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Published in final edited form as: Dev Psychobiol. 2019 Oct 17;62(3):380–385. doi: 10.1002/dev.21928

NMDA RECEPTORS AND THE ONTOGENY OF POSTSHOCK AND RETENTION FREEZING DURING CONTEXTUAL FEAR CONDITIONING

Lauren A Miller 1, Nicholas A Heroux 1, Mark E Stanton 1
PMCID: PMC7085965  NIHMSID: NIHMS1051710  PMID: 31621064

Abstract

The ontogeny and NMDA-receptor (NMDAR) mechanisms of context conditioning were examined during standard contextual fear conditioning (sCFC) - involving context and context-shock learning in the same trial - as a comparison with our previous reports on the Context Pre-exposure Facilitation Effect (CPFE), which separates these two types of learning by 24 hours. In Experiment 1, systemic administration of the NMDAR antagonist, MK-801, prior to conditioning disrupted retention but not post-shock freezing during sCFC in PD31 rats. Experiment 2 replicated and extended this effect to PD17 vs. PD31 rats. Consistent with Experiment 1, pre-training MK-801 spared post-shock freezing but impaired retention freezing in PD31 rats. In contrast, pre-training MK-801 disrupted post-shock freezing in PD17 rats, which showed no retention freezing regardless of drug. These results reveal developmental differences in the role of NMDAR activity in the acquisition vs. retention of a context-shock association during sCFC in pre-weanling and adolescent rats.

Keywords: hippocampus, amygdala, NMDA receptor, contextual fear conditioning, ontogeny

1. Introduction

Contextual fear conditioning has been a useful tool for studying the neurobiology and ontogeny of learning and memory (Schiffino, Murawski, Rosen, & Stanton, 2011; Jablonski, Schiffino, & Stanton, 2012; Rudy, 2009). During standard contextual fear conditioning (sCFC), learning about a novel context and acquiring a context-shock association occurs within the same training session. This procedure usually consists of a 2–3min exposure to the context, followed by foot-shock (e.g., during single-trial conditioning). Successful acquisition of a context-shock association can be measured directly after the context-shock pairing (post-shock freezing) or 24hrs later (retention freezing). In contrast, in a variant of contextual fear conditioning called the Context Preexposure Facilitation Effect (CPFE), rats explore the context, acquire a context-shock association, and retrieve/express contextual fear across three phases separated by 24hrs each (context preexposure, training, and testing).

Procedurally, because context and contextual fear learning happen concurrently in sCFC, it is difficult to separately analyze the neural processes underlying each component. In addition, learning about the context in sCFC is reinforcement-driven (i.e., by foot-shock) whereas learning about the context in the CPFE is incidental (i.e., in the absence of reinforcement). While single-trial contextual fear conditioning may require the hippocampus, the sCFC task can be learned with either a hippocampus-dependent, conjunctive representation of context or with feature-based, elemental contextual cues that do not depend on hippocampus (Rudy, 2009; Wiltgen et al., 2009; Zelikowsky et al., 2013). In contrast, the hippocampus is required during all three phases of the CPFE (Matus-Amat et al., 2004). More specifically, the hippocampus is required for binding together the features of the context on the preexposure day, for retrieval of the conjunctive context memory via pattern completion during training, and for the retrieval of the contextual fear memory on the retention day (Matus-Amat et al., 2004; Matus-Amat et al., 2009; Rudy, 2009).

Previous research on the ontogeny of contextual fear conditioning has shown that 24hr retention freezing in the sCFC and the CPFE paradigms emerges between PD17–24 (Rudy, 1993; Rudy & Morledge, 1994; Schiffino et al., 2011; Jablonski et al., 2012). Meanwhile, freezing measured directly following the termination of a shock, known as post-shock freezing, is shown as early as PD18 in sCFC (Rudy & Morledge, 1994). NMDA receptors (NMDARs) are known to be necessary for acquisition and retention of fear during the CPFE in adolescent rats (Heroux, Robinson-Drummer, Rosen & Stanton, 2016) and in sCFC in adult rats (Maren, Aharonov, Stote, & Fanselow, 1996). However, whether this role of NMDARs in sCFC changes across ontogeny is not known. The present study sought to extend Heroux et al.’s (2016) previous research on NMDARs and the CPFE by examining their role in sCFC across ontogeny in two experiments.

Experiment 1 determined if systemic administration of the NMDAR antagonist, MK-801, would disrupt encoding (post-shock freezing) and 24-hour retention of the context-shock association during single-trial sCFC in adolescent (PD31) rats. Experiment 2 extended the results of Experiment 1 by comparing preweanling (PD17) vs. adolescent (PD31) rats for these effects of systemic MK-801.

2. Experiment 1

We’ve previously shown that systemic MK-801 administration on the preexposure or training days of the CPFE disrupts post-shock and retention freezing in PD31 rats (Heroux et al., 2016). However, no studies of this type have been performed with sCFC. Experiment 1 therefore sought to examine the role of NMDAR activity in both post-shock and retention test freezing of sCFC in PD31 rats.

2.1. Methods

2.1.1. Subjects

Animal husbandry was as described in our previous reports (Heroux et. al., 2016). Subjects for Experiment 1 were 55 Long Evans rats (26 females and 29 males), derived from 11 litters at the Office of Laboratory Animal Medicine at the University of Delaware. Time-mated females were housed with breeder males overnight and were examined for an ejaculatory plug the following day and, if found, that day was designated as gestational day (GD) 0. Dams were housed in clear polypropylene cages measuring 45 cm × 24 cm × 21 cm with standard bedding and access to ad libitum water and rat chow. Rats were maintained on a 12:12 h light/dark cycle with lights on at 7:00 am. Date of birth was designated as postnatal day (PD) 0. Litters were culled on PD3 to eight pups (usually 4 males and 4 females) and were paw-marked with subcutaneous injections of non-toxic black ink for later identification. Pups were weaned from their mother on PD21 and housed with same-sex litter mates in 45 cm × 24 cm × 17 cm cages. On PD29 rats were individually housed in small white polypropylene cages (24 cm × 18 cm × 13 cm) with ad libitum access to water and rat chow for the remainder of the experiment. All subjects were treated in accordance with a protocol approved by the Institutional Animal Care and Use Committee at the University of Delaware following guidelines established by the National Institute of Health.

2.1.2. Apparatus and stimuli

The apparatus and stimuli used have been previously described (Heroux et. al, 2016). Fear conditioning occurred in four Plexiglas chambers measuring 16.5 cm × 12.1 cm × 21.6 cm which were arranged in a 2 × 2 formation on a Plexiglas stand within a fume hood to provide ambient light and background noise (Context A). Each chamber had a grid floor made of 9 stainless steel bars (11.5 cm from the top of the chamber), 0.5 cm in diameter and spaced 1.25 cm apart. The 2 second, 1.5 mA footshock unconditioned stimulus (US) was delivered using a shock scrambler (Med Associates, Georgia, VT ENV-414S) connected to the grid floor of the chamber. Videos of each session (training, testing) were recorded using FreezeFrame 3.0 software (Actimetrics, Wilmette IL) with freezing defined as a bout of 0.75 s or longer without a change in video pixilation.

2.1.3. Design and procedure

The single-trial sCFC procedure has been described previously (Heroux, Robinson-Drummer, Sanders, Rosen, & Stanton, 2017) and took place over the course of two days from PD31–32 (± 1 day). Rats received three minutes of context exposure ending in two 1.5mA shocks occurring 1 second apart. Thus a single trial of context exposure terminated with reinforcement by this pair of shocks. The rats remained in the context following reinforcment for a 3-minute post-shock freeze testing then were promptly returned to their home cages. About 24 hours later, the rats were brought back for a 5-minute retention-freezing test. Rats were assigned to either the delayed-shock group just described or an immediate-shock control group that fails to acquire contextual fear (Fanselow, 1990; Heroux et al., 2017). The immediate-shock group received the two foot-shocks within 3–7 sec of being placed in the training chamber. No more than one same-sex littermate was assigned to a given condition, with rare exceptions where data from these littermates was averaged to yield a single data point. Load order and composition was counterbalanced across the shock variable (Immediate-shock vs. Delayed-shock) and sex (Male vs. Female) for both days.

On the first day of the behavioral protocol, rats were removed from individual housing cage (PD31), weighed, then places in transport cages of clear Lexan (11 cm × 11 cm × 18 cm) covered on all sides with orange construction paper to obscure visual cues during transport. The rats were carted over and remained in a hallway adjacent to the testing room for <5 min before training while the fear chambers were cleaned with 5% ammonium hydroxide solution. The weighing, cleaning, and transport protocol was consistent across all experimental sessions and days.

2.1.4. Data and statistical analysis

As previously described (Robinson-Drummer, Chakraborty, Heroux, Rosen, & Stanton, 2018), a human observer blind to the experimental groups verified the freezing threshold setting with FreezeView 3.0 (Actimetrics, Wilmette IL) by sorting the session and adjusting the threshold if necessary to ensure that small mov ements were not recorded as freezing. The software program computes a “motion index” that was adjusted to set a freezing threshold separately for each animal (per software instructions). Once set, the threshold did not change during a session. We have validated this procedure against other scoring methods (e.g., hand scoring of video records by two blind observers) and found that it is very reliable in all age groups (unpublished observations). Freezing behavior was scored as the total percent time spent freezing (defined as the cessation of all movement except breathing) over a 3- min post-shock freezing test and a 5-min retention testing session.

Once percent freezing was reliably determined, the data were imported into STATISTICA 64 data analysis software, and freezing behavior was analyzed with between-groups ANOVA (see Results section for details). Data from immediate-shock rats were pooled across drug because performance was low and didn’t differ by drug treatment (all ps > 0.16; except in one instance where MK rats froze 0.15% (+/− 0.097) and SAL rats froze 1.21% (+/− 0.372, p < .01). The Pooled-Imm-shock group also simplifies the design and reduces animal use. Data were analyzed with a 2 (Phase; Post-shock vs. Retention) x 3 (Condition; Delayed Shock-Saline vs. Delayed Shock-MK-801 vs. Pooled-Imm Shock) × 2 (Sex; male vs. female) factorial ANOVA. Group contrasts were performed with planned comparisons. These comparisons test a priori hypotheses concerning drug effects in Delayed shock groups and performance of each of these groups against control levels (Pooled-Imm Shock). A rat was excluded from analysis as an outlier if it had a score ± 2 standard deviations from its group mean. However, the average Z-score for removed outliers across all experiments was 3.28 ± 0.35.

2.2. Results

Data from 8 rats were removed from analysis as outliers, indicated in brackets after these resulting group sizes: Pooled-Imm-shock-post-shock (n= 8 [2]), Pooled-Imm-shock retention (n= 8 [2]), Post-shock-Saline (n= 10 [1]), Post-shock-MK-801 (n= 12 [1]), Retention-Saline (n= 11 [1]), Retention-MK-801 (n= 10 [1]).

Results of Experiment 1 are shown Figure 1. ANOVA indicated no main effect or interaction of Sex (ps > .254) so the data were collapsed across this variable and analyzed via 3 (Condition; Delayed-Shock-Saline vs. Delayed-Shock-MK-801 vs. Pooled-Imm-Shock) x 2 (Phase; Post-shock vs. Retention) between-groups factorial ANOVA. ANOVA revealed a main effect of condition [F(2,53) = 13.164, p < .00003] but no interaction between condition and phase [F(2,53) = 0.546, p > 0.582]. Planned comparisons showed a main effect of drug [F(1,53) = 8.101, p < .007] within the Retention phase that was not present during the Post-shock phase (p > 0.12). Within the retention phase, there was also a significant difference between Pooled-Imm-Shock vs. Delayed-Shock-Saline groups [F(1,53) = 17.805, p < .0001] but not vs. the Delayed-Shock-MK-801 group (p > .13). These comparisons indicate that MK-801 eliminated retention of contextual fear. In the post-shock phase, the Delayed-Shock-Saline group showed elevated freezing over the Pooled-Imm-Shock group [F(1,53) = 8.708, p < .005] but did not differ from the Delayed-Shock-MK-801 group (p > .124). The Delayed-Shock-MK-801 group also did not differ from the Pooled-Imm-Shock group (p > .11). This experiment shows that 24hr retention of a context-shock association is dependent on NMDA receptor functioning in adolescent rats. However, it is ambiguous whether acquisition of the association (measured in post-shock freezing) is dependent on NMDA receptor plasticity as the MK-801 group failed to differ from both the saline and control (Imm-Shock) groups.

Figure 1:

Figure 1:

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Effects of the NMDA receptor antagonist, MK-801, during both post-shock and retention freezing measures of sCFC. PD31 rats that received MK-801 show disrupted levels of freezing on the retention freezing test but not the post-shock freezing test. * indicates a significant difference between the delayed saline and delayed MK-801 group. # indicates a significant group difference from Pooled-Imm-Shock.

3. Experiment 2

Experiment 2 sought to replicate and extend the previous experiment by examining differences between PD17 vs. PD 31 rats in the effects of MK-801 on post-shock vs. retention test freezing. It also reexamined effects that were observed in Experiment 1 by manipulating phase (post-shock vs. retention freezing) as a within-groups repeated measure rather than a between-groups factor.

4.1. Methods

4.1.1. Subjects, Apparatus, and stimuli, procedures, and data analysis

Animal husbandry was as described previously. Subjects for Experiment 2 were 108 Long Evans rats (55 females and 53 males), derived from 28 litters. The apparatus, and stimuli, training procedures, and data analysis were the same as in Experiment 1, with two exceptions: PD17 rats were included to provide an age comparison, and phase of testing (post-shock vs. retention) was a repeated measure within subjects.

3.2. Results

Data from 12 rats were removed from analysis as outliers, indicated in brackets behind the resulting group sizes as follows: PD17-Delayed-Shock MK-801 (n = 22 [2]), PD17-Delayed-Shock-Saline (n = 22 [2]), PD17-Pooled-Imm-Shock (n = 21 [3]), PD31-Delayed-Shock-MK-801 (n = 13 [1]), PD31-Delayed-Shock-Saline (n = 15 [1]), PD31-Pooled-Imm-Shock (n = 15 [3]).

Results of Experiment 2 were analyzed separately by age so as not to violate the heterogeneity of variance assumption of ANOVA. Extending the results from Experiment 1, Figure 2 shows that, on PD31, MK-801 impaired freezing in the retention test but not the post-shock test. In contrast, on PD17, MK-801 appeared to impair freezing only during the post-shock phase because no retention of freezing was present regardless of drug.

Figure 2:

Figure 2:

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Effects of systemic administration of MK-801 prior to training on post-shock and retention test freezing during sCFC in PD17 (left panel) and PD31 (right panel) rats. MK-801 disrupted post-shock freezing in PD17 rats, which showed no retention regardless of drug. In PD31 rats, MK-801 disrupted retention freezing but not post-shock freezing. # significant difference from Pooled-Imm-Shock (p < .025). * significant difference between drug conditions (p < .01).

ANOVA for PD17 rats (Figure 2, left panel) indicated no main effect or interaction of Sex (ps > 0.22) so the data were collapsed across this variable and analyzed via 3 (Condition; Delayed shock-MK-801 vs Delayed Shock-Saline vs Pooled-Imm-Shock) x 2 (Phase; Post-shock vs. Retention) between-within ANOVA. The ANOVA revealed a main effect of Condition [F(2,62) = 12.30, p < .001] and Phase [F(1,62) = 25.23, p < .001] and a significant interaction of Phase x Condition [F(2,62) = 14.56, p < .001]. Planned comparisons revealed that, during the post-shock phase, rats in the Delayed-Shock-Saline group froze significantly more than rats in the Delayed-Shock-MK-801 [F(1,62) = 14.86, p < .001] and Pooled-Imm-Shock groups [F(1,62) = 27.13, p < .001], with no difference between these latter two groups [F(1,62) = 1.96, p > .16]. During the retention phase, planned comparisons revealed no group differences of any kind, indicating lack of retention freezing in PD17 rats (ps > 0.45). This experiment demonstrates that NMDAR activity is required for the acquisition and immediate expression of a context-shock association during sCFC in PD17 rats.

ANOVA for PD31 rats (Figure 2, right panel) also indicated no main effect or interaction of Sex (ps > 0.343) so the data were collapsed across this variable and analyzed via 3 (Condition; Delayed-shock-MK-801 vs Delayed-Shock-Saline vs Pooled-Imm-Shock) x 2 (Phase; Post-shock vs. Retention) between-within ANOVA, which revealed a main effect of condition [F(2,34) = 7.910, p < .002]. There was no main effect or interaction involving the phase. Planned comparisons revealed that, during post-shock freezing, both delayed-shock-saline and MK-801 groups differed from the Pooled-Imm-Shock group ([F(1,34) = 7.662, p < .01]; and [F(1,34) = 5.603, p < .024], respectively) but that these groups did not differ from one another [F(1,34) = 0.175, p > 0.677]. However, during retention freezing, there was a training effect in the saline group [F(1,34) = 15.541, p < .0004] but not the MK-801 group [F(1,34) = 1.079, p > .306], and a drug effect in the two delayed-shock groups [F(1,34) = 9.197, p < .005]. This suggests that unlike PD17 rats, NMDAR activity is not required for post-shock freezing in PD31 rats. At this older age, NMDAR activity is necessary only for the retention of a context-shock association.

5. Discussion

This study sought to investigate the ontogeny and the neural mechanisms of post-shock and retention test freezing during single-trial standard contextual fear conditioning. Experiment 1 extended previous studies by examining the role of NMDARs in sCFC in PD31 rats and found them to be involved in retention but not acquisition of the context shock association. Experiment 2 replicated and extended the previous experiment by comparing the effects of pre-training MK-801 in PD17 vs. PD31 rats. In contrast to the selective role in retention found at PD31, NMDAR activity is apparently necessary for acquisition of the context shock association in in PD17 rats. Overall, these findings suggest there are developmental differences in learning vs. retention as well as in the role of NMDARs in post-shock vs. retention-test freezing during sCFC.

The present findings concerning sCFC are relevant to our previous studies of the ontogeny of post-shock and retention freezing in the CPFE paradigm. Post-shock and retention freezing in the CPFE develops between PD17 and 24 (Schiffino et. al., 2011; Jablonski et. al., 2012). Both measures of freezing are also disrupted by systemic administration of MK-801 in adolescent (PD31) rats, although retention-test freezing is more sensitive than post-shock freezing to the dose of MK-801 (Heroux et al., 2016). Other studies have shown that post-shock freezing in the sCFC paradigm is present in PD18 rats and retention freezing begins to develop around PD23 (Rudy & Morledge, 1994; Rudy, 1993; Stanton, 2000). Retention can be improved in PD17–18 rats by using discrete CSs in the “foreground,” and/or salient, local contextual cues, and/or multiple reinforced trials (Park, Ganella & Kim, 2017; Quinn, Skipper & Claflin, 2014; Revillo, Cotella, Paglini & Arias, 2015). The present study is unique in that it directly examines age differences in the effects of MK-801 on both post-shock and retention freezing during single-trial contextual fear conditioning.

It has been previously shown that NMDARs are involved in learning tasks during the pre-weanling period of development (Lincoln, Coopersmith, Harris, Cotman, & Leon, 1988; Highfield, Nixon, & Amsel, 1996; Langton, Kim, Nicholas, & Richardson, 2007). The role of the NMDARs in learning and memory has been previously examined by our lab in developmental studies of the CPFE (Schiffino et al., 2011; Heroux et al., 2016) and various hippocampal-dependent object recognition tasks (Jablonski, Schreiber, Westbrook, Brennan, & Stanton, 2013; Ramsaran, Sanders & Stanton, 2017); as well as T-maze working memory and reversal tasks (Chadman, Watson & Stanton, 2006; Watson & Stanton, 2009; Watson, Herbert & Stanton, 2009). In the CPFE, systemic NMDAR antagonism during context preexposure or training phases disrupts retention test freezing in PD24 and PD31 rats (Burman, Murawski, Schiffino, Rosen & Stanton, 2009; Heroux et al., 2016). Intra-cranial infusion studies in adolescent and adult rats have shown that hippocampal and amygdalar NMDAR activity is required for context vs. contextual fear learning in the CPFE, respectively (Matus-Amat, Higgins, Sprunger, Wright-Hardesty, & Rudy, 2007; Schiffino et al., 2011; Miller, Heroux & Stanton, 2018). Overall these previous studies support the present findings indicating a role of NMDA receptor activity in the ontogeny of contextual fear conditioning.

To our knowledge, there are no studies of adult rats involving systemic administration of NMDAR antagonists prior to training in single-trial sCFC. It is therefore difficult to assess how findings from studies of adult rats would compare with those of the present study. However, Maren et al. (1996) found that antagonizing amygdala NMDA receptors with APV, impaired both post-shock and retention freezing in adult rats trained on sCFC. This contradicts our finding of spared post-shock freezing in PD31 rats. This contradiction may reflect methodological differences between Maren et al. (1996) and the present study, such as the longer ITI with more shocks---they used 3-shocks with 20s between the shocks, while the current study used a single pair of shocks separated by 1s. Another difference is the duration of their post-shock freezing test---64s compared to 180s in the current study. The contradiction is unlikely to reflect the route or the type of NMDAR-antagonist administered, however, because we have recently found that micro-infusions of APV into the basolateral amygdala impairs retention freezing while sparing post-shock freezing in PD31 rats trained with the same sCFC protocol used in this study (Miller, Heroux, and Stanton, 2018). Although we cannot rule out effects of behavioral parameters, it seems more likely that there is an NMDAR-independent form of neural plasticity that can mediate post-shock freezing in PD31 rats trained with our sCFC protocol. The results of Experiment 2 suggest that this NMDAR-independent mechanism of post-shock freezing does not operate in PD17 rats, raising the possibility that adolescent mechanisms of fear encoding may differ from infant and adult mechanisms (King, Pattwell, Sun, Glatt, & Lee, 2013; McCallum, Kim, & Richardson, 2010). In summary, context-shock associations established during the CPFE vs. sCFC appear to be differentially sensitive to NMDAR antagonism when assessed immediately (post-shock) but not after a (24-hour) retention interval. In addition, NMDAR-receptor independence of post-shock freezing during sCFC develops between PD17 and PD31.

In conclusion, this study shows that NMDARs play a different role in standard contextual fear conditioning across development. By contrast with our previous studies of the CPFE, the present findings also suggest both commonalities and dissociations across age and task that may reflect poor long-term memory of configural context representations during early ontogeny.

Acknowledgments

Author Notes: This work was supported by NIH grants 1-R01-HD075066–01A1 to MES and 1-F31-AA026503–01 to NAH; and by UNIDEL funds to MES.

Footnotes

Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

The authors have no conflicts of interest to declare concerning this work.

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