Abstract

The term “metaplasticity” refers to the modulation of the ability to induce synaptic plasticity of the form of long-term potentiation (LTP) or long-term depression (LTD) following prior activation of the synapses. While often electrophysiological manipulations are used to demonstrate this phenomenon, prior behavioral manipulations such as exposure to stress were also found to affect the ability to induce LTP and LTD. Interestingly, amygdala stimulation was found to have effects on subsequent LTP induction that resemble those of stress. Here, we report that exposure to stress or basolateral amygdala (BLA) stimulation induces a form of metaplasticity, which prevents the ability of a second episode of stress or BLA activation to suppress LTP in the ventral hippocampus-medial prefrontal cortex (mPFC) pathway. This form of metaplasticity is N-methyl-D-aspartic acid (NMDA)-dependent since the injection of the NMDA partial agonist D-cycloserine prevented the inhibition of LTP induced by prior exposure of stress or BLA activation. Furthermore, blocking NMDA receptors by MK801 before the exposure to stress prevented the ability of the emotional manipulation to inhibit the subsequent modulation of plasticity, resulting in impaired LTP in the mPFC. Taken together, these findings demonstrate a new form of NMDA-dependent emotional metaplasticity in the ventral hippocampus-mPFC pathway.

Introduction

“Metaplasticity” was coined to describe modulation of the ability to induce synaptic plasticity by a history of activity within the involved network (Abraham and Bear 1996). Employing different protocols of prior synaptic activation affected the likelihood of inducing long-term potentiation (LTP) or long-term depression (LTD) in the hippocampus (Abraham et al. 2001; Zelcer et al. 2006) and cortex (Froc and Racine 2004).

Heterosynaptic-induced metaplasticity was also described in the hippocampus (Abraham and Goddard 1983; Doyère et al. 1997; Abraham et al. 2007). Specifically, prior amygdala activation was found to affect the induction of LTP in the hippocampus. Priming the basolateral amygdala (BLA) reduced the threshold for LTP induction (Ikegaya et al. 1995), altered the maximal level of potentiation (Akirav and Richter-Levin 1999; Vouimba and Richter-Levin 2005; Vouimba et al. 2007), and promoted late-phase LTP (Korz and Frey 2003). These effects are region specific since amygdala priming was found to enhance LTP in the dentate gyrus (DG) while suppressing it in CA1 (Vouimba and Richter-Levin 2005).

Exposure to stress was suggested to induce “behavioral” metaplasticity similar to that observed after amygdala priming (Abraham and Tate 1997; Kim and Yoon 1998). Exposure to stress suppressed the ability to induce LTP in the CA1 (Foy et al. 1987; Xu et al. 1997; Maroun and Richter-Levin 2003) and enhanced LTP in the DG, similar to the differential effects of amygdala priming on hippocampal subregions (Kavushansky et al. 2006). Taken together, these observations raise the possibility that the activation of the BLA mediates, at least in part, the metaplastic effects of stress in the hippocampus.

Most studies addressing the metaplastic effect of stress on LTP have mainly focused on the hippocampus. However, plasticity such as LTP can easily be induced in the medial prefrontal cortex (mPFC; Jay et al. 1995; Gurden et al. 2000; Maroun and Richter-Levin 2003), and exposure to stress suppresses LTP in the mPFC (Maroun and Richter-Levin 2003; Rocher et al. 2004).

Several lines of evidence suggest that emotional arousal activates the BLA and that this activation results in modulation of memory-related processes in the hippocampus (for review, see Cahill and McGaugh 1998; McGaugh 2000; Richter-Levin and Akirav 2000; Roozendaal 2000; Abe 2001; Packard and Cahill 2001).

The purposes of this study were to assess whether BLA activation will mimic stress effects on LTP in the mPFC and to examine the mechanisms by which BLA activation or exposure to stress modulates LTP in the ventral hippocampus-mPFC pathway.

We first established that both stress and BLA priming suppress the ability to induce LTP in the mPFC. We further show that exposure to behavioral stress or BLA stimulation induces a form of metaplasticity, which prevents the ability of a second episode of stress or BLA activation to suppress LTP in mPFC. We finally show the dependency of this form of metaplasticity on N-methyl-D-aspartic acid (NMDA) receptor activation.

Materials and Methods

Electrophysiology

Male Sprague Dawley rats (280–380 g) were anesthetized (with 40% urethane and 5% chloral hydrate in saline, 0.5 ml/100 g, intraperitoneally [i.p.]) and placed in a stereotaxic frame, with body temperature maintained at 37 ± 0.5 °C. The procedures were performed in strict accordance with University of Haifa regulations and National Institute of Health (NIH) guidelines (NIH publication number 8023). In brief, small holes were drilled into the skull to allow the insertion of electrodes into the brain. A single recording microelectrode (glass, tip diameter of 2–5 μm, filled with 2M NaCl, resistance of 1–4 M) was slowly lowered into the mPFC (anteroposterior, 3.0–3.3 mm anterior to bregma, 0.7–1.0 mm lateral, 3.8–4.8 mm below pial surface).

A bipolar 125-μm stimulating electrode was implanted in the area of the CA1/subicular region of the ventral hippocampus (6.3–6.8 posterior to bregma, 5.5 mm lateral, 4.0–5.8 mm below pial surface). An additional stimulating electrode was lowered to the BLA (anteroposterior, −3 mm relative to bregma, 5.0 mm lateral, −7.6 mm ventral). The evoked responses were digitized (10 kHz) and analyzed using the Cambridge Electronic Design (CED, Cambridge, UK) 1401+ and its Spike2 software. Offline measurements were made of the amplitude of field postsynaptic potentials (fPSPs) using averages of 5 successive responses to a given stimulation intensity applied at 0.1 Hz. Test stimuli (monopolar pulses, 100 μs duration) were delivered at 0.1 Hz. After positioning the electrodes, the rats were left for 30 min before commencing the experiment.

LTP Induction

Theta burst stimulation (TBS) protocol: theta-like high-frequency stimulation at 100 Hz to the ventral hippocampus (3 sets of 10 trains, each train consisted of 10 pulses at 100 Hz, intertrain interval of 200 ms, interset interval of 1 min).

For all the experiments, baseline responses were established by means of delivering stimulation intensity (50–150 μA) sufficient to elicit a response representing 25–30% of the maximal amplitude of the evoked field potentials.

TBS was delivered at the same intensity and pulse duration as the test stimuli during establishment of the baseline responses. Evoked field potentials at the baseline intensity were recorded from the mPFC for up to 60 min following the application of TBS. LTP was measured as an increase in fPSP amplitude. Changes in the fPSP amplitude were measured as a percentage change from the baseline.

TBS was applied in all groups within 1 hr 30 min following anesthesia.

Amygdala Priming

The BLA was primed according to previous work (1 V, 50-μs pulse duration, 10 trains of 5 pulses at 100 Hz, intertrain interval of 200 ms; Vouimba and Richter-Levin 2005) either 30 s or 1 h before TBS was applied to the ventral hippocampus.

Behavioral Stress Protocol

Stress was evoked by placing the rats on an elevated platform (EP) (12 × 12 cm) in a brightly lit room for 30 min (Xu et al. 1997; Maroun and Richter-Levin 2003).

After the termination of the stressor, rats were immediately anesthetized and taken for electrophysiological testing.

For the 2 episodes of exposure to stress, rats were placed on the EP for 30 min and then taken to home cage for 30 min before being reexposed to the EP stress for additional 30 min.

Drugs

D-cycloserine (DCS: a partial NMDA receptor agonist, 15mg/kg i.p) was from Sigma (St Louis, MO). This dose was based on a previous work showing facilitation of extinction of fear following systemic injection (Ledgerwood et al. 2005).

The NMDA receptor antagonist, [1]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK801; Biotrend GmbH, Cologne, Germany), was dissolved in saline (0.1 mg/kg, i.p.). This dose of MK801 is based on our previous work showing that it does not impair the induction of LTP (Rosenblum et al. 1999).

The drugs were injected 30–40 min before the exposure to stress (when applicable) or the application of TBS. Controls received physiological saline at the same time as the drug groups.

Histology

Histological verification of the locations of the stimulating electrode in the BLA was performed. After the electrophysiological testing, marking lesions was made by passing anodal current (10 mA for 3 s). Only animals that had their stimulating electrode in the BLA were included (Fig. 1).

Figure 1.

A diagram depicting a coronal section of the rat brain (3.00 mm posterior to bregma; Paxinos and Watson, 1998) showing electrode placements in the BLA.

Figure 1.

A diagram depicting a coronal section of the rat brain (3.00 mm posterior to bregma; Paxinos and Watson, 1998) showing electrode placements in the BLA.

Statistical Analysis

Differences were determined using one-way or repeated measures analysis of variance (ANOVA). All post hoc comparisons were made using the least significant difference multiple comparison test.

Results

The Effects of Behavioral Stress and Amygdala Activation on the Induction of LTP in the Ventral Hippocampus-mPFC

All the groups received TBS to the ventral hippocampus, and specifically, 4 groups were tested in this experiment: rats that only received TBS (TBS only, n = 7), rats that were exposed to EP and received TBS (EP, n = 5), rats with BLA priming 30 s before TBS (BLA-30sec, n = 9), and rats with BLA priming 1 h before the application of TBS (BLA-1hr, n = 6).

One-way ANOVA showed similar stimulus intensities applied for all the groups (F3,23 = 1.01, not significant [n.s.]), and a comparison between the groups using ANOVA with repeated measures for the time points before the application of TBS did not reveal a significant difference in fPSP amplitude (F3,23 = 0.77, n.s.) indicating a similar baseline. The average of the amplitudes during baseline recording is presented in Table 1.

Table 1

The baseline amplitude of the fPSP in the mPFC in the different groups

Group Baseline amplitude (mV) 
TBS only 4.23 ± 0.63 
BLA-30sec 4.08 ± 1.06 
BLA-1hr 3.89 ± 0.37 
EP 4.21 ± 0.97 
EP-EP 3.89 ± 0.75 
BLA-BLA 3.88 ± 0.50 
EP + priming 3.62 ± 0.63 
DCS 4.92 ± 0.83 
DCS + EP 4.33 ± 0.98 
DCS + BLA 4.21 ± 0.88 
MK801 4.54 ± 0.72 
MK801 + EP + priming 3.63 ± 0.65 
Group Baseline amplitude (mV) 
TBS only 4.23 ± 0.63 
BLA-30sec 4.08 ± 1.06 
BLA-1hr 3.89 ± 0.37 
EP 4.21 ± 0.97 
EP-EP 3.89 ± 0.75 
BLA-BLA 3.88 ± 0.50 
EP + priming 3.62 ± 0.63 
DCS 4.92 ± 0.83 
DCS + EP 4.33 ± 0.98 
DCS + BLA 4.21 ± 0.88 
MK801 4.54 ± 0.72 
MK801 + EP + priming 3.63 ± 0.65 

Note. Table 1 summarizes the amplitude of the fPSP of the different groups and shows that the groups did not differ in their baseline amplitude, suggesting that the different manipulations did not affect baseline transmission. The comparison between the relevant groups for each experiment is detailed in the text.

ANOVA with repeated measures on the levels of potentiation at the different time points following the application of TBS revealed that the 4 groups significantly differed (F3,23 = 7.12, P = 0.001; Fig. 2) without a significant effect of post-TBS time or significant interaction between treatment and time, indicating that there was no difference between groups in this respect.

Figure 2.

Overall, 4 groups were tested: rats that only received TBS (TBS only, n = 7), rats that were exposed to EP and received TBS (EP, n = 5), rats with BLA priming 30 s before TBS (BLA-30sec, n = 9), and rats with BLA priming 1 h before the application of TBS (BLA-1hr, n = 6). ANOVA analysis with repeated measures on post-TBS time points revealed that the 4 groups significantly differed in the levels of potentiation following the application of TBS (F3,23 = 7.12, P = 0.001). Exposure to behavioral stress or activation of the BLA 30 s or 1 h before TBS to the ventral hippocampus inhibited LTP in the mPFC. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Figure 2.

Overall, 4 groups were tested: rats that only received TBS (TBS only, n = 7), rats that were exposed to EP and received TBS (EP, n = 5), rats with BLA priming 30 s before TBS (BLA-30sec, n = 9), and rats with BLA priming 1 h before the application of TBS (BLA-1hr, n = 6). ANOVA analysis with repeated measures on post-TBS time points revealed that the 4 groups significantly differed in the levels of potentiation following the application of TBS (F3,23 = 7.12, P = 0.001). Exposure to behavioral stress or activation of the BLA 30 s or 1 h before TBS to the ventral hippocampus inhibited LTP in the mPFC. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Post hoc analysis revealed that the TBS group was significantly different from the other groups. The TBS group had intact levels of LTP in the mPFC as a response to TBS stimulation to the ventral hippocampus (133.6 ± 5.7%) compared with the EP group (95.5 ± 8.4%, P < 0.002) to the BLA-30sec (92.7 ± 6. 3%, P < 0.0001) and to the BLA-1hr (105.1 ± 7.6%, P < 0.001).

Our data suggest that exposure to the EP stressor or activation of the amygdala 30 s or 1 h before the application of TBS to the ventral hippocampus inhibited the ability to induce LTP in the mPFC. The data indicate that both EP stressor and the specific protocol used in this study of electrical activation of the BLA prior to TBS to the ventral hippocampus resulted in a form of metaplasticity that impaired LTP induction in the mPFC (Fig. 2).

Stress and Amygdala Activation Effects on Metaplasticity of Prior Experience in the Ventral Hippocampus-mPFC

Here, we examined how exposure to stress or electrical activation of the BLA would affect the response of the mPFC to a subsequent emotional experience.

Five groups were tested all of which received TBS: a group that underwent 2 consecutive episodes of stress (each episode of 30 min on the EP, separated by 30 min at home cage, EP-EP, n = 5) and then received TBS, a group that underwent 2 consecutive amygdala priming episodes and then received TBS (1 h and 30 s before TBS, BLA-BLA, n = 6), a group exposed to the EP stress and BLA priming 30 s before TBS (EP + priming, n = 6), a control group that received only TBS (TBS only, n = 6), and an additional group that was exposed to a single episode of EP (EP, n = 4).

One-way ANOVA for the analysis of the stimulus intensities that were applied showed that there was no significant difference between the groups (F4,24 = 0.52, n.s.).

Comparison between the groups before the application of TBS with repeated measures ANOVA did not reveal a significant difference in fPSP amplitude at any time point pre-TBS (F4,22 = 1.24, n.s.) indicating a similar baseline. The average of the amplitudes during baseline recording is presented in Table 1.

ANOVA with repeated measures following the application of the TBS revealed significant differences between the groups (F4,22 = 6.85, P = 0.001; Fig. 3). Post hoc analysis showed that while the EP-EP, BLA-BLA, and the EP + priming groups exhibited normal and intact levels of LTP that were comparable with the levels of the TBS-only group (TBS only: 129.7 ± 6.6%, EP-EP: 136.6 ± 7.2%, EP + priming: 129.1 ± 6.5%, BLA-BLA: 138.14 ± 6.3%), the group that underwent a single episode of stress had impairment of LTP (EP: 99.16 ± 6.1%, P < 0.001 compared with all groups). There was no effect of time (post-TBS) and the interaction between treatment and time was not significant, indicating that there was no difference between groups in this respect.

Figure 3.

Five groups were tested: a group that underwent 2 consecutive episodes of stress (each episode of 30 min on the EP, separated by 30 min at home cage, EP-EP, n = 5) and then received TBS, a group that underwent 2 consecutive amygdala priming episodes and then received TBS (1 h and 30 s before TBS, BLA-BLA, n = 6), a group exposed to the EP stress and the amygdala BLA priming 30 s before TBS (EP + priming, n = 6), a group that was exposed to a single episode of EP (EP, n = 4), and a control group that received only TBS (TBS only, n = 6). ANOVA analysis with repeated measures on the post-TBS time points revealed significant differences between the groups (F4,22 = 6.85, P = 0.001). The group of a single exposure to EP had impairment in LTP, and the other groups with 2 episodes of BLA/EP or combined manipulations had intact levels of LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Figure 3.

Five groups were tested: a group that underwent 2 consecutive episodes of stress (each episode of 30 min on the EP, separated by 30 min at home cage, EP-EP, n = 5) and then received TBS, a group that underwent 2 consecutive amygdala priming episodes and then received TBS (1 h and 30 s before TBS, BLA-BLA, n = 6), a group exposed to the EP stress and the amygdala BLA priming 30 s before TBS (EP + priming, n = 6), a group that was exposed to a single episode of EP (EP, n = 4), and a control group that received only TBS (TBS only, n = 6). ANOVA analysis with repeated measures on the post-TBS time points revealed significant differences between the groups (F4,22 = 6.85, P = 0.001). The group of a single exposure to EP had impairment in LTP, and the other groups with 2 episodes of BLA/EP or combined manipulations had intact levels of LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

The Role of the NMDA Receptor in Metaplasticity of Emotional Modulation of LTP in the Ventral Hippocampus-mPFC

The results of Experiments 1 and 2 show that while a single episode of either activation of the BLA or exposure to the EP stress inhibited LTP in the mPFC, 2 episodes of BLA activation or 2 exposures to the EP, or the combination of both EP and BLA activation resulted in intact levels of LTP. These results suggest that electrical activation of the BLA or exposure to the EP stress induced a form of metaplasticity that prevented the ability of a subsequent experience—episode of stress or BLA activation—to suppress LTP in the mPFC.

LTP in the mPFC was previously found to be NMDA dependent (Jay et al. 1995; Maroun and Richter-Levin 2003), and the involvement of the NMDA receptors in metaplasticity is well established (Mockett et al. 2002; MacDonald et al. 2007).

Based on this, in the following experiment, we examined whether this novel form of metaplasticity described above is also NMDA dependent.

Two mirror experiments were conducted. In the first experiment, the partial NMDA agonist DCS was used to assess whether systemic activation of the NMDA receptors by the injection of DCS could mimic the first episode either of the EP stress or of BLA priming. To that end, rats were injected with DCS and were either exposed to the EP or had the BLA activated.

In the second experiment, we aimed to examine whether blocking the NMDA receptors by injecting the NMDA receptors antagonist MK801 would prevent the combined effect of EP and BLA activation on the induction of LTP (combined EP + BLA results in intact levels of LTP; Fig. 3).

The Effects of Activating the NMDA Receptors

Six groups were tested: rats that were exposed to the EP and received TBS (EP, n = 7), rats that were BLA primed 30 s before TBS to the ventral hippocampus (BLA-30sec, n = 6), rats with the NMDA partial agonist (DCS, n = 5), rats that were injected with DCS and placed on the EP and then TBS was applied (DCS + EP, n = 5), rats that were injected with DCS and then the BLA was primed 30 s before TBS to the ventral hippocampus (DCS + BLA, n = 6), and a control group that received only TBS (TBS only, n = 4).

The control groups received physiological saline injections at the same time as the drug groups.

The behavior of saline- and DCS-treated rats on the EP (i.e., urination, defecation, freezing) was not different (data not shown).

One-way ANOVA showed that similar stimulus intensities were applied (F5,27 = 1.3, n.s.). Using ANOVA with repeated measures on the fPSP amplitude before the application of TBS did not reveal significant differences in fPSP amplitude (F5,27 = 0.26, n.s.) indicating a similar baseline. The average of the amplitudes during baseline recording is presented in Table 1.

ANOVA with repeated measures on the time points following the application of TBS showed significant differences between the groups (F5,27 = 12.13, P < 0.0005; Fig. 4). The interaction between treatment and time (post-TBS) was not significant, indicating that there was no significant difference between groups in this respect.

Figure 4.

Six groups were tested: rats that were exposed to the EP and received TBS (EP, n = 7), rats that were BLA primed 30 s before TBS to the ventral hippocampus (BLA-30sec, n = 6), rats with the NMDA partial agonist (DCS, n = 5), rats that were injected with DCS and placed on the EP and then TBS was applied (DCS + EP, n = 5), rats that were injected with DCS and then the BLA was primed 30 s before TBS to the ventral hippocampus (DCS + BLA, n = 6), and a control group that received only TBS (TBS only, n = 4). The control groups received physiological saline injections at the same time as the drug groups. ANOVA with repeated measures analysis revealed significant differences between the groups (F5,27 = 12.13, P < 0.0005). The injection of DCS reversed the impairing effect of the EP or amygdala priming on LTP since the DCS + EP and the DCS + BLA had intact levels of LTP comparable with those of TBS group. The DCS-alone group did not differ from the TBS group, indicating that DCS alone did not cause a further enhancement in the potentiation levels beyond the control levels. The EP and the BLA-primed groups failed to induce LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Figure 4.

Six groups were tested: rats that were exposed to the EP and received TBS (EP, n = 7), rats that were BLA primed 30 s before TBS to the ventral hippocampus (BLA-30sec, n = 6), rats with the NMDA partial agonist (DCS, n = 5), rats that were injected with DCS and placed on the EP and then TBS was applied (DCS + EP, n = 5), rats that were injected with DCS and then the BLA was primed 30 s before TBS to the ventral hippocampus (DCS + BLA, n = 6), and a control group that received only TBS (TBS only, n = 4). The control groups received physiological saline injections at the same time as the drug groups. ANOVA with repeated measures analysis revealed significant differences between the groups (F5,27 = 12.13, P < 0.0005). The injection of DCS reversed the impairing effect of the EP or amygdala priming on LTP since the DCS + EP and the DCS + BLA had intact levels of LTP comparable with those of TBS group. The DCS-alone group did not differ from the TBS group, indicating that DCS alone did not cause a further enhancement in the potentiation levels beyond the control levels. The EP and the BLA-primed groups failed to induce LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

The EP and the BLA-primed groups did not express LTP, confirming the data from the previous experiment that both stress and BLA priming impair the induction of mPFC LTP (97.4 ± 6.5% and 90.3 ± 7%, respectively; P < 0.005 for both compared with the TBS group). In contrast, the DCS reversed the impairing effect of the EP or BLA priming since the DCS + EP (122.5 ± 7.6%) and the DCS + BLA (144.5 ± 7%) did not differ in the levels of potentiation from TBS-only group (137.79 ± 8.5%).

Similarly, the DCS group did not differ from the TBS-only group (148.7 ± 7.7%), indicating that the DCS alone did not cause a further enhancement in the potentiation levels beyond the control levels.

The Effects of Blocking the NMDA Receptors

Four groups were tested: rats that received MK801 at a dose of 0.1 mg/kg (i.p.); we have previously shown that this dose does not affect LTP in the DG of the hippocampus (Rosenblum et al. 1999; MK801, n = 5); rats that were exposed to the EP and then had the amygdala primed 30 s before TBS to the ventral hippocampus (EP + BLA, n = 6); rats that were injected with MK801 and exposed to the EP and had their BLA primed 30 s before TBS to the ventral hippocampus (MK801 + EP + BLA, n = 5), and control rats that had TBS only (TBS only, n = 5).

The control group received physiological saline injections at the same time as the drug groups.

The behavior of saline- and MK801-treated rats on the EP (i.e., urination, defecation, freezing) was not different (data not shown).

Similar stimulus intensities were applied (F3,17 = 0.8, n.s.), and a comparison between the groups before the application of TBS did not reveal a significant difference in fPSP amplitude (F3,17 = 1.70, n.s.) indicating a similar baseline. The average of the amplitudes during baseline recording is presented in Table 1.

ANOVA with repeated measures on the time points following TBS showed that the groups significantly differed (F3,17 = 9.13, P < 0.005; Fig. 5), without significant differences in time post-TBS (F < 1) or interaction between treatment and time (F < 1).

Figure 5.

Four groups were tested: rats that received MK801 at a dose of 0.1 mg/kg (i.p., MK801, n = 5), rats that were exposed to the EP and then had the amygdala primed 30 s before TBS to the ventral hippocampus (EP + BLA, n = 6), rats that were injected with MK801 and exposed to the EP and had their BLA primed 30 s before TBS to the ventral hippocampus (MK801 + EP + BLA, n = 5), and control rats that had TBS only (TBS only, n = 5). The control group received physiological saline injections at the same time as the drug groups. ANOVA with repeated measures revealed that the groups significantly differed (F3,17 = 9.13, P < 0.005). The injection of the MK801 at this dose did not block the induction of LTP, and its level was not statistically different from control levels of LTP in the TBS group. However, the blockade of NMDA receptors prevented the EP stressor from blocking the impact of BLA priming on mPFC LTP, resulting in impaired levels of LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Figure 5.

Four groups were tested: rats that received MK801 at a dose of 0.1 mg/kg (i.p., MK801, n = 5), rats that were exposed to the EP and then had the amygdala primed 30 s before TBS to the ventral hippocampus (EP + BLA, n = 6), rats that were injected with MK801 and exposed to the EP and had their BLA primed 30 s before TBS to the ventral hippocampus (MK801 + EP + BLA, n = 5), and control rats that had TBS only (TBS only, n = 5). The control group received physiological saline injections at the same time as the drug groups. ANOVA with repeated measures revealed that the groups significantly differed (F3,17 = 9.13, P < 0.005). The injection of the MK801 at this dose did not block the induction of LTP, and its level was not statistically different from control levels of LTP in the TBS group. However, the blockade of NMDA receptors prevented the EP stressor from blocking the impact of BLA priming on mPFC LTP, resulting in impaired levels of LTP. Inset: representative average waveforms. Horizontal bar = 10 ms, vertical bar = 0.2 mV. Arrow denotes the application of TBS.

Similar to previous data (Rosenblum et al. 1999), the injection of the MK801 at this dose did not block the induction of LTP, and its level was not statistically different from control levels of LTP (122.9 ± 5.5% and 131.8 ± 5.4%, respectively, n.s.). However, the injection of MK801 prior exposure to the EP blocked stress-induced metaplasticity since following MK801, the EP stress failed to block the impact of BLA priming on mPFC LTP, and this group had impaired levels of LTP and was significantly different from the 2 other groups (95.9 ± 5.5% different from both groups, P < 0.005).

Discussion

The ventral hippocampus is reciprocally connected with the BLA and mPFC (Groenewegen et al. 1990; Jay and Witter 1991), suggesting an intensive interaction between these structures. The BLA was found to modulate plasticity in the hippocampus (Richter-Levin 2004). However, the ability of the BLA to modulate plasticity in the ventral hippocampus-mPFC pathway was not yet studied.

The present report demonstrate that similar to behavioral stress, electrical BLA activation suppressed the ability to induce LTP in the mPFC (Maroun and Richter-Levin 2003; Rocher et al. 2004). Priming the BLA (30 s prior to TBS to the ventral hippocampus) or spaced activation (1 h prior to TBS to the ventral hippocampus, a time interval similar to that of the exposure to stress) suppressed LTP in the mPFC, indicating that suppression of LTP is not due to the interval between the activation of the BLA or exposure to stress and TBS but rather the fact that the amygdala was activated. These results further strengthen the view that the effects of stress on plasticity are mediated, at least in part, by amygdala activation (Richter-Levin 2004). Furthermore, they show that this pathway expresses opposite effects to those observed in the DG (Ikegaya et al. 1995; Akirav and Richter-Levin 1999) and similar to those observed in the CA1 subregion (Maroun and Richter-Levin 2003; Vouimba and Richter-Levin 2005; Vouimba et al. 2007).

The impairment of mPFC-LTP following stress is congruent with data showing that exposure to stress has detrimental effect on mPFC-dependent behaviors, such as working memory tasks (e.g., Murphy et al. 1996; Mizoguchi et al. 2000).

Interestingly, adrenalectomy (Mizoguchi et al. 2004), acute or chronic corticosterone treatment (Bardgett et al. 1994; Roozendaal et al. 2004), or infusion of a glucocorticoid receptor agonist directly into certain subregions in the mPFC (Roozendaal et al. 2004) also impaired performance on working memory tasks. These effects are reminiscent of the findings that adrenalectomy or corticosterone administration or exposure to stress produced dendritic retraction in mPFC (Wellman 2001; Izquierdo et al. 2006; Cerqueira et al. 2007).

Furthermore, other mPFC-dependent memory tasks, like extinction of fear conditioning were also found to be impaired following exposure to behavioral stress (Izquierdo et al. 2006; Akirav and Maroun 2007; Akirav et al. 2009). Interestingly, the suppression of LTP in the PFC by stress was suggested to underlie stress-induced impairment of extinction (Herry and Garcia 2002; Maroun and Richter-Levin 2003; Maroun 2006). Stress-induced impairment is suggested to be of relevance to anxiety disorders, such as post-traumatic stress disorder (Izquierdo et al. 2006; Akirav and Maroun 2007; Akirav et al. 2009).

The main question of the current study was whether prior activation would include an additional type of metaplasticity or in other words whether electrical stimulation of the BLA or behavioral exposure to the stressor could induce changes that would affect at later stages the ability to induce further changes in the mPFC.

Indeed, the results show that prior exposure to the EP stress suppressed the ability of a subsequent stress exposure to inhibit LTP induction. Similarly, prior BLA activation also suppressed the ability of subsequent BLA priming to inhibit LTP induction in the mPFC. Interestingly, prior stress exposure also prevented the ability of amygdala priming to inhibit LTP induction in the mPFC, suggesting that similar mechanisms were activated by prior stress exposure and prior electrical activation of the BLA (the effects are summarized in Table 2). The results clearly demonstrate the formation of a type of an emotional metaplasticity that inhibits the response of the mPFC to a subsequent emotional event for at least 40 min.

Table 2

The effect of the different manipulations on the ability to induce LTP in the ventral hippocampus-mPFC pathway

Group LTP No LTP 
TBS only Normal LTP  
BLA-30sec  Inhibition of LTP 
BLA-1hr  Inhibition of LTP 
EP  Inhibition of LTP 
EP-EP Normal LTP  
BLA-BLA Normal LTP  
EP + priming Normal LTP  
DCS Normal LTP  
DCS + EP Normal LTP  
DCS + BLA Normal LTP  
MK801 Normal LTP  
MK801 + EP + priming  Inhibition of LTP 
Group LTP No LTP 
TBS only Normal LTP  
BLA-30sec  Inhibition of LTP 
BLA-1hr  Inhibition of LTP 
EP  Inhibition of LTP 
EP-EP Normal LTP  
BLA-BLA Normal LTP  
EP + priming Normal LTP  
DCS Normal LTP  
DCS + EP Normal LTP  
DCS + BLA Normal LTP  
MK801 Normal LTP  
MK801 + EP + priming  Inhibition of LTP 

The manipulations of prior activation either behaviorally by exposure to stress or the electrical activation of the BLA did not affect baseline transmission as no effect was observed on the fPSP amplitude. Furthermore, Mockett and Hulme (2008) suggest that the induction of a metaplastic state through synaptic activation, while most easily observed when no change in basal synaptic transmission, is induced and the critical element is the modification of the response to later synaptic stimulation compared with that of nonprimed pathways.

Caution is, however, appropriate. Although there were no obvious alterations in baseline transmission, with our present sample sizes (ranging from 4–9 per group for each comparison), we cannot exclude the possibility that differences may have occurred following the different manipulations.

The finding that prior exposure to stress would “protect” from subsequent aversive effects of stress is at first glance counterintuitive. However, the emotional manipulations applied here cannot be considered traumatic. The current findings should be looked at in the context of responses to emotional challenges within the range of a normative experience. We have previously demonstrated that exposure of rats to a mild stress resulted in reorganization of maps of activation of relevant brain areas, including the amygdala and hippocampus (Akirav et al. 2001; Kogan and Richter-Levin 2008). Such remapping of activation was not associated with impaired performance in a learning task but rather with alterations of the characteristics of the formed memory that could be described as shifts in learning strategies (Kogan and Richter-Levin 2008). The exposure to a single mild stress experience may be seen as potentially threatening and thus leading to the suppression of LTP in the mPFC and a parallel increased activation of the amygdala. Repeated exposure to such a mild stressor without significant aversive outcomes should mark this event as less relevant and thus may lead to a shift to a less emotional map of activation that includes the full involvement of mPFC plasticity in the learning.

In line with this view, it is expected that a traumatic experience will suppress LTP in the mPFC even when it precedes an additional emotional experience. The current findings should thus be seen within the context of emotional learning. The form of metaplasticity described here contributes to our understanding of the regulation of adaptive behavior like extinction of fear conditioning (Morgan et al. 1993; Milad and Quirk 2002; Akirav et al. 2006; Akirav and Maroun 2007).

The Role of NMDA Receptors in Metaplasticity

The involvement of the NMDA receptor in some forms of LTP and metaplasticity is well established (Mockett et al. 2002; MacDonald et al. 2007).

Here, we examined whether NMDA activation is also required for this emotional type of metaplasticity. This was examined in 2 mirror sets of experiments; activation of NMDA receptors by DCS induced metaplastic effects similar to those of prior exposure to stress or to BLA priming, that is, DCS blocked the ability of exposure to behavioral stress or BLA manipulations to inhibit LTP induction in the mPFC. Complementary to that, blocking of the NMDA receptors by MK801 before the exposure to stress prevented the ability of this emotional manipulation to inhibit subsequent emotional modulation of plasticity and hence resulting in impaired LTP in the mPFC. When the same dose of MK801 was administered alone, it did not affect LTP in the mPFC, consistent with our previous work that this dose does not affect LTP in the DG of the hippocampus (Rosenblum et al. 1999).

These results show that MK801 prevented the ability of the emotional manipulation to inhibit subsequent modulation of plasticity, resulting in impaired LTP in the mPFC. (The main effects of the different manipulations are summarized in Table 2.) The results may suggest that the threshold of affecting metaplasticity might be lower than synaptic plasticity as was previously suggested that metaplasticity could also occur when priming stimulations fail to induce persistent changes in synaptic plasticity in the hippocampus (Mockett and Hulme 2008; Xu et al. 2009).

The facilitatory effect of DCS has been previously reported. Specifically, it was shown that a single dose of DCS injected 24 h post head injury prevented impairment in LTP in the hippocampus and rescued the cognitive impairments associated with the trauma (Yaka et al. 2007). Consistent with that, NMDA receptor activation through its glycine-binding site rescued age-related deficits in LTP (Billard and Rouaud 2007).

Furthermore, it was previously shown that DCS administration enhanced the extinction of conditioned fear (Walker et al. 2002; Ledgerwood et al. 2003, 2005; Akirav et al. 2009) and facilitated fear extinction in patients with anxiety disorders when it is combined with exposure therapy but not when it is given alone (Ressler et al. 2004; Hofmann et al. 2006). In contrast, administration of DCS with no exposure therapy is not effective (Heresco-Levy et al. 2002). This latter finding is consistent with our finding that DCS alone did not cause further enhancement of the magnitude of LTP. We have recently found that when DCS before the exposure to the EP stressor prevents the impairing effect of stress on extinction (Akirav et al. 2009).

Taken together, these findings report a novel form of emotional metaplasticity in the hippocampus-PFC and show that the activation of this type of emotional metaplasticity is NMDA dependent.

These mechanisms of metaplasticity might be potential targets to treat cognitive impairments associated with exposure to stress.

Funding

National Institute for Psychobiology to M.M.

Conflict of Interest: None declared.

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