The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex

Abstract

Stress hormones released by an experience can modulate memory strength via the basolateral amygdala, which in turn acts on sites of memory storage such as the cerebral cortex [McGaugh, J. L. (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience, 27, 1–28]. Stimuli that acquire behavioral importance gain increased representation in the cortex. For example, learning shifts the tuning of neurons in the primary auditory cortex (A1) to the frequency of a conditioned stimulus (CS), and the greater the level of CS importance, the larger the area of representational gain [Weinberger, N. M. (2007). Associative representational plasticity in the auditory cortex: A synthesis of two disciplines. Learning & Memory, 14(1–2), 1–16]. The two lines of research suggest that BLA strengthening of memory might be accomplished in part by increasing the representation of an environmental stimulus. The present study investigated whether stimulation of the BLA can affect cortical memory representations. In male Sprague–Dawley rats studied under urethane general anesthesia, frequency receptive fields were obtained from A1 before and up to 75 min after the pairing of a tone with BLA stimulation (BLAstm: 100 trials, 400 ms, 100 Hz, 400 μA [±16.54]). Tone started before and continued after BLAstm. Group BLA/1.0 (n = 16) had a 1 s CS–BLAstm interval while Group BLA/1.6 (n = 5) has a 1.6 s interval. The BLA/1.0 group did develop specific tuning shifts toward and to the CS, which could change frequency tuning by as much as two octaves. Moreover, its shifts increased over time and were enduring, lasting 75 min. However, group BLA/1.6 did not develop tuning shifts, indicating that precise CS–BLAstm timing is important in the anesthetized animal. Further, training in the BLA/1.0 paradigm but stimulating outside of the BLA did not produce tuning shifts. These findings demonstrate that the BLA is capable of exerting highly specific, enduring, learning-related modifications of stimulus representation in the cerebral cortex. These findings suggest that the ability of the BLA to alter specific cortical representations may underlie, at least in part, the modulatory influence of BLA activity on strengthening long-term memory.

Introduction

It is well known that memories for emotional events are more robust than memories for neutral events (McGaugh, 2004). For example, stimuli that are rated as emotionally salient are better remembered than stimuli that are rated as neutral (Bradley et al., 1992, Cahill et al., 1994, Kleinsmith et al., 1963, Sharot and Yonelinas, 2008). Many studies in both the human and animal literatures have established that post-training increases of stress can also enhance memory consolidation (Cahill and Alkire, 2003, Cahill et al., 2003, Hui et al., 2006, Kim et al., 2001, McCarty and Gold, 1981, Shors, 2001). Also, post-training systemic administration of stress hormones, such as corticosterone and epinephrine, is sufficient to enhance memory consolidation (Gold and van Buskirk, 1975, Gold et al., 1975, Hui et al., 2004, Kety, 1972, McGaugh and Roozendaal, 2002, Ogren et al., 1980, Ridley et al., 1981, Roozendaal et al., 1996).

Many lines of evidence have implicated the basolateral amygdala (BLA) as a substrate for stress-related modulation of memory. For example, post-training stimulation of the BLA is sufficient to induce enhanced memory consolidation for the training experience (Bergado et al., 2006, Gold et al., 1975). Further, post-training administration of stress hormones into the BLA enhances memory consolidation in a variety of tasks (Fekete et al., 1985, Gallagher and Kapp, 1981, Gallagher et al., 1977, Hui et al., 2004, Hui et al., 2006, Introini-Collison et al., 1989, Liang et al., 1986, Roozendaal, Castello, et al., 2008, Yang et al., 2006). Third, human imaging studies have also linked enhanced memory consolidation to amygdala activation. For example, PET and fMRI studies have shown that the level of activation in the BLA at the time of experiencing either negative or positive emotional experiences predicts the strength of memory at the time of recall (Cahill et al., 1996, Canli et al., 2000, Hamann et al., 1999, Hamann et al., 2002).

Animal studies have also linked physiological activation of the BLA to the modulation of emotional memory. Thus, emotional arousal in animals produces prolonged (hours) increased neuronal firing in the BLA (Pelletier, Likhtik, Filali, & Paré, 2005). Moreover, direct application of corticosterone to the BLA increases the excitability of its principal neurons (Duvarci & Paré, 2007). Direct drug infusion in the BLA can also enhance emotional memory (Fekete et al., 1985, Liang and Lee, 1988, Liang et al., 1990, Roozendaal and McGaugh, 1997, Roozendaal, Schelling, et al., 2008, Yang et al., 2006).

The enhancement of memory consolidation due to emotional learning and the application of stress hormones to the BLA are dependent on the activation of β-adrenergic receptors within this structure (LaLumiere et al., 2004, McGaugh, 1989, Quirarte et al., 1997, Roozendaal et al., 2002). Lesions of the BLA or infusions of β-adrenergic receptor antagonists into the BLA block enhancement of memory consolidation (Roozendaal and McGaugh, 1996, Roozendaal, Okuda, et al., 2006, Roozendaal, Hui, et al., 2006). However, the memory enhancing effects of stress, β-adrenergic receptor activation and other modulating treatments are not due to memory enhancement within the BLA itself. For example, lesions of the stria terminalis, efferents of BLA principle neurons, block the enhancement of memory consolidation due to the application of glucocorticoid receptor agonists to the BLA (Roozendaal and McGaugh, 1996, Setlow et al., 2000). Studies have identified the efferent sites of BLA modulatory effects, including the hippocampus, caudate, and cerebral cortex (McGaugh, 2002, Packard et al., 1994, Roozendaal and McGaugh, 1996).

BLA stimulation enhances cortical activation (Dringenberg et al., 2001, Dringenberg and Vanderwolf, 1996). Previous studies have also found evidence for other BLA interactions with cortical function. For example, stimulation of the BLA enhances cortical LTP (Dringenberg, Kuo, & Tomaszek, 2004). However, the means by which the BLA modulates memory in target structures, such as the cortex, are unknown. To address this issue, it would be helpful to identify a memory trace and then observe its modulation by the BLA. Such a candidate for a memory trace is available in the form of CS-specific associatively induced receptive field plasticity in the primary auditory cortex (A1) (Weinberger, 2004).

Classical and instrumental conditioning specifically modify the representations of sounds in A1 that acquire behavioral significance. Such learning causes the frequency receptive fields of cortical neurons to shift toward and to the frequency of the conditioned stimulus (Bakin and Weinberger, 1990, Gao and Suga, 1998, Kisley and Gerstein, 2001). These tuning shifts produce an increase in the number of neurons that become best tuned to the CS frequency, thus increasing the area of representation of the CS frequency. The magnitude of gain in the CS representation is an increasing function of the level of behavioral importance of the CS (Rutkowski and Weinberger, 2005, Weinberger, 2007). Thus, the amount of representational expansion may serve as a memory code for the learned behavioral significance of stimuli (Weinberger, 2001, Weinberger, 2003).

Associative representational plasticity has the major attributes of memory itself and therefore, may constitute a neural memory trace. It is associative (requires pairing), highly specific (responses to frequencies a small fraction of an octave away are attenuated) (Bakin et al., 1992, Bakin and Weinberger, 1990), discriminative (shifts to a CS+, loses response to a CS−) (Edeline & Weinberger, 1993), develops rapidly (within 5 trials) (Edeline, Pham, & Weinberger, 1993), consolidates (becomes stronger over days without further training) (Galván & Weinberger, 2002) and is enduring (tracked as long as 8 weeks) (Weinberger, Javid, & Lepan, 1993). In toto, these attributes of associative representational plasticity satisfy the criteria for constituting a neural memory trace (Weinberger, 2004).

As the BLA modulates memories, including those stored at least in part in the cerebral cortex, and as associatively induced CS-specific tuning shifts may constitute cortical representations of memory, then the BLA may modulate memories by promoting specific tuning shifts in the cortex. The goal of this study was to conduct an initial test of this hypothesis. A tone was paired with stimulation of the BLA to determine if it is capable of producing CS-specific tuning shifts similar to those that develop during behavioral learning.