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. Author manuscript; available in PMC: 2019 Aug 1.
Published in final edited form as: Behav Neurosci. 2018 Jul 5;132(4):240–246. doi: 10.1037/bne0000247

Chronic nicotine exposure in pre-adolescence enhances later spontaneous recovery of fear memory

Dana Zeid 1, Thomas J Gould 1,*
PMCID: PMC6095659  NIHMSID: NIHMS960690  PMID: 29975080

Abstract

Pre-adolescent mice have been shown to be differentially susceptible to the effects of both acute and chronic nicotine exposure on contextual fear learning relative to adults. For this study, we tested the effects of chronic nicotine exposure in pre-adolescence on adulthood extinction and spontaneous recovery of fear memory in a model in which contextual fear acquisition occurred prior to nicotine exposure. Pre-adolescent (PND 23) and adult (PND 53) male C57BL/6J mice underwent contextual fear conditioning and were then exposed to chronic nicotine at 12.6mg/kg/day for 12 days via osmotic minipump. Eighteen days following the removal of nicotine, both groups of mice underwent fear extinction, followed by a spontaneous recovery session a week later. History of chronic nicotine did not affect later extinction of fear memory adult-trained mice, while adolescent-trained mice exhibited a global impairment in retention of fear memory that precluded detection of effects of early nicotine on later fear extinction. However, it was found that adult spontaneous recovery of fear memory was impaired in mice exposed to nicotine as adults and enhanced in mice exposed to nicotine as pre-adolescents. These results may indicate greater vulnerability to recurrence of traumatic memory as well as compromised inhibitory control in young smokers.

Keywords: nicotine, adolescence, learning, extinction, spontaneous recovery

Introduction

The processing and retention of fear memory is a coordinated act that involves the contribution of multiple, distinct domains, each of which follows a different developmental trajectory. It has been shown that conditioned fear acquisition, extinction, and spontaneous recovery each involve distinct neural substrates (Huang, Shyu, Hsiao, Chen, & He, 2013; Milad & Quirk, 2002; Rogan, Stäubli, & LeDoux, 1997), which encompass brain regions whose functioning is dependent upon developmental stage (Baker, Den, Graham, & Richardson, 2014; Gogolla, Caroni, Lüthi, & Herry, 2009; Hartley & Lee, 2015). Nicotine exposure is known to modify fear learning at the level of acquisition, extinction, and spontaneous recovery (Gould & Wehner, 1999; Kutlu & Gould, 2014; Kutlu, Tumolo, Holliday, Garrett, & Gould, 2016), and its effects are additionally moderated by age (Kutlu, Zeid, Tumolo, & Gould, 2017; Portugal, Wilkinson, Turner, Blendy, & Gould, 2012).

Fear extinction is a process whereby fear response diminishes following continued non-reinforced exposure to a previously fear-eliciting stimulus, and acute nicotine exposure has been found to impair extinction in adult mice, while pre-adolescent and adolescent mice appear to be protected from this impairment (Kutlu et al., 2017). Pre-adolescents and adolescents are additionally protected from acute nicotine’s enhancement of spontaneous recovery, a phenomenon in which a previously extinguished fear response re-appears following a delay (Kutlu et al., 2017). However, few studies have investigated the effects of history of chronic nicotine exposure on later extinction and spontaneous recovery of fear memory, and none to our knowledge have compared its effects in adolescents and adults.

We have previously shown that extinction occurring either during the administration of chronic nicotine or in the withdrawal period is impaired (Kutlu, Oliver, Huang, Liu-Chen, & Gould, 2016), although this finding does not directly address the question of whether a history of chronic nicotine exposure affects later extinction of fear memory. Tian and colleagues (2008) found that chronic intermittent nicotine injections impaired later cued fear extinction and enhanced contextual fear extinction in adult rats, although fear acquisition occurred following chronic nicotine in this particular model. Indeed, the fact that chronic nicotine additionally modifies initial acquisition of fear memory makes the isolation of its effects on extinction and spontaneous recovery challenging. All previous work in this area has studied extinction and spontaneous recovery when the initial fear acquisition occurred during or after chronic nicotine exposure. We attempted to surmount this challenge by utilizing a unique model of chronic nicotine exposure in pre-adolescence, for which chronic nicotine exposure occurred following fear acquisition, and extinction and spontaneous recovery occurred later in life.

This design may speak to adolescents’ unique vulnerability to or protection against the potential effects of past use of nicotine on extinction and spontaneous recovery of early fear memory. Following reports that chronic nicotine exposure in early adolescence, but not in adulthood, impairs later contextual fear acquisition (Holliday et al., 2016; Portugal et al., 2012), we hypothesized that pre-adolescent mice would be uniquely vulnerable to the effects of chronic nicotine on later extinction and spontaneous recovery of a fear memory acquired prior to the exposure, as compared to adults.

Methods

Subjects

Subjects were pre-adolescent (PND 23 at day 1 of fear conditioning) and adult (PND 53 at day 1 of fear conditioning) male C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME). In mice, biological and behavioral development (i.e. puberty, increased impulsivity, social maturation) analogous to the adolescent period in humans has been identified between postnatal days 28–40 (Hefner & Holmes, 2007; Keene et al., 2002; Terranova, Laviola, De Acetis, & Alleva, 1998). Pre-adolescence, the period just prior to adolescence, has been defined as PND 23 in C57BL/6J mice. Previous work has shown that pre-adolescent mice exhibit distinct behavioral and biological responses to nicotine relative to their adolescent (PND 38) counterparts (Kutlu et al., 2017; Portugal et al., 2012). Animals were group-housed and maintained at a 12h light/dark cycle (lights on at 7:00am and lights off at 7:00pm). Ad libitum access to food and water was provided. All behavioral procedures occurred between 8:00 am and 7:00 pm. All behavioral procedures were approved by the Pennsylvania State University Institutional Animal Care and Use Committee.

Drug administration

Nicotine hydrogen tartrate salt (12.6mg/kg/day freebase, Sigma, St. Louis, MO) dissolved in 0.9% saline was administered subcutaneously through osmotic mini-pumps (Alzet, Model 1002, Durect, Cupertino, CA). Pre-adolescent conditioned mice were PND 25 and adult conditioned mice were PND 55 at the time of surgery. Mini-pumps were surgically implanted through an incision on the upper back of the mouse while mice were under 2–5% isoflurane anesthetic. Control mice received a mini-pump containing only saline. Surgeries were performed under aseptic conditions. Nicotine dosage was chosen based on the previous findings showing deficits in contextual fear learning during extinction testing at this dose (Kutlu et al., 2016).

Apparatus

Behavioral experiments took place in four identical chambers (18.8 × 20 × 18.3 cm) placed in sound attenuating boxes (Med Associates, Fairfax, VT). Ventilation fans mounted in the backs of the chambers produced a background noise (65 dB), and a mounted speaker provided the 30-s white noise (85 dB) that served as a conditioned stimulus (CS). Chamber walls were composed of Plexiglas, and chamber floors were metal grids (0.20 cm in diameter and 1.0 cm apart) connected to a shock generator, which delivered a 2-s, 0.57-mA foot shock unconditioned stimulus (US). The stimuli were controlled by an IBM-PC compatible computer running Med-PC software.

Behavioral procedures and experimental design

Across behavioral sessions, the dependent variable was freezing, defined as absence of voluntary movement aside from respiration. Freezing behavior was live scored using a time sampling method, in which subjects were observed for 1 second every 10 seconds and scored as active or freezing. Experimenters were blind to drug conditions. Mice were first trained and tested in a contextual/cued fear conditioning paradigm with an auditory cue serving as the foreground stimulus and context serving as the background stimulus. Previous work has found no difference in the effects of nicotine on contextual fear conditioning with context as a background stimulus versus a foreground stimulus (André, Gulick, Portugal, & Gould, 2008; Davis, Porter, & Gould, 2006). On day 1 of contextual fear training, mice received two white noise-footshock pairings. Specifically, training sessions consisted of 2 minutes of free movement within the chamber to measure baseline freezing followed by 30 seconds of white noise. The 0.57 mA shocks were 2 seconds in length and co-terminated with white noise. Two minutes later, another 30 seconds of white noise with a co-terminating 2 second 0.57 mA shock occurred. Pre-adolescent mice were PND 23 and adult mice were PND 53 on training day.

24 hours later, mice were returned to the training context for retention testing to determine initial freezing to the context. For contextual freezing, mice were placed back in the training context for five minutes in the absence of foot-shocks, and conditioned freezing was measured. On day 3, 24 hours following contextual fear testing, all mice underwent mini-pump implantation surgery. Nicotine solution or saline was administered via osmotic mini-pump for 12 days, after which pumps were removed (on day 15). Pump removal was followed by a 17-day waiting period in order to allow pre-adolescent mice to mature and eliminate any potential effects of nicotine withdrawal. Contextual fear extinction began on day 33, when the pre-adolescent exposed group were PND 55 and the adult group were PND 85. Contextual fear extinction occurred over 5 days, and procedures were identical to contextual fear testing procedures (for 5 consecutive sessions, conditioned freezing was measured in training context for five minutes in the absence of foot-shocks). Spontaneous recovery of fear memory was measured 7 days following the final extinction session (on day 44, when the pre-adolescent group were PND 66 and the adult group were PND 96). The spontaneous recovery session was identical to the testing and extinction sessions (conditioned freezing measured over 5 minutes in absence of foot-shock). Sample sizes were 11–15 per group. See Figure 1 for a schematic representation of the experimental design.

Figure 1.

Figure 1

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Schematic representation of experimental design.

Statistical analysis

For adulthood extinction, a three-way repeated measures ANOVA (Age × Drug × Trial) was used to analyze freezing scores at α= 0.05, followed by Bonferroni-corrected t-tests to test freezing between pre-adolescent and adult conditioned mice during each extinction trial. A binned within-extinction trial data analysis was also performed for pre-adolescent conditioned mice. Data binning was achieved by dividing data points within extinction trials into three parts: first 100 seconds, second 100 seconds, and third 100 seconds. The first and third 100 second bins were compared in a three-way repeated measures ANOVA (Drug × Trial × Bin) in order to test within-trial extinction. Spontaneous recovery was analyzed with a two-way ANOVA (Age × Drug), followed by Bonferroni-corrected t-tests to compare the effect of history of chronic nicotine on spontaneous recovery of fear memory within age groups. Bonferroni-corrected t-tests were used to compare initial fear acquisition on test day in pre-adolescent and adult mice. Corrected degrees of freedom and t-values are reported for all t-tests in which Levene’s test for equality of variances indicated unequal variances between groups.

Results

Pre-adolescent mice show enhanced baseline fear acquisition

An initial independent samples t-test indicated that pre-adolescent mice exhibited enhanced contextual fear acquisition (Figure 2) relative to adults t(50) = 2.16, p<.05, which may be consistent with findings that pre-adolescent mice exhibit enhanced cued fear conditioning relative to adults (Hefner & Holmes, 2007), although this bias has not been consistently demonstrated for contextual fear acquisition in our previous findings (Kutlu et al., 2017).

Figure 2.

Figure 2

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Top panel PND23 percent freezing during test day, extinction, and spontaneous recovery trials; Bottom panel: PND53 percent freezing during test day, extinction, and spontaneous recovery trials. * denotes significance at p < .025

Chronic nicotine exposure in pre-adolescence and adulthood does not affect later extinction of fear memory

A three-way repeated measures ANOVA (Age × Drug × Trial) was used to compare the effects of history of chronic nicotine exposure in pre-adolescence vs. adulthood on later extinction of fear memory (Figure 2). The Age × Drug interaction was not significant F(1, 48) = 2.361, p = .131. No significant main effect of history of chronic nicotine on extinction was found, although the effect approached significance F(1, 48) = 3.210, p = .079. A main effect of age on extinction of fear memory was found F(1, 48) = 26.088, p < 0.001, with mice experiencing fear conditioning in pre-adolescence exhibiting lower overall freezing across extinction trials relative to mice experiencing fear conditioning in adulthood. A significant main effect of trial was found F(1, 192) = 9.458, p < 0.001, as well as a significant interaction between age and trial F(1, 192) = 3.569, p < 0.01. Follow-up, Bonferroni-corrected t-tests were performed to test freezing between pre-adolescent and adult- conditioned mice during each extinction trial. Adult mice exhibited higher freezing during trial one t(36.340) = 5.572, p<0.01, trial two t(50) = 4.918, p<0.01, and trial four t(32.177) = 5.251, p<0.01.

Pre-adolescent conditioned mice show significant within-extinction-trial freezing in adulthood

The above extinction data appear to indicate that, while a relatively normal decline of fear memory appeared to occur in mice that underwent fear conditioning at age PND 53, mice that were fear conditioned at age PND 23 exhibited an apparently impaired initial recall (extinction day 1) and subsequently attenuated extinction of fear memory 33 days later. Thus, we performed an additional analysis of binned, within-extinction trial data in order to examine whether pre-adolescent conditioned mice showed within-session extinction.

A three-way repeated measures ANOVA (Drug × Trial × Bin) found significant within-trial extinction in the pre-adolescent conditioned mice (F[1, 26] = 50.641, p < .001), indicating that some fear memory was retained from the original fear conditioning session, although it was much more quickly extinguished relative to the extinction of adult-conditioned mice and only detectable within trials (Figure 3). This is consistent with reports that early fear memories are more labile due to developing neural circuitry in the amygdala and hippocampus (Gogolla et al., 2009; Pattwell et al., 2012). The main effect of drug was not significant (F[1, 26] = .150, p = .702). Additionally, no significant interaction between drug and extinction day (F[4, 26] = 1.305, p = .273) or drug and bin (F[1, 26] = .813, p = .375) was found. Follow-up, Bonferroni corrected paired-samples t-tests indicated significant differences between Bin 1 and Bin 3 on extinction days 1, 2, and 3, but not on days 3, 4, and 5 (Figure 3).

Figure 3.

Figure 3

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Within-trial extinction in PND23-conditioned mice as a function of percent freezing between first and third 100-second time bins. * denotes significance at p < .01

Chronic nicotine exposure in pre-adolescence vs. adulthood has opposite effects on later spontaneous recovery of fear memory

A two-way ANOVA (Age × Drug) was performed to test the effects of history of chronic nicotine exposure in pre-adolescence vs. adulthood on later spontaneous recovery of fear memory following fear extinction. A significant Age × Drug interaction was found F(1, 48) = 15.513, p < 0.001. Follow up, Bonferroni-corrected independent samples t-tests indicated that, for the pre-adolescent nicotine exposed group, history of chronic nicotine significantly enhanced spontaneous recovery of distant fear memory t(21.564) = 2.420, p<0.025, while, for the adult nicotine exposed group, history of chronic nicotine significantly decreased spontaneous recovery of fear memory t(22) = 3.236, p<0.025 (Figure 2).

Discussion

For the present study, we modeled the effects of history of chronic nicotine on later extinction and spontaneous recovery in pre-adolescent and adult mice when contextual fear conditioning took place prior to nicotine exposure. It was found that history of chronic nicotine largely did not affect later extinction of contextual fear memory in pre-adolescent exposed mice or adult exposed mice; however, chronic nicotine enhanced spontaneous recovery of the contextual fear memory in adult mice that were exposed to nicotine during pre-adolescence and adolescence, while it impaired spontaneous recovery in adult exposed mice. Findings of impaired spontaneous recovery of contextual fear memory in male mice following chronic nicotine exposure in adulthood are in line with recent work from our laboratory (Tumolo, Kutlu, & Gould, 2018), although spontaneous recovery was tested when both contextual fear acquisition and extinction occurred prior to nicotine exposure for the latter study. These results further support the idea that, while adolescents are generally uniquely sensitive to nicotine exposure in terms of learning and memory, different components of learning are differentially affected by nicotine exposure, a phenomenon that may be explained by the fact that fear acquisition, retention, extinction, and spontaneous recovery are thought to involve distinct brain regions, each of which develop at a different rate (Baker et al., 2014; Gogolla et al., 2009; Hartley & Lee, 2015; Huang et al., 2013; Milad & Quirk, 2002; Rogan, et al., 1997).

For instance, the hippocampus, involved both in acquisition and recall of fear memory, is generally fully mature by late adolescence, while the prefrontal cortex, which is critically involved in extinction and spontaneous recovery of fear memory, does not complete development until early adulthood (Diamond, 2002; Gogtay et al., 2006; Maren, 2001). Although both of these regions are still plastic during early adolescence, nicotine exposure during this period likely affects each of them uniquely due to their independent developmental trajectories. Further, nicotinic receptors exhibit distinct expression and binding patterns during adolescence that vary between brain regions. For example, α4β2 nAChRs bind with higher affinity in adolescents relative to adults across the brain, while α7 nAChR binding is enhanced in young mice relative to adults in only selected brain regions, including the hippocampus (Doura, Gold, Keller, & Perry, 2008). During pre-adolescence, α5 nAChR expression is higher in cortical layer V than in hippocampus, but expression in both regions declines to modest levels in adulthood (Winzer-Serhan & Leslie, 2005). Thus, the effects of nicotine exposure on different learning and memory paradigms will depend highly upon the developmental state of the relevant neural substrates at the time of exposure.

This study is the first to demonstrate the effects of chronic nicotine exposure in pre-adolescence versus adulthood on spontaneous recovery of fear memory in a model that avoids the potential confound of initial fear conditioning following nicotine exposure — an important control considering that chronic nicotine exposure has been found to affect later acquisition of fear memory in adolescent-exposed mice (Mateos et al., 2011; Portugal et al., 2012; Spaeth et al., 2010). Specifically, for this experiment, mice of both age groups were trained and tested in a contextual fear conditioning paradigm just prior to the initiation of chronic nicotine exposure. Eighteen days following the removal of nicotine, subjects underwent fear extinction followed by a spontaneous recovery session. This experimental design is additionally favorable in that it may more closely approximate the effects of adolescent nicotine use following early trauma on later extinction therapy. Accordingly, these data suggest that chronic use of nicotine products following traumatic experiences in pre-adolescence may increase susceptibility to spontaneous recovery of fear memories later in life. Extinction of fear memory is thought to be dependent upon the potentiation of prefrontal cortex inhibitory circuitry, and subsequent depression of this inhibition is thought to underlie spontaneous recovery (Cruz, López, & Porter, 2014); thus, it is possible that the enhanced spontaneous recovery of fear memory associated with chronic nicotine exposure in pre-adolescence may additionally indicate generally compromised later inhibitory control in adolescents exposed to nicotine. Indeed, it has been found that adolescent nicotine exposure impacts later prefrontal cortex synaptic plasticity, and rodents chronically exposed to nicotine in adolescence exhibit reduced impulse control during adulthood (Counotte et al., 2009; Goriounova & Mansvelder, 2012). Prospective work should specifically examine this possibility through identification of overlapping neural circuitry underlying enhancement of spontaneous recovery and reduced inhibitory control in pre-adolescents exposed to nicotine.

Limitations of this study include all male subjects and the use of a single learning paradigm. Future work should test for sex differences in this effect within multiple learning paradigms alongside tests of potential biological mechanisms. We additionally only tested chronic nicotine exposure at one dose and in one age group. Previous work has found that nicotine’s effects on adolescent learning are dose- and age-dependent, with higher doses producing greater alterations of learning and later adolescents showing less vulnerability to nicotine’s effects (Portugal et al., 2012). Despite our finding of significant within-session extinction, the global impairment of fear memory retention exhibited by pre-adolescent trained mice may have precluded our ability to detect extinction differences between pre-adolescent trained treatment groups. This represents an interesting potential area of inquiry for future studies, which should aim to identify conditions under which extinction recall is more robust in pre-adolescent trained mice as well as potential mechanisms underlying diminished extinction recall in this age group.

In sum, this study is the first to show differential impacts of history of nicotine exposure on spontaneous recovery of fear memory between pre-adolescents and adults in a model avoiding the confound of behavioral training during or after nicotine. The finding of adult impaired spontaneous recovery in pre-adolescent exposed subjects may suggest greater vulnerability to recurrence of traumatic memory as well as compromised inhibitory control as a result of early nicotine exposure.

Acknowledgments

This work was funded with grant support from the National Institute on Drug Abuse (T.J.G., DA017949; 1U01DA041632), Jean Phillips Shibley Endowment, and Penn State Biobehavioral Health Department. We would like to acknowledge Dr. Munir Gunes Kutlu’s assistance in early experimental design. We declare no potential conflict of interest.

References

  1. André JM, Gulick D, Portugal GS, Gould TJ. Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice. Behavioural brain research. 2008;190(2):174–181. doi: 10.1016/j.bbr.2008.02.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baker KD, Den ML, Graham BM, Richardson R. A window of vulnerability: Impaired fear extinction in adolescence. Neurobiology of learning and memory. 2014;113:90–100. doi: 10.1016/j.nlm.2013.10.009. [DOI] [PubMed] [Google Scholar]
  3. Counotte DS, Spijker S, Van de Burgwal LH, Hogenboom F, Schoffelmeer AN, De Vries TJ, … Pattij T. Long-lasting cognitive deficits resulting from adolescent nicotine exposure in rats. Neuropsychopharmacology. 2009;34(2):299. doi: 10.1038/npp.2008.96. [DOI] [PubMed] [Google Scholar]
  4. Cruz E, López AV, Porter JT. Spontaneous recovery of fear reverses extinction-induced excitability of infralimbic neurons. PloS one. 2014;9(8):e103596. doi: 10.1371/journal.pone.0103596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davis JA, Porter J, Gould TJ. Nicotine enhances both foreground and background contextual fear conditioning. Neuroscience letters. 2006;394(3):202–205. doi: 10.1016/j.neulet.2005.10.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Diamond A. Normal development of prefrontal cortex from birth to young adulthood: Cognitive functions, anatomy, and biochemistry. Principles of frontal lobe function. 2002:466–503. [Google Scholar]
  7. Doura MB, Gold AB, Keller AB, Perry DC. Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure. Brain research. 2008;1215:40–52. doi: 10.1016/j.brainres.2008.03.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gogolla N, Caroni P, Lüthi A, Herry C. Perineuronal nets protect fear memories from erasure. Science. 2009;325(5945):1258–1261. doi: 10.1126/science.1174146. [DOI] [PubMed] [Google Scholar]
  9. Gogtay N, Nugent TF, Herman DH, Ordonez A, Greenstein D, Hayashi KM, … Thompson PM. Dynamic mapping of normal human hippocampal development. Hippocampus. 2006;16(8):664–672. doi: 10.1002/hipo.20193. [DOI] [PubMed] [Google Scholar]
  10. Goriounova NA, Mansvelder HD. Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood. Frontiers in synaptic neuroscience. 2012:4. doi: 10.3389/fnsyn.2012.00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gould TJ, Wehner JM. Nicotine enhancement of contextual fear conditioning. Behavioural brain research. 1999;102(1):31–39. doi: 10.1016/s0166-4328(98)00157-0. [DOI] [PubMed] [Google Scholar]
  12. Hartley CA, Lee FS. Sensitive periods in affective development: Nonlinear maturation of fear learning. Neuropsychopharmacology. 2015;40(1):50–60. doi: 10.1038/npp.2014.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hefner K, Holmes A. Ontogeny of fear-, anxiety-and depression-related behavior across adolescence in C57BL/6J mice. Behavioural brain research. 2007;176(2):210–215. doi: 10.1016/j.bbr.2006.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holliday ED, Nucero P, Kutlu MG, Oliver C, Connelly KL, Gould TJ, Unterwald EM. Long-term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice: comparisons of adult and adolescent nicotine exposure. European Journal of Neuroscience. 2016;44(10):2818–2828. doi: 10.1111/ejn.13398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Huang ACW, Shyu BC, Hsiao S, Chen TC, He ABH. Neural substrates of fear conditioning, extinction, and spontaneous recovery in passive avoidance learning: A c-fos study in rats. Behavioural brain research. 2013;237:23–31. doi: 10.1016/j.bbr.2012.09.024. [DOI] [PubMed] [Google Scholar]
  16. Keene DE, Suescun MO, Bostwick MG, Chandrashekar V, Bartke A, Kopchick JJ. Puberty is delayed in male growth hormone receptor gene-disrupted mice. Journal of andrology. 2002;23(5):661–668. [PubMed] [Google Scholar]
  17. Kutlu MG, Gould TJ. Acute nicotine delays extinction of contextual fear in mice. Behavioural brain research. 2014;263:133–137. doi: 10.1016/j.bbr.2014.01.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kutlu MG, Oliver C, Huang P, Liu-Chen LY, Gould TJ. Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation. Neuropharmacology. 2016;109:341–348. doi: 10.1016/j.neuropharm.2016.06.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kutlu MG, Tumolo JM, Holliday E, Garrett B, Gould TJ. Acute nicotine enhances spontaneous recovery of contextual fear and changes c-fos early gene expression in infralimbic cortex, hippocampus, and amygdala. Learning & Memory. 2016;23(8):405–414. doi: 10.1101/lm.042655.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kutlu MG, Zeid D, Tumolo JM, Gould TJ. Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery. Brain Research Bulletin. 2017 doi: 10.1016/j.brainresbull.2017.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Maren S. Neurobiology of Pavlovian fear conditioning. Annual review of neuroscience. 2001;24(1):897–931. doi: 10.1146/annurev.neuro.24.1.897. [DOI] [PubMed] [Google Scholar]
  22. Mateos B, Borcel E, Loriga R, Luesu W, Bini V, Llorente R, … Viveros MP. Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long-lasting memory impairments and changes in brain nicotinic and CB1 cannabinoid receptors. Journal of psychopharmacology. 2011;25(12):1676–1690. doi: 10.1177/0269881110370503. [DOI] [PubMed] [Google Scholar]
  23. Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;420(6911):70–74. doi: 10.1038/nature01138. [DOI] [PubMed] [Google Scholar]
  24. Pattwell SS, Duhoux S, Hartley CA, Johnson DC, Jing D, Elliott MD, … Soliman F. Altered fear learning across development in both mouse and human. Proceedings of the National Academy of Sciences. 2012;109(40):16318–16323. doi: 10.1073/pnas.1206834109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Portugal GS, Wilkinson DS, Turner JR, Blendy JA, Gould TJ. Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning. Neurobiology of learning and memory. 2012;97(4):482–494. doi: 10.1016/j.nlm.2012.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rogan MT, Stäubli UV, LeDoux JE. Fear conditioning induces associative long-term potentiation in the amygdala. Nature. 1997;390(6660):604–607. doi: 10.1038/37601. [DOI] [PubMed] [Google Scholar]
  27. Spaeth AM, Barnet RC, Hunt PS, Burk JA. Adolescent nicotine exposure disrupts context conditioning in adulthood in rats. Pharmacology Biochemistry and Behavior. 2010;96(4):501–506. doi: 10.1016/j.pbb.2010.07.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Terranova ML, Laviola G, De Acetis L, Alleva E. A description of the ontogeny of mouse agonistic behavior. Journal of comparative psychology. 1998;112(1):3. doi: 10.1037/0735-7036.112.1.3. [DOI] [PubMed] [Google Scholar]
  29. Tian S, Gao J, Han L, Fu J, Li C, Li Z. Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats. Neuroscience. 2008;153(4):935–943. doi: 10.1016/j.neuroscience.2008.03.005. [DOI] [PubMed] [Google Scholar]
  30. Tumolo JM, Kutlu MG, Gould TJ. Chronic nicotine differentially alters spontaneous recovery of contextual fear in male and female mice. Behavioural brain research. 2018;341:176–180. doi: 10.1016/j.bbr.2018.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Winzer-Serhan UH, Leslie FM. Expression of α5 nicotinic acetylcholine receptor subunit mRNA during hippocampal and cortical development. Journal of Comparative Neurology. 2005;481(1):19–30. doi: 10.1002/cne.20357. [DOI] [PubMed] [Google Scholar]

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