shahrokh D, Bagot R, Caldji C, Bredy T, Szyf M, Meaney MJ. Epigenetic programming of stress responses through variations in maternal care. Ann N Y Acad Sci. 2004;1036(1):167–180. doi: 10.1196/annals.1330.011. [DOI] [PubMed] [Google Scholar]
  28. Fordyce DE, Wehner JM. Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. Brain Res. 1993;619(1):111–119. doi: 10.1016/0006-8993(93)91602-o. [DOI] [PubMed] [Google Scholar]
  29. Fulk LJ, Stock HS, Lynn A, Marshall J, Wilson MA, Hand GA. Chronic physical exercise reduces anxiety-like behavior in rats. Int J Sports Med. 2004;25:78–82. doi: 10.1055/s-2003-45235. [DOI] [PubMed] [Google Scholar]
  30. Garcia C, Chen MJ, Garza AA, Cotman CW, Russo-Neustadt A. The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity. Neuroscience. 2003;119(3):721–732. doi: 10.1016/s0306-4522(03)00192-1. [DOI] [PubMed] [Google Scholar]
  31. Gomes da Silva S, Unsain N, Mascó DH, Toscano-Silva M, de Amorim HA, Silva Araujo BH, Arida RM. Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats. Hippocampus. 2012;22(2):347–358. doi: 10.1002/hipo.20903. [DOI] [PubMed] [Google Scholar]
  32. Gomez-Pinilla F, Zhuang Y, Feng J, Ying Z, Fan G. Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci. 2011;33(3):383–390. doi: 10.1111/j.1460-9568.2010.07508.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Grealy MA, Johnson DA, Rushton SK. Improving cognitive function after brain injury: the use of exercise and virtual reality. Arch Phys Med Rehabil. 1999;80(6):661–667. doi: 10.1016/s0003-9993(99)90169-7. [DOI] [PubMed] [Google Scholar]
  34. Hopkins ME, Bucci DJ. BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory. Neurobiol Learn Mem. 2010;94(2):278–284. doi: 10.1016/j.nlm.2010.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hopkins ME, Nitecki R, Bucci DJ. Physical exercise during adolescence versus adulthood: differential effects on object recognition memory and brain-derived neurotrophic factor levels. Neuroscience. 2011;194:84–94. doi: 10.1016/j.neuroscience.2011.07.071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA. Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Be. 2003;75(1):81–88. doi: 10.1016/s0091-3057(03)00044-3. [DOI] [PubMed] [Google Scholar]
  37. Jukic AMZ, Lawlor DA, Juhl M, Owe KM, Lewis B, Liu J, Longnecker MP. Physical activity during pregnancy and language development in the offspring. Paediatr Perinat Epidemiol. 2013;27(3):283–293. doi: 10.1111/ppe.12046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kim YP, Kim H, Shin MS, Chang HK, Jang MH, Shin MC, Kim CJ. Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neurosci Lett. 2004;355(1):152–154. doi: 10.1016/j.neulet.2003.11.005. [DOI] [PubMed] [Google Scholar]
  39. Kim H, Lee SH, Kim SS, Yoo JH, Kim CJ. The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups. Int J Dev Neurosci. 2007;25(4):243–249. doi: 10.1016/j.ijdevneu.2007.03.003. [DOI] [PubMed] [Google Scholar]
  40. Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N. Serotonin is required for exercise-induced adult hippocampal neurogenesis. The Journal of Neuroscience. 2013;33(19):8270–8275. doi: 10.1523/JNEUROSCI.5855-12.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kodomari I, Wada E, Nakamura S, Wada K. Maternal supply of BDNF to mouse fetal brain through the placenta. Neurochem Int. 2009;54(2):95–98. doi: 10.1016/j.neuint.2008.11.005. [DOI] [PubMed] [Google Scholar]
  42. Koenig JI, Elmer GI, Shepard PD, Lee PR, Mayo C, Joy B, Brady DL. Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. Behav Brain Res. 2005;156(2):251–261. doi: 10.1016/j.bbr.2004.05.030. [DOI] [PubMed] [Google Scholar]
  43. Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR, Colcombe A. Ageing, fitness and neurocognitive function. Nature. 1999;400(6743):418–419. doi: 10.1038/22682. [DOI] [PubMed] [Google Scholar]
  44. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001;58(3):498–504. doi: 10.1001/archneur.58.3.498. [DOI] [PubMed] [Google Scholar]
  45. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. Trends Neurosci. 2010;33(12):569–579. doi: 10.1016/j.tins.2010.09.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Leasure JL, Jones M. Forced and voluntary exercise differentially affect brain and behavior. Neuroscience. 2008;156(3):456–465. doi: 10.1016/j.neuroscience.2008.07.041. [DOI] [PubMed] [Google Scholar]
  47. Lee HH, Kim H, Lee JW, Kim YS, Yang HY, Chang HK, Kim CJ. Maternal swimming during pregnancy enhances short-term memory and neurogenesis in the hippocampus of rat pups. Brain Dev. 2006;28(3):147–154. doi: 10.1016/j.braindev.2005.05.007. [DOI] [PubMed] [Google Scholar]
  48. Levine S. Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology. 2005;30(10):939–946. doi: 10.1016/j.psyneuen.2005.03.013. [DOI] [PubMed] [Google Scholar]
  49. Lin TW, Chen SJ, Huang TY, Chang CY, Chuang JI, Wu FS, Jen CJ. Different types of exercise induce differential effects on neuronal adaptations and memory performance. Neurobiol Learn Mem. 2012;97(1):140–147. doi: 10.1016/j.nlm.2011.10.006. [DOI] [PubMed] [Google Scholar]
  50. Liu YF, Chen HI, Wu CL, Kuo YM, Yu L, Huang AM, Jen CJ. Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol. 2009;587(13):3221–3231. doi: 10.1113/jphysiol.2009.173088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Lou SJ, Liu JY, Chang H, Chen PJ. Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res. 2008;1210:48–55. doi: 10.1016/j.brainres.2008.02.080. [DOI] [PubMed] [Google Scholar]
  52. Marco EM, Adriani W, Llorente R, Laviola G, Viveros MP. Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure. Neurosci Biobehav R. 2009;33(4):498–507. doi: 10.1016/j.neubiorev.2008.03.008. [DOI] [PubMed] [Google Scholar]
  53. Moffett MC, Vicentic A, Kozel M, Plotsky P, Francis DD, Kuhar MJ. Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmcol. 2007;73(3):321–330. doi: 10.1016/j.bcp.2006.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet. 1999;23(3):314–318. doi: 10.1038/15490. [DOI] [PubMed] [Google Scholar]
  55. Neeper SA, Gómez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 1996;726(1):49–56. [PubMed] [Google Scholar]
  56. Nishio H, Kasuga S, Ushijima M, Harada Y. Prenatal stress and postnatal development of neonatal rats—sex-dependent effects on emotional behavior and learning ability of neonatal rats. Int J Dev Neurosci. 2001;19(1):37–45. doi: 10.1016/s0736-5748(00)00070-8. [DOI] [PubMed] [Google Scholar]
  57. Nitert MD, Dayeh T, Volkov P, Elgzyri T, Hall E, Nilsson E, Ling C. Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes. 2012;61(12):3322–3332. doi: 10.2337/db11-1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Parnpiansil P, Jutapakdeegul N, Chentanez T, Kotchabhakdi N. Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup. Neurosci Lett. 2003;352(1):45–48. doi: 10.1016/j.neulet.2003.08.023. [DOI] [PubMed] [Google Scholar]
  59. Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM, Corbett D. Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia. Neuroscience. 2005;136(4):991–1001. doi: 10.1016/j.neuroscience.2005.08.037. [DOI] [PubMed] [Google Scholar]
  60. Ploughman M, Granter-Button S, Chernenko G, Attwood Z, Tucker BA, Mearow KM, Corbett D. Exercise intensity influences the temporal profile of growth factors involved in neuronal plasticity following focal ischemia. Brain Res. 2007;1150:207–216. doi: 10.1016/j.brainres.2007.02.065. [DOI] [PubMed] [Google Scholar]
  61. Rice D, Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–533. doi: 10.1289/ehp.00108s3511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Robinson AM, Bucci DJ. Physical exercise during pregnancy improves object recognition memory in adult offspring. Neuroscience. 2014;256:53–60. doi: 10.1016/j.neuroscience.2013.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Rosenzweig MR, Bennett EL. Psychobiology of plasticity: effects of training and experience on brain and behavior. Behav Brain Res. 1996;78(1):57–65. doi: 10.1016/0166-4328(95)00216-2. [DOI] [PubMed] [Google Scholar]
  64. Sandi C, Loscertales M, Guaza C. Experience-dependent Facilitating Effect of Corticosterone on Spatial Memory Formation in the Water Maze. Eur J Neurosci. 1997;9(4):637–642. doi: 10.1111/j.1460-9568.1997.tb01412.x. [DOI] [PubMed] [Google Scholar]
  65. Seoane A, Tinsley CJ, Brown MW. Interfering with Fos expression in rat perirhinal cortex impairs recognition memory. Hippocampus. 2012;22(11):2101–2113. doi: 10.1002/hipo.22028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Smith JW, Seckl JR, Evans AT, Costall B, Smythe JW. Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats. Psychoneuroendocrinology. 2004;29(2):227–244. doi: 10.1016/s0306-4530(03)00025-8. [DOI] [PubMed] [Google Scholar]
  67. Hosseini-Sharifabad M, Hadinedoushan H. Prenatal stress induces learning deficits and is associated with a decrease in granules and CA3 cell dendritic tree size in rat hippocampus. Anat Sci Int. 2007;82(4):211–217. doi: 10.1111/j.1447-073X.2007.00186.x. [DOI] [PubMed] [Google Scholar]
  68. Titterness AK, Wiebe E, Kwasnica A, Keyes G, Christie BR. Voluntary exercise does not enhance long-term potentiation in the adolescent female dentate gyrus. Neuroscience. 2011;183:25–31. doi: 10.1016/j.neuroscience.2011.03.050. [DOI] [PubMed] [Google Scholar]
  69. Van Hoomissen JD, Holmes PV, Zellner AS, Poudevigne A, Dishman RK. Effects of β-Adrenoreceptor Blockade During Chronic Exercise on Contextual Fear Conditioning and mRNA for Galanin and Brain-Derived Neurotrophic Factor. Behav Neurosci. 2004;118(6):1378–1390. doi: 10.1037/0735-7044.118.6.1378. [DOI] [PubMed] [Google Scholar]
  70. Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience. 2003;122(3):647–657. doi: 10.1016/j.neuroscience.2003.08.001. [DOI] [PubMed] [Google Scholar]
  71. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20(10):2580–2590. doi: 10.1111/j.1460-9568.2004.03720.x. [DOI] [PubMed] [Google Scholar]
  72. Wan H, Aggleton JP, Brown MW. Different contributions of the hippocampus and perirhinal cortex to recognition memory. J Neurosci. 1999;19(3):1142–1148. doi: 10.1523/JNEUROSCI.19-03-01142.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Wan H, Warburton EC, Zhu XO, Koder TJ, Park Y, Aggleton JP, Brown MW. Benzodiazepine impairment of perirhinal cortical plasticity and recognition memory. Eur J Neurosci. 2004;20(8):2214–2224. doi: 10.1111/j.1460-9568.2004.03688.x. [DOI] [PubMed] [Google Scholar]
  74. Warburton EC, Glover CP, Massey PV, Wan H, Johnson B, Bienemann A, Brown MW. cAMP responsive element-binding protein phosphorylation is necessary for perirhinal long-term potentiation and recognition memory. J Neurosci. 2005;25(27):6296–6303. doi: 10.1523/JNEUROSCI.0506-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Warburton E, Brown MW. Findings from animals concerning when interactions between perirhinal cortex, hippocampus and medial prefrontal cortex are necessary for recognition memory. Neuropsychologia. 2010;48(8):2262–2272. doi: 10.1016/j.neuropsychologia.2009.12.022. [DOI] [PubMed] [Google Scholar]
  76. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Meaney MJ. Epigenetic programming by maternal behavior. Nature neurosci. 2004;7(8):847–854. doi: 10.1038/nn1276. [DOI] [PubMed] [Google Scholar]
  77. Weinstock M. The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav Immun. 2005;19(4):296–308. doi: 10.1016/j.bbi.2004.09.006. [DOI] [PubMed] [Google Scholar]
  78. Wolff GL, Kodell RL, Moore SR, Cooney CA. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998;12(11):949–957. [PubMed] [Google Scholar]
  79. Zhu XO, Brown MW, McCabe BJ, Aggleton JP. Effects of the novelty or familiarity of visual stimuli on the expression of the immediate early gene c-fos in rat brain. Neurosci. 1995;69(3):821–829. doi: 10.1016/0306-4522(95)00320-i. [DOI] [PubMed] [Google Scholar]
  80. Zhu XO, McCabe BJ, Aggleton JP, Brown MW. Mapping visual recognition memory through expression of the immediate early gene c-fos. Neuroreport. 1996;7(11):1871–1875. doi: 10.1097/00001756-199607290-00037. [DOI] [PubMed] [Google Scholar]

RESOURCES