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. Author manuscript; available in PMC: 2025 Sep 7.
Published in final edited form as: Neuroscience. 2025 Feb 1;569:288–297. doi: 10.1016/j.neuroscience.2025.01.065

Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical protein kinase C in the anterior cingulate cortex

William Almaguer-Melian 1,*, Daymara Mercerón-Martínez 1,*, Laura Alacán-Ricardo 2, Arturo Bejerano Pina 2, Changchi Hsieh 3, Jorge A Bergado-Rosado 4, Todd Charlton Sacktor 3,5
PMCID: PMC12413895  NIHMSID: NIHMS2106596  PMID: 39900220

Abstract

Although many studies have addressed the role of the amygdala in modulating long-term memory, it is not known whether weak training plus amygdala stimulation can transform a short-term memory into a remote memory. Object place recognition (OPR) memory after strong training remains hippocampus-dependent through the persistent action of protein kinase Mzeta (PKMζ) for at least 6 days, but it is unknown whether weak training plus amygdala stimulation can transform short-term memory into an even longer memory, and whether such memory is stored through more persistent action of PKMζ in hippocampus. We trained male rats (150 total in our study) to acquire OPR and 15 min or 5 h later induced a brief pattern of electrical stimulation in basolateral amygdala (BLA). Our results reveal that a short-term memory lasting <4 h can be converted into remote memory lasting at least 3 weeks if the BLA is activated 15 min, but not 5 h after learning. To examine how this remote memory is maintained, we injected ZIP, an inhibitor of atypical protein kinase Cs (aPKCs), PKMζ and PKCι/λ, into either hippocampal CA1, dentate gyrus (DG), or anterior cingulate cortex (ACC). Our data reveal amygdala stimulation produces consolidation into remote memory, not by persistent aPKC activation in the hippocampal formation, but in ACC. Our data establish a powerful modulating role of the BLA in forming remote memory and open a path in the search for neurological restoration of memory, based on enhancing synaptic plasticity in aging or neurodegenerative disorders such as Alzheimer’s disease.

Keywords: remote memory, aPKC, PKMζ, PKMzeta, PKM-zeta, anterior cingulate cortex

Introduction

Learning and memory constitute the basis by which animals build internal models of the world in the domains of space and time, allowing useful predictions founded upon stored experience. Understanding the mechanisms of memory is one of the fundamental challenges of neuroscience. In particular, how of all the information that our nervous system continuously processes, only some is selected for permanent storage. Extensive literature shows that the basolateral amygdala (BLA) is a critical region for memory consolidation (McGaugh JL, 2002; McGaugh JL, 2015; Parent MB et al., 1995; Roozendaal B and McGaugh JL, 1997). Pharmacological studies have shown that post-training BLA interference disrupts the consolidation of memories (Hatfield T and McGaugh JL, 1999; Nedaei SE et al., 2016; Packard MG et al., 1994; Sardari M et al., 2015), whereas post-training intra-BLA administration of norepinephrine promotes memory consolidation (LaLumiere RT et al., 2003; Roesler R et al., 2021). Moreover, β-adrenergic antagonists administered in BLA prevents the memory reinforcement produced by systemic administration of epinephrine, glucocorticoid agonists, the opioid antagonist naltrexone, or ketamine (Campolongo P et al., 2009; Liang KC et al., 1986; Morena M et al., 2021; Quirarte GL et al., 1997). In addition, noradrenergic activation of the BLA enhances the consolidation of object recognition memory, suppressing anterior insular cortex activity (Chen Y et al., 2018; Chen YF et al., 2022). More recently, optogenetic stimulation of BLA projections to the medial entorhinal cortex immediately after memory acquisition was found to enhance spatial and contextual memory retention (Wahlstrom KL et al., 2018). Human studies furthermore showed that electrical stimulation of the amygdala leads to improved memory (Inman CS et al., 2018). Interestingly, we have repeatedly observed that BLA stimulation can improve spatial learning skills in rats with profound cognitive deficits produced by lesions of the fimbria fornix, suggesting that similar procedures could contribute to the recovery of memory capacities in humans (Almaguer-Melian W et al., 2005; Mercerón-Martínez D et al., 2018; Mercerón-Martínez D et al., 2020; Merceron-Martinez D et al., 2016; Mercerón-Martínez D et al., 2016; Mercerón-Martínez D et al., 2022; Mercerón-Martínez D et al., 2013).

In addition to BLA regulating memory consolidation, studies of synaptic plasticity such as long-term potentiation (LTP), a cellular model of memory (Bailey CH et al., 2015; Bliss TV and Lomo T, 1973; Matthies H, 1989), suggest underlying mechanisms for how amygdala activity can modulate memory. These studies have shown that amygdala stimulation can modulate LTP in the dentate gyrus (DG) (Akirav I and Richter-Levin G, 1999; Akirav I and Richter-Levin G, 1999; Ikegaya Y et al., 1994; Ikegaya Y et al., 1995; Ikegaya Y et al., 1995). Likewise, emotional-motivational behavioral stimulation can prolong short-lasting early-LTP (E-LTP) into long-lasting late-LTP (L-LTP) (Almaguer-Melian W et al., 2010; Seidenbecher T et al., 1997). Similarly, direct stimulation of the BLA within a time window close to that of LTP induction, prolongs early-LTP into late-LTP (Frey S et al., 2001). Conversely, transient or permanent inactivation of the BLA abolishes the behavioral reinforcing effects on LTP (Almaguer-Melian W et al., 2003). The neural pathways involved in the BLA reinforcement of LTP include adrenergic terminals from the locus coeruleus and cholinergic afferents from the medial septum (Bergado JA et al., 2007). More recently, we have provided data showing that BLA stimulation for 15 min daily for 4 days after water maze training promotes recovery of spatial memory and LTP that was impaired by fimbria-fornix injury, suggesting a possible functional relationship between the recovery of synaptic plasticity and the recovery of memory (Mercerón-Martínez D, et al., 2022).

Memory and LTP share molecular mechanisms that, in a temporally sequenced manner, sustain their expression through different phases (Reymann K et al., 1988). Intermediate and long-term phases depend on multiple protein kinases and protein synthesis during its initial consolidation period (Krug M et al., 1984).

Beyond this initial consolidation period, the maintenance of late-LTP and long-term memory have been proposed to fundamentally depend on the persistent action of atypical protein kinase C (aPKC), comprised of 2 isoforms, protein kinase Mzeta (PKMζ), an unusual, autonomously active PKC (Sacktor TC and Hell JW, 2017), and the redundant, closely related isoform, PKCι/λ, (Patel H and Zamani R, 2021; Tsokas P et al., 2016). PKMζ consists of the independent catalytic domain of aPKCζ (Hernandez AI et al., 2003; Sacktor TC et al., 1993). Most PKCs contain a regulatory domain, with second messenger-binding sites and an autoinhibitory sequence, that inhibits the activity of a catalytic domain (Nishizuka Y, 1995). Second messengers activate these full-length PKCs by binding to the regulatory domain and causing a conformational change that releases the autoinhibition. As second messengers increase only transiently, the activation of most PKCs is brief. PKMζ, in contrast, lacks a regulatory domain and is thus autonomously active without second-messenger stimulation (Sacktor TC, et al., 1993). Instead, PKMζ activity is regulated by the amount of the kinase, which increases via new protein synthesis in late-LTP and long-term memory consolidation (Hernandez AI, et al., 2003; Hsieh C et al., 2016; Osten P et al., 1996; Tsokas P, et al., 2016). After synthesis, PKMζ then binds to the postsynaptic scaffolding protein, kidney and brain expressed protein, KIBRA, and the continual interaction of the two proteins maintains synaptic potentiation at activated synapses and long-term spatial memory in hippocampus (Tsokas P et al., 2024; Vogt-Eisele A et al., 2013). With genetic deletion of PKMζ, the other aPKC, PKCι/λ, becomes persistently active, compensating for the absence of PKMζ to maintain late-LTP and long-term memory (Tsokas P, et al., 2016).

Object placement recognition (OPR) memory produced by strong training is hippocampus-dependent through the persistent action of aPKC for at least 6 days (Hardt O et al., 2010), but it is not known whether weak OPR training plus amygdala stimulation can transform a short-term memory or (<4 h) into an even longer remote memory lasting weeks, and whether such a memory might be stored through even more persistent activation of aPKC in hippocampus. To examine these questions, we applied the aPKC inhibitor ZIP (Sacktor TC and Fenton AA, 2012) to trained animals to ascertain whether BLA stimulation can maintain remote memory by persistently activating PKMζ or PKCι/λ, either in the hippocampal formation or in cortical regions such as the anterior cingulate cortex (ACC). ZIP is a cell-permeable myristoylated peptide that reproduces the autoinhibitory sequence of the PKCζ and PKCι/λ regulatory domain (Ling DS et al., 2002). Applications of ZIP thus reconstitute the autoinhibition of the PKCζ regulatory domain missing in PKMζ, suppressing PKMζ or PKCι/λ activity. ZIP blocks the synaptic potentiating action of postsynaptically perfused PKMζ or PKCι/λ, but not potentiation caused by activation of full-length conventional or novel PKCs (Tsokas P, et al., 2016), and the agent reverses established late-LTP and long-term memory for at least 1 month after initial learning (Pastalkova E et al., 2006; Serrano P et al., 2005). Our data suggest that BLA stimulation within the initial modulation window of neural plasticity (Frey U and Morris RG, 1997; Frey U and Morris RG, 1998) induces remote memory formation by the persistent action of aPKC in ACC. These results show that concurrent amygdala activation can convert an incidental short-term memory of daily experience (<4 h) into a remote memory that could potentially last a lifetime in neocortex, opening new possibilities for its use to improve memory capacity in memory disorders such as Alzheimer’s disease.

Materials and Methods

Animals

We used 150 eight-week-old male Wistar rats weighing 270 to 300 g at the beginning of the experiment. Animals were provided by the Cuban National Center for Laboratory Animals (CENPALAB) and maintained in translucent plastic cages (5 animals per cage) under controlled environmental conditions (23 °C, constant humidity, 12-h light-dark cycles) with free access to food and water throughout the experiment.

Ethics

All rats were handled and maintained according to the international ethic norms for the use of laboratory animals, and abide by the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) revised 1996, the UK Animals (Scientific Procedures) Act 1986 and associated guidelines, and the European Communities Council Directive of 24 November, 1986 (86/609/EEC). We also comply with the Cuban regulations published by CENPALAB and the internal regulations of the International Center for Neurological Restoration (CIREN). All efforts were made to reduce pain and discomfort. We have formed experimental groups with the smallest number of animals without affecting the methodological robustness of the experiments. Three days before beginning the behavioral studies, the animals were gently handled by the experimenter for about 2 h to reduce handling stress.

Chronic implantation of electrodes and intra-cerebral injection cannulae

Electrodes and injection cannulae were stereotactically implanted under anesthesia by intraperitoneal injection of ketamine (50 mg/10 ml), diazepam (10 mg/1 ml), and atropine (0.5 mg/1 ml) in a volume of 1 mL/100 g body weight. We bilaterally implanted the cannula in DG (anteroposterior [AP] = −3.8 mm, mediolateral [ML] = ±2.0 mm, and dorsoventral [DV] = −3.5 mm from bregma), cornu ammonis 1 (CA1: AP = −4.0; ML = ±4.0, and DV = −3.0 mm from bregma) or ACC (AP = +2.7; ML = ±0.6, and DV = −2.7), according to experimental group. After the cannulae were fixed with dental acrylic cement, we proceeded to bilaterally implant BLA electrodes (AP = −3.1 mm, ML = ±4.7 mm, and DV = −8.5 mm) (Paxinos G and Watson C, 1998). We attached 3 miniscrews to strengthen the preparation, and custom-made stainless steel 0.125 mm bipolar electrodes with epoxy-insulated wires were connected to a socket and fixed with dental acrylic cement (Veracril, New Stetic, Antioquia, Colombia). Representative images verifying the correct placement of the implanted cannulas and electrodes, and schematics of placements are shown in Supplementary Figure 1 (Fig. S1).

OPR memory test

To test our working hypothesis, we used OPR, a one-trial spatial memory task, based on the spontaneous activity of the animals to preferentially explore novelty within a familiar environment. The behavioral task was completed in three steps. On the first day, habituation was performed in an open field (50 x 50 cm), illuminated by a 40 W light bulb placed 1 m above the floor (30 lux). On one of the walls was fixed a spatial cue, consisting of a letter-type sheet with a black, 650 dpi, bold capital A. Animals were placed in the center of the open field, facing the spatial reference, and allowed to freely explore the arena for 5 min. Twenty-four hours later memory was acquired by placing two identical objects (white plastic bottles filled with water to ensure stability) in the open field. The animals were free to explore both objects for 3 min. The third step was the memory retention test, which was performed 2 h, 4 h, 24 h, or 21 days after acquisition. For the retention test, one of the objects (left bottle) was moved to a new location, and the animals were allowed to explore freely for 3 min. We measured exploration time for an object as the time in which the rat stayed with its head close (within ~2 cm) to the front of the object and sniffing (Bevins RA and Besheer J, 2006; Goh JJ and Manahan-Vaughan D, 2013; Ledonne A et al., 2018) or with its forelimbs on the object and sniffing (Ballarini F et al., 2009; Mumby DG et al., 2002). The mean exploration time of the changed object, presented as the percentage of the total exploration time of the two objects, is used for statistical analysis both during the acquisition and memory test phase in the main figures. A discrimination index is also calculated as: (time with novel location – time with familiar location)/(time with novel location + time with familiar location) (Denninger JK et al., 2018), and the indices are presented in Supplementary figures (Fig. S2–4), as well as the time of exploratory activity of two objects during acquisition and memory test phases in Table S1 (Bekci E et al., 2024; Neves L et al., 2022; Sinani A et al., 2022). We include in the analysis only data from animals exploring the objects for at least 1 s (Mumby DG, et al., 2002), but no animal explored less than 5 s; therefore, no animals were excluded from the experiments. All behavioral studies were conducted between 09:00-12:30 h to reduce circadian influences.

BLA stimulation

The stimulation was applied simultaneously to both BLA regions and consisted of 3 trains of 15 impulses at 200 Hz, as previously described (Frey S, et al., 2001). Each stimulus was 0.2 ms in duration, and the trains were delivered with 10 s intertrain intervals. The stimulation intensity was 400 μA each side. We applied this tetanus 15 min or 5 h after memory acquisition.

Experimental groups

The study design consisted of three experiments. Experiment I was to establish baseline values of short-term memory retention without BLA stimulation. Experiment II was to study the effect of BLA stimulation on the formation of long-term and remote memory. Experiment III was to examine whether the maintenance of remote memory (21 days) facilitated by amygdala stimulation depends on persistent aPKC action. To test this hypothesis, we injected ZIP (10 nmol in 1 μL in each side; Tocris Bioscience, UK) or vehicle (NaCl, 0.9%, pH 7.0) on day 19 in DG, CA1, or ACC.

Short- and long-term memory

  • 1

    Control 2 h: rats performed OPR memory test 2 h post-acquisition trial, n = 10

  • 2

    Control 4 h: rats performed OPR memory test 4 h post-acquisition trial, n = 13

  • 3

    Control 24 h: rats performed OPR memory test 24 h post-acquisition trial, n = 12

Amygdala stimulation facilitating long-term memory to remote memory

  • 4

    BLA-15 min + 24 h: rats received amygdala stimulation 15 min post-acquisition and performed OPR memory test 24 h post-acquisition trial, n = 7

  • 5

    BLA-5 h + 24 h: rats received amygdala stimulation 5 h post-acquisition and performed OPR test 24 h post-acquisition trial, n = 11

  • 6

    Control + 21 days: rats performed OPR memory test 21 days post-acquisition trial, n = 10

  • 7

    BLA-15 min + 21 days: rats received amygdala stimulation 15 min post-acquisition and performed OPR memory test 21 days post-acquisition trial, n = 10

Mapping aPKC-dependent remote memory storage by amygdala stimulation

  • 8

    Control DG + 21 days: rats received OPR memory testing 21 days post-acquisition, n = 14

  • 9

    BLA DG-NaCl: rats received amygdala stimulation 15 min post-acquisition, NaCl injections into DG on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 9

  • 10

    BLA DG-ZIP: rats received amygdala stimulation 15 min post-acquisition, ZIP injections into DG on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 11

  • 11

    Control CA1 + 21 days: rats received OPR memory testing 21 days post-acquisition, n = 10

  • 12

    BLA CA1-NaCl: rats received amygdala stimulation 15 min post-acquisition, NaCl injections into CA1 on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 11

  • 13

    BLA CA1-ZIP: rats received amygdala stimulation 15 min post-acquisition, injections into CA1 on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 9

  • 14

    BLA+ACC-NaCl: rats received amygdala stimulation 15 min post-acquisition, NaCl injections into AAC on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 7

  • 15

    BLA+ACC-ZIP: rats received amygdala stimulation 15 min post-acquisition, injections into AAC on day 19 post-acquisition, and OPR memory testing 21 days post-acquisition, n = 6

Statistical analysis

We first confirmed the normal distribution of the data using the Kolmogorov Smirnov test, and variance homogeneity by the Barlett’s test. For statistical analysis of data we used repeated measures ANOVA, using Tukey’s test for post hoc analysis. Statistical significance was defined as p < 0.05. In the graphs that appear in the figures, letters were placed to specify the significant differences between the exploration time during the acquisition and the memory test, and between the experimental groups. Equal letters denote that there are no significant differences, whereas different letters denote significant differences.

Results

Short-term memory for OPR

Animals were first habituated to an empty arena (Fig. 1A), in which the number of visits to the borders of the box rapidly decreases (repeated measures ANOVA, main effect of time is significant, F4, 84 = 243.22, p < 0.000001, η2p = 0.92, followed by the post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). The number of visits is indistinguishable between the groups that were randomly selected to be trained the next day (repeated measures ANOVA, main effect of group, F1, 21 = 2.14, p = 0.28, η2p = 0.075).

Fig. 1.

Fig. 1.

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Behavioral performance in OPR during short-term memory retrieval. (A) Habituation of 5-min exposures to open field shows no difference between 2 h and 4 h groups. (B) OPR retrieval test during short-term memory shows retention at 2 h, but not 4 h after learning. Above, schematic of experimental procedures. Below, means and standard error of the mean. Different letters denote significant differences, and same letters denote no significant differences.

We next defined the duration of a short-term memory for OPR. Twenty-four hours after habituation, animals were returned to the arena, which now contained two identical objects. Fig. 1B shows that whereas animals have no initial preference for one object or the other in this and subsequent experiments (~50% for each object, Supplementary Table S1), they explore the object that had been moved to a different location more when the retention test is carried out 2 h after training, but not when testing is delayed to 4 h (Fig. 1B, repeated measures ANOVA, main effect of group, F1, 21 = 13.41, p = 0.0015, η2p = 0.39; learning-memory test, F1, 21 = 8.94, p = 0.0070, η2p = 0.30; interaction of group and learning-memory test, F1, 21 = 12.97, p = 0.0017, η2p = 0.38, followed by post hoc Tukey HSD test; different letters mean significant differences; same letters denote no significant differences). The analysis using discrimination index shows similar results, that the animals at 2 h, but not 4 h, spend more time exploring the object with a changed position than the object with a familiar position (Fig. S2).

Amygdala stimulation facilitates long-term and remote OPR memory formation

We next examined whether amygdala stimulation after weak training facilitates the formation of long-term memory. Prior to training, habituation of animals occurs without any group difference (Fig. 2A, repeated measures ANOVA, main effect of time, F4, 108 = 127.32, p < 0.000001, η2p = 0.83; group, F2, 27 = 0.18, p = 0.84, η2p = 0.013. Significant differences are analyzed by post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). After short-term memory training, we stimulated the BLA and tested 24 h later. When the BLA was stimulated 15 minutes after training, retention of object placement memory was significantly longer than that of control, non-stimulated animals, or animals that receive BLA stimulation 5 hours after training after short-term memory had faded (Fig. 2B, repeated measures ANOVA, main effect of group, F2, 27 = 32.70, p < 0.000001, η2p = 0.71, effect of learning-memory test, F1, 27 = 7.46, p = 0.011, η2p = 0.22, interaction of group and learning-memory test, F2, 27 = 4.99, p = 0.014, η2p = 0.27, followed by post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). Control non-stimulated animals show no retention. Analysis using the discrimination index shows similar results (Fig. S3A–B). Thus, BLA activation prolongs a short-term memory trace, but only when it occurs within a time window close to training.

Fig. 2.

Fig. 2.

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Behavioral performance in the OPR task during long-term and remote memory retrieval facilitated by amygdala stimulation. (A) Habituation of 5-min exposures to open field shows no difference between groups. (B) Effect of time-dependent BLA stimulation on prolonging memory duration. Above, schematic of the experiment procedures. Below, means and standard error of the mean. (C) Habituation of 5 min exposures to open field shows no difference between groups. (D) OPR memory retention test shows BLA stimulation facilitates remote memory formation. Above, schematic of experimental procedures. Below, means and standard error of the mean. Different letters denote significant differences, and same letters denote no significant differences.

We then assessed whether amygdala stimulation also promotes remote memory formation lasting weeks. Prior to training, habituation of animals occurs without any group difference (Fig. 2C, repeated measures ANOVA, main effect of time, F4, 72 = 142.73, p < 0.000001, η2p = 0.89; group, F1, 18 = 1.78, p = 0.29, η2p = 0.061). Significant differences are analyzed by the post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). Stimulation of the amygdala 15 min after training causes the exploration time of the object in the new position to be greater than that of the object in the familiar position 21 days after training (Fig. 2D, repeated measures ANOVA, main effect of group, F1, 18 = 5.98, p = 0.025, η2p = 0.25; effect of learning-memory test, F1, 18 = 8.20, p = 0.010, η2p = 0.31; interaction of group and learning-memory test, F1, 18 = 13.40, p = 0.0018, η2p = 0.43, followed by post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences).

Remote OPR memory storage facilitated by amygdala stimulation depends on persistent aPKC action in ACC

We then examined the location of long-term memory storage for BLA stimulation-facilitated OPR. Strong OPR training without stimulation produces a memory that remains hippocampus-dependent and sensitive to ZIP for at least 6 days, and thereafter fades (Hardt O, Migues PV, Hastings M, Wong J and Nader K, 2010). BLA stimulation might make this hippocampus-dependent memory more persistent. Alternatively, memories can be initially stored in hippocampus and then become dependent on extrahippocampal regions during remote memory storage, and BLA stimulation might induce this consolidation at the systems level. To distinguish between these possibilities, we inhibited PKMζ in three memory-relevant regions: DG, CA1, and ACC. Figs. 3A, C, and E show habituation without group differences (Fig. 3A, repeated measures ANOVA, main effect of time, F4, 124 = 368.58, p < 0.000001, η2p = 0.92, group, F2, 31 = 1.57, p = 0.22, η2p = 0.092; Fig. 3C, time, F4, 108 = 70.03, p < 0.000001, η2p = 0.72, group, F2, 27 = 0.27, p = 0.77, η2p = 0.020; Fig. 3E, time, F4, 44 = 87.46, p < 0.000001, η2p = 0.89, group, F1, 11 = 1.02, p = 0.33, η2p = 0.085, followed by post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). We injected ZIP 19 days after training, and then tested retention 2 days later, a duration that allows for elimination of ZIP in order to test the inhibitor’s effect on memory maintenance (Pastalkova E et al., 2006). The results reveal that blocking aPKC in the DG or CA1 has no disruptive effect on remote memory retention after training facilitated by BLA stimulation (Fig. 3B, repeated measures ANOVA, main effect of group, F2, 31 = 3.96, p = 0.030, η2p = 0.20, learning-memory test, F1, 31 = 21.14, p = 0.000068, η2p = 0.41, interaction of group and learning-memory test, F2, 31 = 5.09, p = 0.012, η2p = 0.25; Fig. 3D, main effect of group, F2, 27 = 6.17, p = 0.0062, η2p = 0.31, learning-memory test, F1, 27 = 21.18, p = 0.000089, η2p = 0.44, interaction of group and learning-memory test, F2, 27 = 5.43, p = 0.010, η2p = 0.29, followed by the post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences). In striking contrast, ZIP completely disrupts memory maintenance when applied in the ACC (Fig. 3F, repeated measures ANOVA, main effect of group, F1, 11 = 74.63, p = 0.000003, η2p = 0.87, learning-memory test, F1, 11 = 27.50, p = 0.00028, η2p = 0.71, interaction of group and learning-memory test, F1, 11 = 19.66, p = 0.0010, η2p = 0.64, followed by the post hoc test of Tukey HSD; different letters denote significant differences; same letters denote no significant differences), indicating persistent aPKC activity in this brain region maintains remote OPR memory. Analysis using the discrimination index shows similar results (Fig. S4).

Fig. 3.

Fig. 3.

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ZIP administration in DG, CA1, or ACC on behavioral performance in the OPR task during remote memory facilitated by amygdala stimulation reveals only ACC administration disrupts remote memory maintenance. (A, C, E) Habituation for 5-min exposures to open field shows no difference between groups. (B, D, F) Effects of intracranial DG, CA1, or ACC ZIP administration on BLA-stimulated remote memory. Above, schematic of experimental procedures. Below, means and standard error mean. (B) DG shows no effect; (D) CA1 shows no effect; (F) ACC shows disruption of remote memory. Different letters denote significant differences, and same letters denote no significant differences.

Discussion

In this study we obtained evidence that activation of the amygdala close to the time of memory acquisition produces a consolidation at the systems level through the persistent action of aPKC in the anterior cingulate cortex, all of which contributes to establishing and maintaining a memory remote from experience. We found that BLA activation can facilitate not only the consolidation of short-term memory lasting less than 4 hours (Fig. 1B, Fig. S2) into long-term memory lasting a day (Fig. 2B, Fig. S3A), but also into remote memory lasting weeks (Fig. 2D, Fig. 3B, D, F, and Fig. S3B, Fig. S4A, B, C). This consolidation occurs if the BLA is activated 15 min, but not 5 h, after acquisition (Fig. 2B, Fig. S3A). Our data are in line with previous reports showing that the BLA is a critical region involved in memory consolidation (Campolongo P, et al., 2009; Chen Y, et al., 2018; Chen YF, et al., 2022; Hatfield T and McGaugh JL, 1999; LaLumiere RT, et al., 2003; Liang KC, et al., 1986; McGaugh JL, 2002; McGaugh JL, 2015; Morena M, et al., 2021; Nedaei SE, et al., 2016; Packard MG, et al., 1994; Parent MB, et al., 1995; Quirarte GL, et al., 1997; Roozendaal B and McGaugh JL, 1997; Sardari M, et al., 2015; Wahlstrom KL, et al., 2018), including that BLA stimulation improves object recognition memory (Bass DI et al., 2014). Our findings also support the notion that the BLA consolidates memory through synaptic plasticity such as LTP (Akirav I and Richter-Levin G, 1999; Akirav I and Richter-Levin G, 1999; Almaguer-Melian W, et al., 2010; Almaguer-Melian W, et al., 2003; Bergado JA, et al., 2007; Frey S, et al., 2001; Ikegaya Y, et al., 1994; Ikegaya Y, et al., 1995; Ikegaya Y, et al., 1995; Seidenbecher T, et al., 1997) that is maintained by PKMζ (Ling DS, et al., 2002; Pastalkova E, et al., 2006; Tsokas P, et al., 2024). To these findings, our results add new complexity at the systems level to the BLA’s modulatory role in encoding memory duration. Our data reveal that remote memory facilitated by BLA stimulation is mediated by persistent aPKC activity in the ACC, because the aPKC-inhibitor ZIP abolishes memory when administered on day 19 post-acquisition in ACC, but not in CA1 or DG.

There is general consensus that episodic memory initially depends on the hippocampus (recent memory) as it contributes to coordinating the activation of synapses widely distributed throughout the cortex that participate in memory encoding. Furthermore, successive reactivations of these memory traces coordinated by the hippocampus, contribute to increasing the efficiency of transmission among its cortical elements, thus creating a cortical representation of the experience that is less dependent on the hippocampus, known as remote memory (Dudai Y, 2004; Dudai Y et al., 2015; Hardt O and Nadel L, 2018; Kandel E et al., 2014; Squire LR et al., 2015). This transformation or stabilization of memory seems to imply that memory becomes more generalized, less precise in details (Hardt O and Nadel L, 2018). However, our data suggest that the spatial memory trace facilitated by amygdala activation retains a certain precision even at a remote moment in time, as the animals detect the spatial rearrangement produced by a change in position of one of the objects. In line with this result, previous findings from our laboratory show that animals in which the formation of remote place recognition memory was facilitated by administration of the pleotropic hormone and cytokine, erythropoietin, fail to detect the new spatial change if the spatial cue is removed, suggesting that even at this remote time period memory is spatial (Almaguer-Melian W et al., 2024) (for reviews of erythropoietin, which is also implicated in neuroprotection and recovery of neurological function, see (Hemani S et al., 2021; Jelkmann W, 2016; Urena-Guerrero ME et al., 2020)).

Taking into account that a large group of DG cells is temporarily activated by BLA stimulation (Mercerón-Martínez D, et al., 2020), as well as observations that the DG is important to discriminate very similar contexts (Schmidt B et al., 2012), we injected ZIP into DG to disrupt DG memory traces that may contribute to the maintenance of memory for precise discriminations. However, our data show that this procedure did not abolish the remote memory facilitated by amygdala stimulation (Fig. 3F, Fig. S4C). These results with OPR are in line with contextual fear memory, in which an engram that is formed in the DG becomes silent at a remote memory time point (Kitamura T et al., 2017). However, two issues need to be considered. First, we stimulate the BLA, which in previous studies we have shown produces high c-Fos expression in both prefrontal cortex and DG cells (Mercerón-Martínez D, et al., 2020). These amygdala-activated DG cells might not be required for OPR 3 weeks after training, but could contribute to building a latent trace that can be reactivated at a remote time during memory evocation, providing vividness to the generalized cortical trace (Alam MJ et al., 2018; Tonegawa S et al., 2018). Recent data from our laboratory on erythropoietin-facilitated remote memory support this assumption, since retrieval of the remote memory 21 days after its acquisition produces an increase in hippocampal expression of brain-derived growth factor (BDNF) (Almaguer-Melian W, et al., 2024). Memory retrieval after 21 days with the novel change of position triggers the mechanisms of memory destabilization and subsequent reconsolidation of spatial memory in the hippocampal formation, and the increase in the expression of BDNF could contribute to the re-stabilization and updating of the memory trace (Bekinschtein P et al., 2008; Bekinschtein P et al., 2014; Bekinschtein P et al., 2014; Slipczuk L et al., 2009). We did not test whether ZIP in DG disrupts updating of the remote OPR memory.

Second, DG traces might not be dependent on the persistent action of aPKC, but on other molecules regulating modifications in synaptic strength, such as CaMKII (Bayer KU and Giese KP, 2024), or on neuronal changes outside the synapse (Abraham WC et al., 2019; Zhang W and Linden DJ, 2003). Thus, our results do not eliminate the possibility that there are memory traces not dependent on PKMζ or PKCι/λ that could contribute to maintaining spatial precision memory observed at a remote memory time point (Abraham WC, et al., 2019; Kwapis JL et al., 2009; Serrano P et al., 2008; Tsokas P, et al., 2024). In addition, the activation of hippocampal cells might be required for the retrieval of the memory, even though they may no longer carry memory information. Future studies may clarify whether there are engram cells in DG or CA1 that can provide a memory with sufficient details or are otherwise required to detect the spatial change observed 21 days after learning, whether the systems consolidation to the ACC after BLA-stimulation is a gradual process, and when the spatial memory in ACC becomes sensitive to ZIP.

Which mechanism supports amygdala-stimulation-induced facilitation of remote memory formation in the ACC? As mentioned above, when the amygdala is stimulated 15 minutes, but not 5 hours after acquisition, memory consolidation occurs (Fig. 2B, Fig. S3A), and blocking aPKC action in the ACC on day 19 post-acquisition “erases” this remote memory when measured on day 21 (Fig. 3C, Fig. S4C). The reinforcing effect of amygdala stimulation transforming a short-term memory into a remote memory is in line with the “behavioral tagging” hypothesis. These studies, inspired by the synaptic tagging hypothesis of LTP (Frey U and Morris RG, 1997), have shown that novelty exploration close to the moment of training can produce memory consolidation (Ballarini F, et al., 2009; Moncada D et al., 2015), which depends on new protein synthesis (Moncada D and Viola H, 2007). Indeed, previous results have shown that novelty exploration increases PKMζ and promotes memory consolidation in prelimbic prefrontal cortex in a behavioral-tagging process (Naseem M et al., 2019). This behavioral reinforcing effect can even preserve memory in the face of events that interfere with memory formation and promote forgetting (Almaguer-Melian W et al., 2012). More recently, evidence indicates that memory reconsolidation is also mediated by a “behavioral tagging” process (Rabinovich Orlandi I et al., 2020).

To maintain remote memory, we speculate that once synapse-potentiating, plasticity-related proteins such as PKMζ are initially captured by a synaptic tag, these proteins must remain and possibly be replaced at the specific activated synapses in the ACC throughout memory maintenance, which in our experiments is for at least 21 days. Recently, the postsynaptic scaffolding protein, KIBRA, has been found to act as a “persistent synaptic tag” for newly synthesized PKMζ in late-LTP and spatial long-term memory in hippocampus that can last weeks (Tsokas P, et al., 2024). In this proposed mechanism, KIBRA, which interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) (Mendoza ML et al., 2022), first accumulates at activated synapses. The KIBRA then acts as a synaptic tag to bind PKMζ, and the persistent, autonomous activity of kinase maintains synaptic potentiation by inhibiting GluA2 subunit-dependent AMPAR endocytosis (Migues PV et al., 2010; Patel H and Zamani R, 2021; Yao Y et al., 2008). The resulting increase in postsynaptic AMPARs in turn maintains the accumulation of KIBRA as a persistent synaptic tag at activated synapses (Tsokas P, et al., 2024). In this way the memory persists after experience. Future work using antagonists of KIBRA-PKMζ interaction could test the hypothesis that KIBRA anchors PKMζ to maintain remote memory in AAC. Other newly synthesized proteins might also be captured by the tagged synapses and in this way transform short-term memory to remote memory. For example, we previously showed that amygdala stimulation induces an increase in microtubule-associated protein 2 (MAP2) and growth associated protein 43 (GAP43) in the prefrontal cortex and in hippocampus, suggesting that structural plasticity and synaptogenesis may occur (Mercerón-Martínez D, et al., 2018). Thus, the strengthening of pre-existing synapses maintained by persistent synaptic tagging through PKMζ as well as the generation of new synapses could contribute to the formation of remote memory in the ACC.

Although future studies are required to determine if the effect on remote memory of amygdala stimulation is a process that evolves over weeks or can be faster and occur in days, recent data from our laboratory suggests that it could be rapid. Relatively early expression (24 h) of a remote memory that has been reinforced by systemic administration of erythropoietin produces an increase in activity-regulated cytoskeleton-associated protein (Arc) expression 30 min after retrieval of the memory that is larger in the prefrontal cortex than in hippocampus (Almaguer-Melian W, et al., 2024). Moreover, previous studies have shown that remote memory formation can occur rapidly based on memory schemas (Tse D et al., 2007).

In conclusion, our data strongly indicate that activation of the amygdala shortly after the acquisition of a short-term memory can produce systems consolidation in cortical regions such as the ACC through the persistence of aPKC action. Overall, our results indicate the powerful modulating role of the amygdala on the memory of experiences relevant to the survival of animals. We also provide data suggesting that, in natural conditions, if amygdala activation occurs close to the moment in which the information of an experience is being processed, then the additional activity of the amygdala on the memory trace can help promote the formation of remote memory of some everyday experiences; if it is not activated, memory can be lost in hours to days. Finally, the data presented here opens a path in the search for neurological restoration based on synaptic plasticity mechanisms that can contribute to the recovery of lost functions, particularly in memory loss in aging or neurodegenerative diseases like Alzheimer’s disease. Conversely, as the amygdala is crucial after learning for strengthening aversive long-term memory, reducing PKMζ formation could be useful to prevent conditions like post-traumatic stress disorder that are characterized by an “excess” in memory consolidation (Brewin CR, 2018; Cohen H et al., 2010).

Supplementary Material

Sup Mat

Acknowledgement

The authors want to thank Dr. Alain Y. García Varona and technicians Carlos Adolfo Rodríguez Pujol and Osmay Alfredo Trujillo Batista for the excellent handling and care of the experimental animals. We appreciate the important contribution of Dr. Barbara Estupiñan and Yamile Vega in the histological verifications.

Funds

The funds supporting this study were provided by CIREN and NIH funding RO1 MH115304 (T.C.S), 2R37MH057068 (T.C.S.), and R01 NS108190 (T.C.S).

Footnotes

Ethics statement

The authors have read and have abided by the statement of ethical standards for manuscripts submitted to Neuroscience.

Conflict of interest statement

Declarations of interest: none.

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