Amygdala-hippocampal interactions in synaptic plasticity and memory formation

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Highlights

  • We review research investigating how the amygdala modulates memories of emotional experiences.

  • The amygdala influences memory consolidation and related molecular changes in the hippocampus.

  • The amygdala modulates hippocampal memory via projections to the medial entorhinal cortex.

Abstract

Memories of emotionally arousing events tend to endure longer than other memories. This review compiles findings from several decades of research investigating the role of the amygdala in modulating memories of emotional experiences. Episodic memory is a kind of declarative memory that depends upon the hippocampus, and studies suggest that the basolateral complex of the amygdala (BLA) modulates episodic memory consolidation through interactions with the hippocampus. Although many studies in rodents and imaging studies in humans indicate that the amygdala modulates memory consolidation and plasticity processes in the hippocampus, the anatomical pathways through which the amygdala affects hippocampal regions that are important for episodic memories were unresolved until recent optogenetic advances made it possible to visualize and manipulate specific BLA efferent pathways during memory consolidation. Findings indicate that the BLA influences hippocampal-dependent memories, as well as synaptic plasticity, histone modifications, gene expression, and translation of synaptic plasticity associated proteins in the hippocampus. More recent findings from optogenetic studies suggest that the BLA modulates spatial memory via projections to the medial entorhinal cortex, and that the frequency of activity in this pathway is a critical element of this modulation.

Introduction

On a fundamental level, memory creates who we are. Indeed, without memories, it is difficult to imagine how we would conceive of ourselves and our relationship with the world. Not surprisingly then, how memories are formed and retained has been an enduring question in the field of psychology and neuroscience for over a century, beginning with early psychologists like William James and Hermann Ebbinghaus. Across this time, considerable work has created a framework for how some of this process unfolds. In particular, for declarative-style memories, evidence indicates a critical role for the hippocampus and associated medial temporal lobe structures in the initial formation and consolidation of such memories. Because these memories are the cornerstone for our own sense of self and our explicit connections to the world around us, the systems underlying these memories have received significant attention.

However, not all experiences are successfully transformed into long-lasting memories and, in almost everyone, it appears that the vast majority of one’s daily experiences is not stored in long-term memory form. Rather, evidence suggests that experiences involving emotionally significant events are far more likely to be successfully consolidated into a long-lasting memory than are relatively less emotional experiences. The ability of emotional arousal to influence memory consolidation appears to depend heavily on the amygdala and, in the case of declarative-like memories, its interactions with the hippocampal system. This review will describe how the amygdala and hippocampus act synergistically to create and strengthen the consolidation of these memories.

Beginning with early work by Brenda Milner with patients such as Henry Molaison (H.M.) (Scoville & Milner, 1957), considerable evidence has pointed to the hippocampus and associated medial temporal lobe structures including the rhinal and parahippocampal cortices as critical loci in the formation and consolidation of declarative-style memories. The ability to form new declarative memories is profoundly impaired in patients with significant lesions of the hippocampal formation, such as the famous patient H.M. In contrast, the ability to form non-declarative memories, such as procedural motor skills, appears to be largely intact in these patients (Squire, 2009). These patients with medial temporal lobe lesions also appear to have temporally graded retrograde amnesia for declarative memories of experiences that occurred before the lesion, with more distant events remembered better than those closer in time to the lesion. Thus, it appears that the hippocampus plays a role in the initial formation of such memories as well as the early stages of consolidation of these memories.

The role of the hippocampal system in memory consolidation has been investigated in both human and non-human animals. Declarative memory consists of episodic and semantic memories, and animals demonstrate memory for relationships among experiences, indicating that they, too, have episodic, declarative memories (Bunsey & Eichenbaum, 1996). Evidence suggests that declarative memories eventually undergo a “systems consolidation” in which the memory trace needed for recall shifts from the hippocampus to neocortical structures (Frankland and Bontempi, 2005, Hardt and Nadel, 2018, Kitamura et al., 2017, Klinzing et al., 2019, Takehara-Nishiuchi, 2020). Although beyond the scope of the current review, some theories of systems consolidation argue that this process is actually more complex than a simple trace transfer. Rather, these theories argue that the hippocampus is always involved in the recall of episodic and autobiographical memories and that memories that no longer require the hippocampus for recall have been transformed into schematic maps stored in neocortical regions. Without the hippocampus, these memories are more “gist-like” or semantic in style, rather than the contextually and temporally rich episodic memories (Corkin, 2002, Moscovitch et al., 2016, Winocur and Moscovitch, 2011, Winocur et al., 2010). Regardless of whether a particular memory depends on the hippocampus for recall for a lifetime, it is clear that the initial formation and consolidation of declarative memories depends heavily on an intact and functioning hippocampus as well as associated medial temporal lobe structures. It is likely that the hippocampus mediates spatial and contextual components of memories that involve associations between contextual and emotionally arousing information (Roesler et al., 1998, Roesler et al., 2000, Roesler et al., 2003).

Studies indicate that the information regarding various declarative memories enters the hippocampus through associated nearby cortices including the entorhinal, perirhinal, postrhinal, and medial prefrontal cortices (Dickerson and Eichenbaum, 2010, Eichenbaum, 2017, Squire and Zola-Morgan, 1991). Indeed, evidence suggests that these regions play important roles in the processing and consolidation of recently acquired information. Lesions of the hippocampus alone produce considerably milder dysfunction in memory-based tasks than do lesions that include and extend beyond the hippocampus to include nearby medial temporal lobe cortices (Squire, 2009). Likewise, it is believed that H.M. displayed such profound anterograde amnesia due to his surgical resection encompassing hippocampus-adjacent areas including the anterior parahippocampal cortex (Corkin et al., 1997, Squire, 2009).

Further evidence supporting the crucial role for these associated brain regions in working with the hippocampus proper in memory formation comes from numerous studies examining how these brain systems map spatial and temporal characteristics of the environment. For example, evidence indicates that neurons in the hippocampus, especially those of the dorsal hippocampus, serve as “place cells” that fire in a highly selective manner when the animal is in a specific location in the environment (O'Keefe, 1976, Wilson and McNaughton, 1993). In contrast, recordings from the medial entorhinal cortex have observed “grid cells” that fire in a selective manner in a hexagonal or triangular grid-like fashion across space (Fyhn et al., 2007, Hafting et al., 2005). Though the mechanisms are not fully understood, it is believed that grid cells of the entorhinal cortex then contribute to the place cell encoding in the hippocampus (Moser, Rowland, & Moser, 2015). Although much work has focused on place and grid cells due to the relative ease of identifying such cells, studies have found that hippocampal cells also encode other aspects of the world, such as odor, time, and time–space relationships that are the building blocks for episodic memories (Eichenbaum et al., 1987, Hampson et al., 1993, Leutgeb et al., 2005, Moser et al., 2008). Thus, this encoding across the hippocampus and associated cortices would be expected to form the fundamental basis of declarative memories. Multiple neuronal processes at the molecular level have been uncovered and investigated extensively over the past four decades. The molecular basis of memory formation in the hippocampus, entorhinal cortex, and associated brain structures is beyond the scope of this review, and we direct the reader to recent review articles that focus on the molecular basis of memory formation and storage (Alberini and Kandel, 2014, Asok et al., 2019, Josselyn and Tonegawa, 2020, Leighton et al., 2018, Rao-Ruiz et al., 2021). The complexity of this system with multiple regions and sub-regions provides several avenues by which other regions, such as the amygdala, can influence the different elements of declarative memory processing.

As noted above, considerable evidence indicates that emotional arousal at the time of learning events enhances the consolidation of memories for these events. Emotional arousal increases levels of the stress hormones cortisol (corticosterone in rodents) and epinephrine. Previous findings indicate that systemic administration of these hormones after training enhances the consolidation of memories in rodents (Gold and van Buskirk, 1976a, Gold and Van Buskirk, 1976b, Roozendaal and McGaugh, 1996). Importantly, amygdala lesions prevent the memory-modulating effects of peripheral stress hormones (Roozendaal & McGaugh, 1996), highlighting the critical role of the amygdala in mediating the effects of emotional arousal on memory consolidation. More specifically, it appears that the basolateral amygdala (BLA; also termed basolateral complex), composed of the lateral, basal (also termed basolateral), and accessory basal nuclei (also termed basomedial nucleus; Pitkänen et al., 1997, Price et al., 1987) is the critical amygdala region responsible for this memory modulatory ability (Parent and McGaugh, 1994, Roozendaal and McGaugh, 1997b). Studies suggest that BLA manipulations immediately after training alter the consolidation of memories, including declarative-style ones (Hatfield and McGaugh, 1999, Packard et al., 1994). For example, posttraining intra-BLA infusions of a range of compounds that either stimulate or inhibit specific receptors for neurotransmitters, including acetylcholine, dopamine, noradrenaline, glutamate, γ-aminobutyric acid (GABA), opioids, endogenous cannabinoids, and serotonin, alter memory consolidation (Campolongo et al., 2009a, Campolongo et al., 2009b, Dickinson-Anson and McGaugh, 1997, Ferry and McGaugh, 2008, Introini-Collison et al., 1991, Introini-Collison et al., 1989, Khakpoor et al., 2016, LaLumiere et al., 2004, Nasehi et al., 2016, Power et al., 2003, Roesler et al., 2000, Roesler et al., 2003). Evidence points to an especially important role for noradrenergic inputs to the BLA during emotionally influenced memory consolidation (Gallagher, Kapp, Musty, & Driscoll, 1977). For example, posttraining intra-BLA infusions of norepinephrine enhance consolidation (LaLumiere, Buen, & McGaugh, 2003), whereas β-adrenergic receptor blockade in the BLA prevents the memory-enhancing effects of systemic administration of epinephrine, glucocorticoid agonists, the opioid antagonist naltrexone, ketamine, and the endogenous lipid mediator oleoylethanolamide, among other agents (Campolongo et al., 2009a; Liang et al., 1986, McGaugh et al., 1988, Morena et al., 2021, Quirarte et al., 1997). Moreover, the amount of norepinephrine released in the amygdala immediately following inhibitory avoidance training correlates with the degree of retention two days later (McIntyre, Hatfield, & McGaugh, 2002). This finding suggests that the degree of BLA activation after an emotionally arousing event determines the strength of memory modulation such that greater BLA activation leads to better retention for that event. Indeed, evidence from functional imaging studies in humans supports this, as the degree of amygdala activity during encoding predicts the likelihood of remembering visual images at a later surprise retention test but only for emotionally arousing visual images (Canli, Zhao, Brewer, Gabrieli, & Cahill, 2000). Such work further supports the idea that the amygdala is critical for modulating the strength of different kinds of memories.

Together, the research reviewed above points to a likely complex interaction between the BLA and hippocampal-dependent declarative memory. In particular, it appears that a hippocampus-based system plays an important role in processing and encoding a variety of components of an experience, including time and space, to create a memory. In contrast, the BLA seems to mediate the emotional significance of the event by modulating memory consolidation processes and thereby altering the strength of the resulting memory. The findings of Packard et al. (1994) are particularly seminal in illustrating these interactions. In their work, they found that posttraining amphetamine infusions into the hippocampus, but not caudate, enhanced retention of the spatial version of the water maze, whereas these infusions into the caudate, but not hippocampus, enhanced retention of the cued version of the water maze. In contrast to this double dissociation, posttraining intra-amygdala infusions of amphetamine enhanced the retention of both spatial and cued versions of the water mask task. Moreover, pharmacological inactivation of the amygdala before the retention test for either version did not reverse the enhancement produced by posttraining intra-amygdala infusions of amphetamines. Thus, these findings indicate that a) the amygdala modulates the consolidation of multiple forms of memories that are selectively mediated by other brain regions (i.e., hippocampus for spatial learning and caudate for cued learning) and b) the amygdala is not a critical site of long-term storage of either type of memory. Although there is evidence that the BLA may modulate hippocampal function related to spatial memory retrieval (Roozendaal et al., 2003, Saha et al., 2018), it is particularly clear that a critical interaction between the BLA and hippocampus occurs during the consolidation period of contextual and spatial memory formation. This review, therefore, will focus on the interactions between the amygdala and hippocampus during the consolidation of declarative-style memories.

Section snippets

Anatomical interactions between the hippocampus and amygdala

The following section will review the anatomical connections between the BLA and hippocampal formation, demonstrating that the BLA is poised anatomically to influence hippocampal function through an extensive array of amygdalo-hippocampal efferent projections. Although the amygdala and hippocampus communicate bidirectionally (McDonald and Mott, 2017, Pitkänen et al., 2000), only amygdala projections to the hippocampus will be described given the focus of this article on amygdala modulation of

Amygdala-hippocampal interactions in memory consolidation

As noted in the introductory section, critical work by Packard et al. (1994) pointed to interactions between the amygdala and hippocampus during the consolidation of spatial memories. Since then, much work has further investigated the nature of these interactions during memory consolidation. Indeed, evidence suggests that amygdala manipulations affect learning-related neurochemical and molecular changes in the hippocampus and that BLA activity is required for hippocampal manipulations to

Amygdala-hippocampal interactions in neural activity and synaptic plasticity: Electrophysiological evidence

Consistent with the idea that the BLA modulates hippocampus-dependent memory consolidation, accumulating evidence suggests the BLA has a strong capacity to alter synaptic strength in hippocampal structures. Studies from over 20 years ago indicate that amygdala stimulation modulates hippocampal long-term potentiation (LTP) (Richter-Levin & Akirav, 2000). Priming (i.e., stimulation that facilitates responses to a subsequent stimulus) of the BLA before application of high-frequency stimulation

Conclusions and future directions

The many decades of work discussed in this review indicate that emotional arousal influences memory consolidation by activating the BLA which, in turn, modulates activity and plasticity in a variety of downstream brain regions, including the hippocampus (McGaugh, 2000, McGaugh, 2002, Roesler and McGaugh, 2010). Almost 20 years ago, Jim McGaugh wrote a review in a special issue of this journal where he described amygdala modulation of multiple memory systems (McGaugh, McIntyre, & Power, 2002).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The writing of this article was supported by the National Council for Scientific and Technological Development (CNPq, MCTI, Brazil) grant 305647/2019-9 (R.R.); Rio Grande do Sul State Research Foundation (FAPERGS, RS, Brazil) grant 17/2551-0001 071-0 (R.R.); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) grant R01DK114700 (M.B.P.); and National Institutes of Mental Health (NIMH), NIH grant R01MH104384 (R.L. and C.K.M.). The content

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