Spatial abilities allow animals to retain and cognitively manipulate information about their spatial environment and are dependent upon neural structures that mature during adolescence. Exposure to stress in adolescence is thought to disrupt neural maturation, possibly compromising cognitive processes later in life. We examined whether exposure to chronic unpredictable stress in adolescence affects spatial ability in late adulthood. We evaluated spatial learning, reference and working memory, as well as long-term retention of visuospatial cues using a radial arm water maze. We found that stress in adolescence decreased the rate of improvement in spatial learning in adulthood. However, we found no overall performance impairments in adult reference memory, working memory, or retention caused by adolescent-stress. Together, these findings suggest that adolescent-stress may alter the strategy used to solve spatial challenges, resulting in performance that is more consistent but is not refined by incorporating available spatial information. Interestingly, we also found that adolescent-stressed rats showed a shorter latency to begin the water maze task when re-exposed to the maze after an overnight delay compared with control rats. This suggests that adolescent exposure to reoccurring stressors may prepare animals for subsequent reoccurring challenges. Overall, our results show that stress in adolescence does not affect all cognitive processes, but may affect cognition in a context-dependent manner.
Citation: Chaby LE, Sheriff MJ, Hirrlinger AM, Lim J, Fetherston TB, Braithwaite VA (2015) Does Chronic Unpredictable Stress during Adolescence Affect Spatial Cognition in Adulthood? PLoS ONE 10(11): e0141908. https://doi.org/10.1371/journal.pone.0141908
Editor: Alexandra Kavushansky, Technion - Israel Institute of Technology, ISRAEL
Received: June 29, 2015; Accepted: September 22, 2015; Published: November 18, 2015
Copyright: © 2015 Chaby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: Data are available from Research Gate, the link is www.researchgate.net/publication/283296175_Water_maze_data and the DOI is 10.13140/RG.2.1.1065.6720.
Funding: This work was supported by Pennsylvania Department of Health Tobacco Cure (2013), Project 23 (http://www.portal.state.pa.us/portal/server.pt/community/health_research_program_cure/14189); Penn State's Huck Institute of the Life Sciences (https://www.huck.psu.edu/); Penn State's Eberly College of Science (http://science.psu.edu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
- -. Rats were reared with or without chronic unpredictable stress in adolescence.
- -. In adulthood, spatial cognitive abilities were tested in a radial arm water maze.
- -. Prior-stressed rats began searching faster in the maze after an overnight delay.
- -. Prior stress may facilitate faster action in challenging situations.
- -. Prior stress did not affect learning, reference or working memory, or retention.
Spatial cognition can increase foraging efficiency, enhance the ability to locate mates, improve parental care, help animals minimize their exposure to danger, and, in humans, predict life outcomes , , , . Spatial ability is the set of cognitive processes that allow an individual to recall and manipulate information about spatial objects in their environment, and includes many distinct cognitive processes including learning, memory, and problem solving using spatial information , . In humans, spatial ability can predict educational-vocational track ; adolescents with poor spatial ability show reduced learning  and are less likely to obtain a career in science, engineering, technology, or math . The cues or types of spatial abilities animals rely on can be shaped by their environment ,  and harsh environments or seasonal changes can modulate spatial abilities and their underlying neural physiology , . Over time, exposure to a stressful environment can impair spatial learning and memory ,  and affect place-object memory and object recognition . Stress exposure can alter spatial ability both at the time of exposure and long after the stressful stimulus has been removed, however, the characteristics of these effects can vary across an individual’s lifespan , . Understanding the nature of these processes could inform us about the functionality of such changes within an ecological context, as well as shedding light on life outcomes in human populations.
The effects of exposure to stress on spatial ability appear to be dependent upon age at exposure , ; spatial abilities can be impaired by exposure to stress during prenatal development ,  or in the first few weeks of postnatal life . It has been suggested that exposure to stress in early life may decrease reliance on spatial learning and enhance emotional learning to prepare developing individuals for an uncertain or high-stress environment later in life . Adolescence may also be a period of vulnerability to stress-induced changes in spatial abilities sensu , . McCormick et al.  showed that adult Long-Evans rats exposed to chronic social stress during adolescence spend less time investigating a familiar object if it is moved to a new location compared with unstressed rats, indicating reduced hippocampal-dependent object memory. Similarly, compared with unstressed conspecifics, mice exposed to social instability stress in adolescence spend less time exploring a novel arm of a familiar maze when tested 12 months after chronic stress exposure has ceased, suggesting possible decreases in hippocampal-dependent spatial memory . Sterlemann et al.  also showed that chronic adolescent-stress can cause an impairment in spatial learning that is apparent only after a delay; mice exposed to social instability stress in adolescence took longer to find an escape platform in a Morris water maze in the last 5 of 12 trials, but showed no difference in earlier trials or in a hippocampus-independent learning task.
Despite the clear ramifications of experiencing stress during adolescence , its long-term effects on spatial ability are underexplored and the specific cognitive processes that are affected remain unclear. Differences in spatial ability could be driven by changes in spatial-reference memory, spatial-working memory, or long-term retention of spatial cues. Investigating which processes are affected could inform how deficits in spatial ability may affect other behavioral domains (e.g. foraging, mate location, etc.) and which aspects of cognition may be most vulnerable to lasting changes caused by exposure to stress. For example, deficits caused by adolescent-stress in learning and object memory have only been detected after a time delay , ,  and so may be commonly mediated by impaired retention (reference memory).
Here we tested the hypothesis that rats exposed to chronic adolescent-stress would exhibit deficits in spatial abilities that would be mediated by a subset of cognitive processes, including differences in retention. Specifically, we evaluated several aspects of spatial ability: spatial learning, reference and working memory, and long-term retention of visuospatial cues in a radial arm water maze (RAWM; , ), in rats that experienced chronic stress during adolescence and rats reared in unstressed conditions.
Animals and housing
Male Sprague-Dawley rats (n = 24) were obtained at 21 days of age from Harlan Laboratory in Frederick, Maryland. Following transport, rats were given 7 days to acclimate before handling and experimental procedures began (see Fig 1 for timeline). Animals were randomly assigned to pair-housing in plastic cages (20cm x 26cm x 45cm) with wood chip bedding, two pine wood chews, and two 7.6cm diameter PVC tubes. Cages were changed weekly; wood chews and PVC tubes were replaced when visibly soiled. Standard rat chow (LabDiet® 5001, 23% protein) and tap water were available ad libitum unless otherwise noted. Rats were kept at 20–21°C and 40–45% relative humidity on a 12:12 reversed light/dark cycle; the dark phase was 0900h-2100h. To control for circadian rhythms, all testing began a minimum of 2 hours after the beginning of the dark phase and was completed within 8 hours. Testing order was pseudo-randomized; the order in which individual rats were tested varied each day with treatment groups balanced across the first and last hours of the testing session. Body mass was monitored weekly as an indicator of health throughout adolescence and testing in adulthood. Experiments were approved by the Pennsylvania State University Institutional Animal Care and Use Committee (IACUC), protocol #44459.
Chronic unpredictable stress
Pair-housed rats were randomly assigned to either the adolescent-stress treatment (n = 12) or to the unstressed control group (n = 12). Rats in the adolescent-stress treatment were exposed to physical, social, and predation stressors from 30–70 days of age , . Though some suggest that adolescence concludes at approximately 55 days of age in male rodents, many studies have included a postpubertal “sub-adult” period to cover the entire ontogenetic window of adolescence, 28–80 days of age , , . Adolescent exposure to the chronic unpredictable stress paradigm used here has previously been shown to induce behavioral and cognitive changes in adulthood that correspond to the current age at testing , .
- Physical stressors: (1) Housed in a cage 25% smaller than the home cage for 4 hours, (2) housed with damp bedding for 6 hours, (3) home cage tilted 30° for 6 hours.
- Social stressors: (1) Housed individually for 1 hour, (2) crowding with 2 rat pairs in a standard cage for 4 hours, (3) exposed to bedding from older conspecifics for 12 hours.
- Predation stressors: Exposed for 30 minutes to (1) a continuously moving taxidermied bobcat , (2) Felis catus fur, (3) large cat vocalizations.
Each of the three types of stress were represented twice per week, leaving one rest day. Stressors were presented unpredictably during both phases of the light/dark cycle, but balanced such that within each week rats encountered approximately three stressors between 0–1200h and three stressors between 1200h-2400h. To account for the additional handling and cage changes required to enact the stressors, rats in the control group experienced biweekly handling sessions and cage changes that coincided with stressors requiring new cages. During stress treatments rats were continuously pair-housed unless specified.
Radial arm water maze
Starting 10.5 months after completion of the stress paradigm, rats were tested in a six-arm radial water maze surrounded by an opaque white plastic curtain (Fig 2). Visual cues were attached to the curtain in each cardinal compass direction. The experimenter remained in the same position throughout testing to maintain consistency in visual cues . The water was constantly monitored and maintained between 24–25°C at a depth of 43cm . The water was made opaque using non-toxic Tempera paint .
Goal arm was counterbalanced across treatment condition. For each rat, the goal arm remained the same throughout all trials, but the starting arm was randomized so that rats had to learn a spatial location, and could not rely on a motor rule.
After every exposure to the water maze, rats were briefly towel-dried and transferred to a holding cage that contained a heating pad under dry towels. A heating lamp warmed one side of the holding cage, allowing the rat an option to escape the heat. Rats remained in the holding cage until dry and behaving normally (at least 10–15 minutes). Rats were observed daily following exposure to the water maze; no signs of dehydration, abnormal vocalizations, decreased weight or appetite, postural abnormalities, or labored respiration were detected. Between each trial, any fecal matter was removed from the water with a dip net. During each day of trials, partial water changes were used to maintain cleanliness of the maze. At the end of each day of trials, the maze was drained, wiped clean, and dried thoroughly.
We tested each rat’s ability to associate a maze arm with a platform that allowed them to exit the water (procedures are modeled on ). Each rat was tested on two sequential days, with 15 trials per day, between 387 to 400 days of age. To avoid fatigue from consecutive trials, the training schedule was spaced by grouping rats into two waves that were tested on alternating days (balanced by treatment), by allowing rats to fully recover between trials, and by limiting an individual rat’s testing time to 3 hours per day . The arm containing the platform (the goal arm) remained the same for each rat and was counterbalanced across stress condition. For the initial phase of the water maze, the trials alternated such that the platform was either “invisible” just below the surface of the opaque water or “visible” 2cm above the surface; the first trial of each day was always “visible” in order to facilitate learning of the platform location . After the second training day, the platform was “invisible” in all subsequent exposures to the maze. To begin each trial, a rat was placed at the end of an arm that did not contain the platform. The starting arm was randomized so that rats had to learn the spatial location of the platform and could not rely on a motor rule, e.g. first turn to the left. During the first exposure to the maze, if the rat had not located the platform 1 minute after entering the water, or after 2 minutes on all subsequent learning trials, a hand was placed behind the rat to guide it through the water in the direction of the platform. After the rat was guided to or located the platform, it was removed from the maze after all four feet of the rat were on the platform for 15 seconds. For the reference and working memory trials, if a rat had not located the platform within 2 minutes it would be removed, however, no rat failed to locate the platform within 2 minutes.
To assess spatial ability, we measured the latency to find the platform (contact the platform with a paw or nose), search time (latency to find the platform–latency to first arm entry), and the number of arm entries. An arm entry was defined as having all four paws within a maze arm. We quantified reference memory errors (entering an arm other than the goal arm) and working memory errors (any subsequent re-entries into an arm other than the goal arm; , ). Spatial learning, and reference and working memory, were assessed by comparing improvement in these measures across the 30 trials.
Retention of the location of the platform was tested 3 days after the spatial learning trials , . To test retention, rats underwent a single trial identical to the spatial learning trials with the platform “invisible” just below the surface of the water such that rats had to recall the location from memory. For the retention trials, if a rat had not located the platform within 2 minutes it would be removed, however, no rat failed to locate the platform within 2 minutes.
Latency to enter an arm, latency to locate the platform, search time, number of arm entries, and number of reference and working memory errors were natural log transformed to achieve normality. Three-trial means were calculated for all measures to reduce noise . Learning and memory data were tested using repeated measures analyses of variance (RMANOVA) with stress treatment and time (three-trial means) as fixed effects. To determine whether adolescent-stress affected change across the spatial ability test, we calculated difference scores by subtracting the last three-trial mean from the first three-trial mean. Difference scores were compared using two-tailed t-tests. Retention was tested using t-tests to compare adolescent-stressed and unstressed rat performance. Two rats in the adolescent-stress treatment developed ulcerated tumors; they were removed from testing and are not included in any analyses. Analyses were run using IBM® SPSS® Statistics Version 21; values are reported as means ± standard error.
Exposure to stress during adolescence had no main effect on spatial abilities, including learning, working memory, and reference memory (Table 1, Fig 3). However, we found that unstressed rats reduced their number of arm entries more over time compared with adolescent-stressed rats, suggesting that adolescent-stressed rats were not improving their performance by incorporating spatial information with additional exposure to the task (Fig 3). Similarly, when we compared behaviors during the first block of spatial learning trials with behaviors during the last trial block, we found that adolescent-stressed animals showed a smaller change, compared with unstressed rats, in the number arm entries (23% vs. unstressed: 53%) and reference memory errors (31% vs. unstressed: 55%). This indicates that compared with unstressed rats, adolescent-stressed rats showed less improvement in their spatial learning performance over time, and did not refine their performance when given the opportunity to acquire additional information about their environment while unstressed rats did (Table 2). Thus, despite our findings that adolescent environment does not affect outcomes in spatial learning (or working and reference memory), it would appear that the rate of change in spatial learning performance may be modulated by developmental experiences such that adolescent-stress causes less flexibility in performance. Adolescent-stressed rats also exhibited a decreased latency to begin searching for a platform in the water maze task when returned to the maze after an overnight delay on the second day of trials compared with unstressed rats, suggesting that exposure to chronic stress in adolescence allowed the animals to react to subsequent reoccurring challenges more quickly (Fig 4).
The effects of adolescent-stress on latency to locate the platform (A), arm entries (B), reference memory (C), and working memory (D), means ± SE. *Indicates a significant time effect across all trials. **Indicates significant time and stress x time effects across all trials.
Retention of a platform location in a water maze 3 days after spatial association training was assessed using latency to locate the platform (A) and total number of arm entries before finding the platform (B), means ± SE.
Spatial abilities are dependent upon neural structures that mature during adolescence , . Exposure to chronic stress in adolescence is thought to disrupt the maturation of these structures, possibly compromising their function later in life , . In the current study, we tested the hypothesis that chronic stress in adolescence would impair adult spatial abilities and we found little support for our hypothesis. We show that adolescent-stress exposure had little effect on spatial learning, and found no evidence of impairments in spatial working memory, reference memory, or retention in adulthood. Conversely, we found that unstressed rats show greater improvement in spatial learning performance; over time they decrease the number of arms entered before finding the escape platform compared with adolescent-stressed rats. This suggests that adolescent-stressed rats do not improve their performance by incorporating spatial information with additional exposure to the task. Similarly, compared with unstressed rats, adolescent-stressed rats showed a smaller change in spatial learning measures; both in arms entered (23% vs. unstressed: 53%) and reference memory errors (31% vs. unstressed: 55%), suggesting that unstressed rats improved their performance over time, likely by acquiring spatial information, while adolescent-stressed rats chose a strategy that was not affected by additional information about their environment (Table 2). Interestingly, these differences in the degree of change in spatial learning measures did not affect overall performance between the treatments; possibly reflecting a change in strategy by adolescent stressed rats that results in fairly consistent performance over time compared to unstressed rats. Adolescent-stressed rats also exhibited a shorter latency to begin searching for a platform in the water maze task following an overnight delay compared with unstressed rats, suggesting that exposure to chronic stress in adolescence allowed animals to react to subsequent reoccurring challenges more quickly (Fig 4). Our results were unexpected because exposure to social instability, a chronic stress treatment, during adolescence has previously been shown to impair spatial learning  and spatial memory . The contrast between earlier observations and those reported here suggests that the effects of adolescent-stress may be context-specific, and highlights the difficulty of generalizing results across systems and environments , .
Differences between the RAWM and the open arena tests used in prior studies of adolescent-stress could facilitate the use of different strategies and contribute to differences between the current results and those reported in earlier studies (Morris water maze: , ; object memory tests: , ). One explanation for our findings may lie in the use of alternate strategies in the RAWM by adolescent-stressed rats. The RAWM provides more visual and local cues than open arena tests, which may allow rats to employ an ‘associative learning strategy’ and decrease the need for hippocampally dependent cognitive maps of the environment, thereby masking possible spatial deficits , , . Further, search strategies may differ between open arena tests and the more structured RAWM; in a RAWM, but not an open arena, it is possible to use a ‘working memory strategy’ by entering new arms until locating the platform, without re-entering previous arms . Such an approach would not require retention across trials, just a ‘list-like’ working memory of which arms had been visited within a trial . The current finding that unstressed rats show a greater decrease in errors related to reference memory compared with adolescent-stressed rats, but that stress condition does not affect changes in working memory (Table 2), allows for the possibility that adolescent-stressed rats used working memory to compensate for delays in reference memory, rather than a spatial learning strategy where a mental representation of the spatial environment is constructed and refined over time . A ‘working memory strategy’ would also not be affected by delays between trials, and could explain why the adolescent-stressed animals in the current study appeared to show a smaller change in performance between the last set of trials on the first day and the first set of trials on the second day (separated by an overnight delay), compared with unstressed animals.
A shift in strategy , the flexibility of a strategy, or the ability to abandon an inefficient strategy  can result from exposure to stress. In addition to our current results, we have previously shown that the adolescent-stress procedures used here can induce strategy shifts. In Chaby et al. , we demonstrated that adolescent-stressed rats exhibit the same foraging performance as unstressed rats under standard testing conditions, but adolescent-stress changes foraging behaviors (including the number of patches visited and the latency to visit a patch). This suggests that adolescent-stress induces a change in foraging strategy without altering performance outcome. Additionally, although adolescent-stress does not affect the rate of appetitive associative learning, adolescent-stressed rats show increased decision making speed during associative learning training, again indicating a potential strategy change . We suggest that these stress-induced strategy shifts could be adaptive in unpredictable or high threat contexts. If exposure to stress in adolescence signals that an animal should prepare for an environment where spatial cues will likely be unstable, or dangerous conditions where threat limits the amount of time an animal can spend acquiring spatial information, then it may be advantageous for adolescent-stressed animals to use spatial navigation strategies that enable rapid choices and do not rely on learning and environmental consistency . Adjusting spatial strategies in response to environmental conditions has previously been shown in a teleost fish; stickleback that occupy unstable river environments are less likely to use visual landmarks compared with fish from more stable pond environments .
We also found that adolescent-stressed rats responded more quickly than unstressed rats when re-exposed to the potentially stressful cold water in the RAWM by beginning to search for the escape platform faster after an overnight delay between trials, which may be indicative of preconditioning effects , . This finding also suggests that compared with unstressed rats, rats that experienced reoccurring challenges during the chronic adolescent-stress treatment may have a greater expectation of re-exposure to aversive stimuli that allows them to respond more quickly to reoccurring aversive conditions. An ability to engage in an aversive task more quickly could be beneficial in a context where faster action or escape would be advantageous. Given that chronic exposure to corticosteroids in adolescence can cause changes in impulsivity in adulthood, including increased impulsive choice and decreased impulsive action , it is also possible that changes in impulsivity may mediate changes in the latency to engage in the water maze task.
Overall, though we found little support of the hypothesis that chronic stress in adolescence impairs spatial ability in adulthood, the results indicate that adolescent-stress affects cognition in adulthood in a highly context-specific way. We suggest that exposure to adolescent-stress may cause a shift in strategy that affects behavior but results in equal performance, and increases reliance on working memory while decreasing the use of cognitive spatial maps. In an adverse environment where spatial cues are unstable or the presence of threat restricts the amount of time an animal can spend acquiring spatial information, it may be advantageous to reduce reliance on strategies that depend upon environmental consistency, like cognitive spatial maps, and instead favor strategies that allow rapid decision making. Our results emphasize the idea that stress in adolescence may have lasting effects on not only performance outcomes, but also on the strategies used to achieve potentially complex goals like navigating a spatial environment. Studies that further isolate different components of learning, such as place and spatial associative learning, would further refine these observations. Finally, our results suggest that experiencing reoccurring challenges during adolescence may allow animals to respond more quickly to subsequent reoccurring challenges, which could be valuable in a context where faster action would be advantageous.
We thank our funding sources, Pennsylvania State University’s Huck Institutes of the Life Sciences, Eberly College of Science, and the Pennsylvania Department of Health using Tobacco CURE Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. We also thank Erin Platz, Hannah Cooper, Rachel Reineke, Kendall Warg, Kaitlyn Grubb, and Carl Hirrlinger.
Conceived and designed the experiments: LEC AMH VAB. Performed the experiments: LEC AMH JL TBF. Analyzed the data: LEC JL. Contributed reagents/materials/analysis tools: VAB. Wrote the paper: LEC MJS VAB.
- 1. Gaulin SJC, Fitzgerald RW (1989) Sexual selection for spatial-learning ability. Anim Behav 37, Part 2: 322–331.
- 2. Benhamou S (1994) Spatial memory and searching efficiency. Anim Behav 47: 1423–1433.
- 3. Dukas R (1998) Cognitive Ecology: The Evolutionary Ecology of Information Processing and Decision Making. 1 edition. Chicago: University of Chicago Press.
- 4. Wai J, Lubinski D, Benbow CP (2009) Spatial ability for STEM domains: Aligning over 50 years of cumulative psychological knowledge solidifies its importance. J Educ Psychol 101: 817–835.
- 5. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Meth 11: 47–60.
- 6. Shea DL, Lubinski D, Benbow CP (2001) Importance of assessing spatial ability in intellectually talented young adolescents: A 20-year longitudinal study. J Educ Psychol 93: 604–14.
- 7. Lord TR (1990) Enhancing learning in the life sciences through spatial perception. Innovative Higher Ed 15: 5–16.
- 8. Garber PA, Paciulli LM (1997) Experimental field study of spatial memory and learning in wild capuchin monkeys (Cebus capucinus). Folia Primatol 68: 236–253. pmid:9360308
- 9. Odling-Smee L, Braithwaite VA (2003) The influence of habitat stability on landmark use during spatial learning in the three-spined stickleback. Anim Behav 65: 701–707.
- 10. Shettleworth SJ, Hampton RR, Westwood RP (1995) Effects of season and photoperiod on food storing by black-capped chickadees, Parus atricapillus. Anim Behav 49: 989–998.
- 11. Pravosudov VV, Clayton NS (2002) A test of the adaptive specialization hypothesis: Population differences in caching, memory, and the hippocampus in black-capped chickadees (Poecile atricapilla). Behav Neurosci 116: 515–522. pmid:12148919
- 12. Song L, Che W, Min-Wei W, Murakami Y, Matsumoto K (2006) Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Be 83: 186–193.
- 13. Radecki DT, Brown LM, Martinez J, Teyler TJ (2005) BDNF protects against stress-induced impairments in spatial learning and memory and LTP. Hippocampus 15: 246–253. pmid:15476265
- 14. Bowman RE, Beck KD, Luine VN (2003) Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm Behav 43: 48–59. pmid:12614634
- 15. Frisone DF, Frye CA, Zimmerberg B (2002) Social isolation stress during the third week of life has age-dependent effects on spatial learning in rats. Behav Brain Res 128: 153–160. pmid:11796160
- 16. Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EMM, et al. (2010) Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci 30: 6635–6645. pmid:20463226
- 17. Frankenhuis WE, de Weerth C. (2013) Does early-life exposure to stress shape or impair cognition? Curr Dir Psychol Sci 22: 407–412.
- 18. Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ (1995) Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci 15: 61–69. pmid:7823152
- 19. Lemaire V, Koehl M, Moal ML, Abrous DN (2000) Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci U S A 97: 11032–11037. pmid:11005874
- 20. Yang J, Han H, Cao J, Li L, Xu L (2006) Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring. Hippocampus 16: 431–436. pmid:16598704
- 21. Romeo RD (2015) Perspectives on stress resilience and adolescent neurobehavioral function. Neurobiol Stress 1: 128–133.
- 22. Romeo RD (2013) The teenage brain: The stress response and the adolescent brain. Curr Dir Psychol Sci 22: 140–145. pmid:25541572
- 23. McCormick CM, Thomas CM, Sheridan CS, Nixon F, Flynn JA, Mathews IZ (2012) Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus 22: 1300–1312. pmid:21805526
- 24. Sterlemann V, Rammes G, Wolf M, Liebl C, Ganea K, Müller MB, et al. (2010) Chronic social stress during adolescence induces cognitive impairment in aged mice. Hippocampus 20: 540–549. pmid:19489003
- 25. McCormick CM, Mathews IZ, Thomas C, Waters P (2010) Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models. Brain Cogn 72: 73–85. pmid:19616355
- 26. Diamond DM, Park CR, Heman KL, Rose GM (1999) Exposing rats to a predator impairs spatial working memory in the radial arm water maze. Hippocampus 9: 542–552. pmid:10560925
- 27. Alamed J, Wilcock DM, Diamond DM, Gordon MN, Morgan D (2006) Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice. Nat Protoc 1: 1671–1679. pmid:17487150
- 28. Chaby LE, Cavigelli SA, Hirrlinger AM, Caruso MJ, Braithwaite VA (2014) Chronic unpredictable stress during adolescence causes long-term anxiety. Behav Brain Res 278: 492–495. pmid:25448433
- 29. Chaby LE, Sheriff MJ, Hirrlinger AM, Braithwaite VA (2015) Does early stress prepare individuals for a stressful future? Stress during adolescence improves foraging under threat. Anim Behav 105: 37–45.
- 30. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav R 24: 417–463.
- 31. Schmidt MV, Sterlemann V, Ganea K, Liebl C, Alam S, Harbich D, et al. (2007) Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinol 32: 417–429.
- 32. Blumstein DT, Daniel JC, Springett BP (2004) A test of the multi-predator hypothesis: Rapid loss of antipredator behavior after 130 years of isolation. Ethology 110: 919–934.
- 33. Hodges H, Sowinski P, Sinden JD, Fletcher A, Netto CA (1995) The selective 5-HT3 receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system. Psychopharmacology 117: 318–332. pmid:7770608
- 34. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1: 848–858. pmid:17406317
- 35. Jarrard LE (1993) On the role of the hippocampus in learning and memory in the rat. Behav Neural Biol 60: 9–26. pmid:8216164
- 36. McCracken CB, Grace AA (2013) Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. J Neurosci 33: 17469–17482. pmid:24174680
- 37. Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD, et al. (2006) Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16: 571–576. pmid:16741974
- 38. Isgor C, Kabbaj M, Akil H, Watson SJ (2004) Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 14: 636–648. pmid:15301440
- 39. Sheriff MJ, Love OP (2013) Determining the adaptive potential of maternal stress. Ecol Lett 16: 271–280. pmid:23205937
- 40. Han X, Wang W, Xue X, Shao F, Li N (2011) Brief social isolation in early adolescence affects reversal learning and forebrain BDNF expression in adult rats. Brain Res Bull 86: 173–178. pmid:21801814
- 41. Brown MF, Rish PA, VonCulin JE, Edberg JA (1993) Spatial guidance of choice behavior in the radial-arm maze. J Exp Psychol Anim B 19: 195–214.
- 42. Brown MF (1992). Does a cognitive map guide choices in the radial-arm maze? J Exp Psychol Anim B 18: 56–66.
- 43. Rosenzweig ES, Redish AD, McNaughton BL, Barnes CA (2003) Hippocampal map realignment and spatial learning. Nat Neurosci 6: 609–615. pmid:12717437
- 44. Olton DS, Becker JT, Handelmann GE (1980) Hippocampal function: Working memory or cognitive mapping? Psychobiology 8: 239–246.
- 45. Knierim JJ (2015) From the GPS to HM: Place cells, grid cells, and memory. Hippocampus 25: 719–725. pmid:25788454
- 46. Beilock SL, DeCaro MS (2007) From poor performance to success under stress: Working memory, strategy selection, and mathematical problem solving under pressure. J Exp Psychol Learn 33: 983–998.
- 47. Carr PB, Steele CM (2009) Stereotype threat and inflexible perseverance in problem solving. J Exp Soc Psychol 45: 853–859.
- 48. Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, et al. (2007) Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose–response framework. Toxicol Appl Pharm 222: 122–128.
- 49. Calabrese EJ (2008) Neuroscience and hormesis: Overview and general findings. Crit Rev Toxicol 38: 249–252. pmid:18432418
- 50. Torregrossa MM, Xie M, Taylor JR (2012) Chronic corticosterone exposure during adolescence reduces impulsive action but increases impulsive choice and sensitivity to yohimbine in male Sprague-Dawley rats. Neuropsychopharmacology 37: 1656–1670. pmid:22334120