Rapid synaptic potentiation within the anterior cingulate cortex mediates trace fear learning
© Descalzi et al; licensee BioMed Central Ltd. 2012
Received: 31 December 2011
Accepted: 3 February 2012
Published: 3 February 2012
Although the cortex has been extensively studied in long-term memory storage, less emphasis has been placed on immediate cortical contributions to fear memory formation. AMPA receptor plasticity is strongly implicated in learning and memory, and studies have identified calcium permeable AMPA receptors (CP-AMPARs) as mediators of synaptic strengthening. Trace fear learning engages the anterior cingulate cortex (ACC), but whether plastic events occur within the ACC in response to trace fear learning, and whether GluN2B subunits are required remains unknown. Here we show that the ACC is necessary for trace fear learning, and shows a rapid 20% upregulation of membrane AMPA receptor GluA1 subunits that is evident immediately after conditioning. Inhibition of NMDA receptor GluN2B subunits during training prevented the upregulation, and disrupted trace fear memory retrieval 48 h later. Furthermore, intra-ACC injections of the CP-AMPAR channel antagonist, 1-naphthylacetyl spermine (NASPM) immediately following trace fear conditioning blocked 24 h fear memory retrieval. Accordingly, whole cell patch clamp recordings from c-fos positive and c-fos negative neurons within the ACC in response to trace fear learning revealed an increased sensitivity to NASPM in recently activated neurons that was reversed by reconsolidation update extinction. Our results suggest that trace fear learning is mediated through rapid GluN2B dependent trafficking of CP-AMPARs, and present in vivo evidence that CP-AMPAR activity within the ACC immediately after conditioning is necessary for subsequent memory consolidation processes.
Long term potentiation (LTP) of central synapses is believed to be the basic mechanism that drives memory storage within the brain [1, 2]. Although a critical role for the cerebral cortex in remote fear memory recall has been established , little is known regarding immediate cortical contributions to fear memory formation. Much effort instead has focused on the amygdala, where animal studies revealed that associative fear conditioning, which pairs an arbitrary conditioning stimulus (CS) with a noxious one (US), induces changes in excitatory glutamatergic transmission [4–6], and requires postsynaptic GluA2 expression for memory maintenance . Evidence suggests however that in addition to the amygdala, cortical structures also mediate fear learning. In humans, trace fear conditioning, which introduces a time interval between the CS and the US, activates several brain areas including the amygdala, hippocampus, medial prefrontal cortex (mPFC), and the anterior cingulate cortex (ACC) [8, 9]. The ACC is involved in the processing of pain, emotion, and threat related stimuli [10, 11], and we recently found a trace fear memory enhancement in mice overexpressing Ca2+ ⁄ calmodulin-dependent protein kinase IV (CaMKIV), that corresponded with enhancements of ACC LTP in layer II/III pyramidal neurons . In rats, trace fear conditioning induces ACC c-fos expression, and visual distraction during the time interval separating the CS and US prevents fear memory and c-fos expression .
Glutamatergic synapses in the ACC are plastic [14–16], and the N-methyl-D-aspartate (NMDA) receptors are critical for LTP induction within the ACC . The GluN2B subunit in particular has been found to be a critical mediator of pain induced alterations within the ACC , and forebrain overexpression of GluN2B in mice enhances contextual and auditory fear memory . We previously showed that LTP induction within the ACC corresponds with postsynaptic upregulation of AMPA receptor GluA1 subunits [15, 20]. Interestingly, AMPA receptor plasticity is strongly implicated in learning and memory [5, 21], and several studies suggest that calcium permeable AMPA receptors (CP-AMPARs) mediate synaptic strengthening [22–24]. In particular, in the CA1 region of the hippocampus, transient increases of CP-AMPARs were observed in response to LTP induction through theta burst stimulation  and pairing protocols . However whether such rapid plastic events occur within the cortex in response to trace fear learning, and whether GluN2B subunits are required remains unknown. In the present study, we used integrative methods, including behavioral, pharmacological, biochemical, and electrophysiological, to determine if plasticity related events occur within the ACC during trace fear learning.
Trace fear learning upregulates membrane AMPA receptor GluA1 subunits within the ACC
Activation of NMDA receptor GluN2B subunits is required for the induction of trace fear memory
Trace fear learning induced membrane GluA1 upregulation is GluN2B dependent
Our results revealed that trace fear conditioning rapidly upregulates GluA1 subunits within the ACC, and that NMDA receptor GluN2B subunit activity is required for trace fear conditioning. We thus next sought to determine if treatment with Ro25-6981 prior to trace fear conditioning affects learning induced upregulation of membrane GluA1 within the ACC. We exposed mice to i.p. injections of Ro25-6981 (10 mg/kg i.p.) and either exposed them to trace fear conditioning, or to the chamber alone. Remarkably, treatment with Ro25-6981 prior to training completely blocked trace fear induced membrane GluA1 upregulation within the ACC (chamber: 1.0 ± 0.1; trace fear: 1.1 ± 0.1 times the chamber alone value; Figure 2D), indicating that the downstream target of learning induced GluN2B activity is the AMPA receptor GluA1 subunit. Importantly, the effects of Ro25-6981 treatment on trace fear learning are not due to any analgesic effects that may impair CS-US associations, as i.p. injections of Ro25-6981 had no effect on acute pain nociception as evidenced by similar nociceptive thresholds in hot plate and tail flick assays (Figure 2E).
GluN2B subunits within the ACC are required for trace fear memory
CP-AMPAR activity within the ACC is necessary for trace fear memory consolidation
Trace fear learning rapidly induces functional CP-AMPA receptors within the ACC
Trace fear extinction eliminates NASPM induced attenuation of ACC pyramidal EPSCs
The present study is the first to demonstrate that rapid AMPA receptor potentiation within the ACC mediates trace fear learning. We have identified that trace fear conditioning induces an upregulation of membrane bound GluA1 within the ACC that is evident immediately after conditioning. We have shown that NMDA receptor GluN2B subunit activity within the ACC is critical for trace fear learning, and disruption of these receptors during conditioning prevents AMPA receptor GluA1 subunit upregulation and fear memory retrieval. Furthermore, we found that blockade of CP-AMPAR activity immediately following trace fear conditioning is sufficient to prevent trace fear memory retrieval 24 h later. Accordingly, through the use of transgenic FosGFP mice, we observed that trace fear learning potentiates CP-AMPARs in c-fos expressing ACC pyramidal cells. These findings show that early memory formation occurs within the cortex during trace fear learning, and identifies a critical, rapid synaptic strengthening mechanism that is necessary for consolidation of long term fear memory.
Trace fear learning induces immediate membrane GluA1 upregulation
A key component of LTP induction is the upregulation of postsynaptic AMPA receptors , and AMPA receptor plasticity is strongly implicated in learning and memory [5, 21]. Here we report a rapid increase in membrane GluA1 subunit protein in the ACC of mice extracted immediately after in vivo trace fear learning. This is consistent with recent observations that trace eye blink conditioning induces changes in neuronal firing within the mPFC . Our findings support the notion that experience dependent synaptic activity can "tag" specific synapses for subsequent changes in excitatory transmission . Previous investigations of fear learning have identified changes in excitatory transmission within the hippocampus and amygdala [4–7, 33], and increases of GluA1 in dendritic spines of CA1 neurons have been observed 24 h after contextual fear conditioning . Our results therefore suggest that fear learning is mediated through a complex interplay between various brain areas, and that rapid plasticity within the cortex is in itself a mediator of learning induced alterations that are required for long term memory consolidation. Indeed, the recent findings that CaMKIV is required for translation-dependent early synaptic potentiation within the ACC  and that trace fear memory is enhanced in mice overexpressing CaMKIV , suggest that targeting these early cortical changes induced by learning can alter the strength of the consolidation of the fear memory.
NMDA receptor GluN2B subunit dependent AMPA GluA1 upregulation
We found that in vivo blockade of NMDA receptor GluN2B subunits during trace fear conditioning prevented fear memory recall, and blocked the upregulation of membrane bound GluA1; indicating that GluA1 subunits are the downstream target of experience dependent GluN2B activity. This is in accordance with previous observations that genetic GluN2B overexpression can enhance fear memory acquisition . Although LTP has long been considered to be the neural substrate for learning and memory , and reports have shown that NMDA GluN2B subunit activity is critical for ACC LTP , and that AMPAR insertion corresponds to potentiation of excitatory synaptic transmission [22, 36, 37], this is the first evidence that in vivo trace fear learning induces rapid GluN2B mediated AMPAR insertion within the cortex. Indeed, although various publications implicate NMDA receptors in several brain regions in fear memory, including the amygdala , hippocampus [38, 39], and forebrain , studies had yet to identify the learning related downstream target. In addition, studies have questioned the requirement of NMDA GluN2B receptors in hippocampal LTP and learning [40, 41]. Our findings highlight that there is a critical cortical contribution to fear learning, and that early GluN2B dependent plasticity within the cortex is necessary for long term memory recall.
CP-AMPAR activity within the ACC is necessary for memory consolidation
Mounting evidence indicates that AMPA receptor trafficking is a critical component of synaptic strengthening, and may underlie learning [21, 30, 42]. Accordingly, we observed that in vivo blockade of CP-AMPARs in the ACC immediately following trace fear conditioning robustly blocked memory retrieval 24 h later. In combination with our biochemical and behavioral data, these findings indicate that rapid CP-AMPA receptor upregulation during conditioning is necessary for long term memory consolidation, and is the first account that early memory formation within the ACC is necessary for long term retrieval. Several studies support the recruitment of CP-AMPARs in synaptic strengthening [22–24]. In particular, in the CA1 region of the hippocampus, different LTP induction protocols have been demonstrated to induce transient increases of CP-AMPARs, including theta burst stimulation , and pairing protocol , but see . Of particular interest are previous in vitro observations in the CA1 region of the hippocampus, where LTP induced by a pairing protocol corresponded to rapid CP-AMPAR upregulation  that lasted less than 25 minutes, and was NMDA receptor dependent. Importantly, LTP induction corresponded to increases in sensitivity to the CP-AMPAR channel blocker polyamine toxin philanthotoxin 433 (PhTx). Remarkably, there was a lack of LTP recovery if PhTx was applied immediately after LTP induction, suggesting that activation of new CP-AMPARs immediately after LTP induction is necessary for subsequent LTP. Here we present in vivo evidence that disrupting CP-AMPAR activity within the ACC immediately after conditioning prevents subsequent memory consolidation processes necessary for long term memory retrieval. Thus our findings support the notion that activity-dependent synaptic "tagging" may mediate stabilization of LTP , and that such mechanisms within the cortex are rapidly engaged during trace fear learning.
Recording from fear-triggered ACC neurons
Several studies indicate that memory storage for a given memory is mediated by a select population of neurons [5, 22, 44]. Given that various publications have suggested correlations between c-fos expression and synaptic strengthening and learning [13, 22, 33], we used FosGFP transgenic mice to assess the effects of trace fear conditioning on CP-AMPAR mediated currents. Using whole cell patch clamp recordings of recently activated pyramidal neurons in layer II/III of the ACC, we observed that blockade of CP-AMPARs yielded a reduction of EPSC amplitude to 67% of baseline, significantly greater than in neighbouring FosGFP negative cells, confirming that trace fear conditioning potentiates postsynaptic CP-AMPAR activity. Interestingly, we observed that reconsolidation update extinction training completely reverses this effect, indicating that fear memory is mediated through CP-AMPAR trafficking within the ACC.
We focused our recordings on layer II/III neurons as there is strong evidence that thalamic-ACC evoked potentials extend through layer V/VI of the ACC and into layer II/III . Furthermore, we have previously shown that within the ACC, pyramidal neurons in layer II/III undergo changes in excitatory transmission in response to LTP induction protocols and chronic pain [14, 15, 20]. More importantly, through recordings of layer II/III pyramidal ACC neurons, we identified enhanced LTP in mice overexpressing CaMKIV, which corresponded with enhancements in trace fear learning . Furthermore, although observations within the amygdala have shown that fear memory extinction is mediated through CP-AMPAR removal , and postsynaptic GluA2 expression is required for fear memory maintenance , this is the first report that fear learning corresponds with cortical synaptic CP-AMPAR trafficking. Importantly, although CP-AMPARs are present in interneurons, it is unlikely that our recordings are affected by inhibitory transmission, as picrotoxin was present in all our recordings.
Experiments were performed with adult (8-12 week) male C57/BL6 mice purchased from Charles River (Quebec, Canada) or transgenic FosGFP mice obtained from the laboratory of Dr. Alison Barth (Carnegie Mellon University). Animals were housed under a 12 h light/dark cycle, and all experiments were performed under protocols approved by the University of Toronto Animal Care Committee.
All conditioning was completed in an isolated shock chamber (Medical Associates, St Albans, VT, USA). Trace fear conditioning was performed as reported previously . Briefly, the conditioned stimulus (CS) used was an 80-db white noise, delivered for 15 s, and the unconditioned stimulus (US) was a 0.75-mA electric foot-shock for 0.5 s. Mice were acclimated for 5 min, and were presented with 10 trials in the following order: CS - trace - US - intertrial interval (ITI) (trace period = 30 s, ITI = 210 s). For delay fear conditioning, the conditioning stimulus (CS) used was an 80-db white noise, delivered for 15 s, and the unconditioned stimulus (US) was a 0.75-mA electric foot-shock for 0.5 s that was presented at 14.5 sec into the CS presentation, such that the CS and US co-terminated. Reconsolidation update conditioning was performed as published previously with minor modifications . Briefly, 24 h following exposure to trace fear conditioning, mice were placed in a novel environment and exposed to one presentation of the CS; were then returned to their home cage for 30 min; and were then reintroduced to the novel environment and exposed to 20 CS presentations with an ITI of 143 sec. For memory retrieval tests, mice were introduced to a novel chamber and were acclimated for 5 min and subjected to a presentation of the CS to test for trace fear memory (Huerta, 2000 #210). All data were recorded using the video-based Freeze Frame fear conditioning system and analyzed by Actimetrics Software (Coulbourn Instruments, Wilmette). Average freezing for the baseline and for the trace period (30 s) following the CS during the training and testing sessions were analyzed. Freezing bouts of 1 s or more were considered as freezing (the absence of movement aside from respiration).
ACC cannulae implantation and microinjection
We implanted bi-lateral cannulas into the ACC of mice as reported previously . Briefly, mice were anaesthetized by intraperitoneal (IP) injections of a mixture of 1.3 mL of ketamine (100 mg/ml, Bimeda MTC, Cambridge, Ontario) and 0.5 ml of xylazine (20 mg/ml, Bayer, Toronto, Ontario, Canada) in 8.2 ml of normal saline at a dose of 10 μl per gram body weight. Mice heads were secured on a stereotaxic frame and 24-gauge guide cannulas were implanted bilaterally into the ACC (0.7 mm anterior to bregma, ± 0.3 mm lateral from the midline, 0.9 mm beneath the surface of the skull). Mice were given 2 weeks to recover after cannula implantation. Intra-ACC injections were delivered via a 30-gauge injection cannula that was lowered 0.85 mm further into the brain than the guide. The microinjection apparatus consisted of a Hamilton syringe (10 μl) connected to an injector needle (30 gauge) by a thin polyethylene tube and motorized syringe pump. All infusions consisted of 0.5 μl of solution delivered at a rate of 0.05 μl/min. Injection sites were confirmed at the end of all experiments and sites outside of the ACC region were excluded from the study.
Membrane preparation was performed as previously described  with minor changes. Briefly, ACC samples were dissected in cold D-PBS and resuspended in Buffer 1 (2 mM Tris-EDTA, 320 mM sucrose, 5 mM MgCl2, and 1X protease inhibitor cocktail, pH 7.4), and homogenized. Each sample was centrifuged at 1000 × g for 10 min and the supernatants (S1) were recovered. The remaining pellet (P1) was then resuspended in Buffer 2 (50 mM Tris-HCl, 2 mM Tris-EDTA, 5 mM MgCl2, and 1X phosphatase inhibitor cocktail 1 and 2, pH 7.0) and centrifuged at 1000 × g for 10 min, with its supernatant (S2) collected and combined with S1. The remaining pellet (P2) was resuspended in Buffer 2, and again centrifuged at 1000 × g for 10 min., and its supernatant (S3) was combined with S1 and S2. Combined supernatant fractions (S1, S2 and S3) were finally centrifuged at 39,000 × g for 30 min, the resulting supernatant contained the cytosolic fractions, and the resulting pellet (membrane fractions) was resuspended in Buffer 3 (50 mM Tris-HCl, 2 mM Tris-EDTA, 3 mM MgCl2, and 1X phosphatase inhibitor cocktail 1 and 2, pH 7.4).
Western blot analysis
Western blot was performed as previously described . Sample protein concentrations were quantified using Bradford assay, and electrophoresis of equal amounts of protein was performed on NuPAGE 4-12% Bis-Tris Gels (Invitrogen, Carlsbad, CA). Separated proteins were transferred to polyvinylidene fluoride membranes (Pall Corporation, East Hills, NY) at 4°C overnight for analysis, and were then probed with primary antibodies as follows: anti-GluA1 (1:4000, rabbit polyclonal), anti-GAPDH (1:6000, mouse monoclonal), anti-GluA2/3 (1:1000, rabbit polyclonal), followed by horseradish peroxidase (HRP)-coupled secondary antibody diluted at 1:3000 for 2 hours followed by enhanced chemiluminescence detection of the proteins with Western lightning chemiluminescence reagent plus (PerkinElmer Life Sciences). ImageJ software (National Institute of Health) was used to assess the density of immunoblots by a blind observer.
Immunostaining was performed as described previously [12, 14]. Briefly, mice were anesthetised with isoflurane and perfused with 0.01 mol/l phosphate-buffered saline (PBS; pH 7.4) via the ascending aorta followed by perfusion of 4% paraformaldehyde (PFA) in 0.1 mol/l PB at 4°C. The brains were removed and post-fixed for 4 hours in 4% PFA, after which brains were placed in vials filled with 30% sucrose in 0.1 mol/l PB overnight at 4°C for at least 48 hours, or until the brain fully dropped to the bottom of the jar. Brain sections containing the ACC were cut using a cryostat (Leica) at 30 μm thickness. Briefly, sections were sequentially incubated through the following solutions: (i) a solution of 3% bovine serum albumin (BSA; Sigma, St Louis, USA) and 0.3% Triton X-100 containing anti- c-fos (1:500 abcam) primary antibody for 3 days at 4°C. (ii) Biotin labelled goat anti-rabbit secondary antibody (1:1000 Santa Cruz, CA) for 24 hours at 4°C (iii) Cy3 conjugated streptavidin (1:1000; Santa Cruz, CA, USA) for 2 hours at room temperature. In between each step, sections were rinsed with PBS 3 times for 10 min. Sections were mounted on gelatin coated slides, air-dried, cleared and cover-slipped for observation under a confocal microscope (FV-1000, Olympus, Japan).
Coronal brain slices (300 μm) at the level of the ACC were prepared using standard methods [14, 15, 49] immediately after trace fear conditioning. Slices were transferred to a submerged recovery chamber with oxygenated (95% O2 and 5% CO2) artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 2.5 KCl, 2 CaCl2, 1 MgSO4, 25 NaHCO3, 1 NaH2PO4, and 10 glucose at room temperature for at least 1 hr. Experiments were performed in a recording chamber on the stage of a BX51W1 microscope equipped with infrared differential interference contrast optics for visualization. Excitatory post-synaptic currents (EPSCs) were recorded from layer II/III neurons with an Axon 200B amplifier (Molecular Devices Inc., Sunnyvale, CA, USA), and the stimulations were delivered by a bipolar tungsten stimulating electrode placed in layer V of the ACC. AMPA/KA receptor-mediated EPSCs were induced by repetitive stimulations at 0.05 Hz, and neurons were voltage-clamped at -60 mV (without liquid junction potential correction) in the presence of AP5 (50 μM). The recording pipettes (3-5 MΩ) were filled with a solution containing (in mM) 124 K-gluconate, 5 NaCl, 1 MgCl2, 0.2 EGTA, 10 HEPES, 2 Mg-ATP, 0.1 Na3-GTP, and 10 phosphocreatine disodium (adjusted to pH 7.2 with KOH). Picrotoxin (100 μM) was always present to block γ-aminobutyric acid (A) (GABAA) receptor-mediated inhibitory synaptic currents in all experiments. The initial access resistance was 15-30 MΩ, and it was monitored throughout the experiment. Data were discarded if the access resistance changed > 15% during an experiment. Data were filtered at 1 kHz, and digitized at 10 kHz.
In order to block NMDA receptor GluN2B subunit activity, we used Ro-25-6981 or Ifenprodil (Tocris Bioscience), NMDA receptor antagonists that target the GluN2B subtype [18, 50]. Mice were given i.p. injections of 10 mg/kg doses, and bilateral ACC 0.5 μl infusions (2 μg/μl) for the microinjection studies. To block CP-AMPA receptors we used the antagonist, 1-naphthylacetyl spermine (NASPM).
Nociceptive behavioral tests
In the hotplate test, mice were placed on a standard thermal hotplate with a heated surface (55°C) (Columbus Instruments, Columbus, OH). The latency for nociceptive responses was recorded with a cut-off time of 30 seconds. The spinal nociceptive tail-flick reflex was evoked by radiant heat (Columbus Instruments, Columbus, OH) applied to the underside of the tail, and latencies were measured with a cut-off time of 10 seconds.
Results are expressed as mean ± SEM. Statistical comparisons were made using a one way ANOVA adjusted by the Holm-Sidak test for multiple comparisons, or unpaired student t-tests. In all cases, P < 0.02 is considered statistically significant.
Supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, and NSERC discovery grant 402555. G. Descalzi is funded by the E. Fidlar Ontario Graduate Scholarship; X.-Y.Li, T.Chen, and K. Koga are supported by postdoctoral fellowships from the Fragile × Research Foundation of Canada. We would like to thank Dr. Alison L. Barth for her generous donation of FosGFP transgenic mice; Dr. Sheena Josselyn for her helpful suggestions; and Heather Kang for her help with behavior studies.
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