1.1. The basolateral amygdala and memory consolidation
Emotionally arousing experiences generally create strong, long-lasting memories . Findings of many experiments using rats, as well as human subjects, indicate that arousal-induced release of adrenal hormones epinephrine and cortisol (corticosterone in rats) plays a critical role in modulating the consolidation of memories [4-6]. Systemic administration of epinephrine or corticosterone to rats shortly after training enhances memory on many kinds of learning tasks. [1, 7]. Similarly, human memory is enhanced by post-learning administration of epinephrine or stimulation that induces the release of epinephrine [8, 9]. Further, in human subjects as well as rats, administration of β-adrenoceptor antagonists block the enhancing effects of emotional arousal on memory [1, 5, 10-12].
1.2. Critical role of the basolateral amygdala in modulating memory consolidation
There is also extensive evidence from studies using rats that these adrenal stress hormones influence memory that involves noradrenergic activation of the amygdala [1, 13]. Lesions or pharmacological inactivation of the amygdala, more specifically the basolateral region (BLA), prevent the memory enhancing effects of peripherally administered epinephrine and corticosterone . The release of norepinephrine (NE) within the BLA plays a critical role in modulating memory consolidation. Intra-BLA administration of β-adrenoceptor antagonists blocks epinephrine and corticosterone effects on memory [15, 16] and importantly, posttraining intra-BLA infusions of NE, as well as noradrenergic agonists, enhance memory consolidation [17-20] (Figure 1).
Additionally, arousal-induced training induces the release of NE within the amygdala  and the increase in release correlates with subsequent retention performance . There is also evidence that GABAergic and opioid peptidergic drugs that enhance memory when administered post-training (e.g., picrotoxin, naloxone) enhance the release of amygdala NE and that memory impairing drugs (e.g., muscimol, β-endorphin) decrease amygdala NE release [21, 23]. Thus, GABAergic and opioid drugs act “upstream” from NE within the BLA.
Drugs affecting cholinergic functioning also influence memory consolidation when administered either systemically or intra-amygdally after training [24, 25]. However, cholinergic effects occur “downstream” from NE as blockade of β-adrenoceptors within the BLA does not prevent the memory enhancement induced by systemic intra-amygdala infusions of the muscarinic cholinergic agonist oxotremorine and intra-amygdala administration of the cholinergic antagonist atropine blocks the memory enhancement induced by NE [26, 27]. Intra-amygdala infusions of atropine also block the memory enhancing effects of systemic or intra-amygdala administration of glucocorticoid receptor agonists .The BLA receives a large cholinergic projection from the nucleus basalis (NB) . Thus, as would be expected, in view of the evidence that acetylcholine acts downstream from NE within the amygdala in regulating memory consolidation, lesions of the NB impair memory consolidation and intra-BLA infusions of oxotremorine or the muscarinic agonist physostigmine attenuate the memory impairment .
1.3. BLA influences on memory for different aspects/forms of learning
It is well established that the amygdala is involved in fear-induced training using footshock . However, lesions of the BLA attenuate, but do not prevent, inhibitory avoidance or contextual fear conditioning . One possible interpretation of findings that post-training activation of the BLA with neuromodulatory treatments enhances inhibitory avoidance as well as contextual and cued fear conditioning might be that the stimulation simply potentiates the effects of fear. However, intra-BLA administration of NE or the cholinergic agonist oxotremorine administered following extinction, i.e. when footshock is no longer delivered, enhances extinction of contextual fear conditioning [33, 34]. These findings clearly indicate that BLA influences are not constrained to enhancing associations based on fear .
Findings of experiments using novel object recognition memory clearly demonstrate BLA modulation of memory that is not based on fear motivation. In one experiment , rats were simply placed in a box containing two identical objects (e.g., light bulbs) and allowed to investigate them. On retention tests a day later, they were replaced in the box with one of the same objects and a novel object of approximately the same size. NE infused into the BLA after the original exposure enhanced memory of the objects, as indicated by increased investigation of the novel object on the retention trial (Figure 2). Post-training activation of glucocorticoid receptors in the BLA after training also enhances novel object recognition memory and, importantly, this influence is blocked by intra-BLA infusions of an adrenoceptor antagonist [16, 36].
Many other learning tasks that do not employ fear motivation also have demonstrated BLA influences on memory consolidation. These include: change in reward magnitude , conditioned place preference [38, 39], radial maze training , water maze spatial and cued training , conditioned taste aversion , olfactory conditioning , extinction of conditioned reward , cortical representation of motor skill learning , and as discussed below, learning-induced cortical representation of auditory information .
1.4. BLA interactions with other brain regions in modulating memory consolidation
Each of the learning tasks mentioned above no doubt involves the selective participation of specific brain regions as well as interactions with other regions. The findings of many studies indicate that the amygdala influences memory consolidation via its extensive projections to other brain regions  that are involved in processing different kinds and aspects of information [7, 48]. In an early study, Packard et al.  investigated the effects of post-training activation (using
The evidence that contextual fear conditioning involves learning both that shock is delivered and that it is delivered in a specific context  provided the opportunity to investigate the effects of treatments administered to different brain regions after either exposure to the context or brief shock in the context a day later . Infusions of oxotremorine into the hippocampus selectively enhanced memory of contextual fear conditioning when administered after context exposure and infusions administered into the rostral anterior cingulate cortex selectively enhanced memory when administered after footshock administration. In contrast, infusions into the BLA enhanced memory of contextual fear conditioning when administered after either context exposure or footshock stimulation the following day . Thus, although the hippocampus and rostral cingulate cortex were involved in processing different aspects of contextual fear conditioning (i.e., context
Other studies have reported that electrical stimulation of the BLA enhances the development of long-term potentiation (LTP) in the hippocampus and that infusions of β-adrenoceptor antagonist into the BLA prevent this induction of LTP in the hippocampus as well as stress induced influences on LTP [57-60]. Additionally, and importantly, electrical stimulation of the BLA activates the cortex, as indicated by electroencephalogram (EEG) desynchronization. This effect appears to involve activation of the NB, as inactivation of the NB blocks the BLA-induced activation [61, 62] (Figure 3).
There are other interactions between the BLA and the cerebral cortex. For example, stimulation of the BLA enhances cortical LTP . But, how the BLA modulates memory in the cortex remains unknown. A target memory representation is needed so that its modulation by the BLA could be directly assessed. Fortunately,
2. Primary sensory cortex and memory traces
It may appear strange to study memory traces in a primary sensory cortex, because the traditional assumption has been that these cortical fields function only to
Campbell’s influence has been great, as this formulation still dominates neuroscience, although now at the level of an unconscious assumption. Campbell has been regarded as bearing major responsibility for “removing psychological functions”, such as learning and memory, from A1, S1 and V1 by the rare authors who have analyzed this issue . Campbell’s willingness to do so in the absence of compelling functional data was in keeping with the temper of the times that may itself have reflected British empiricist philosophy, particularly Locke’s distinction between “primary” and “secondary” qualities of objects . His idea that the basic characteristics of sensory stimuli are combined to psychologically yield the objects that give rise to them has the merit of simplicity in explaining perception, and this in turn appeals to “common sense”. Thus, in an era preceding electrophysiology, when Campbell noted certain histological differences between adjacent sensory cortical areas and noted some anecdotal observations of sensory deficits following cortical damage, his leap of logic did not seem so rash.
For more than 100 years, Campbell’s division of labor has remained virtually unquestioned. And thus, alone of all regions of the brain, the function of the primary sensory fields has been “known” prior to actual physiological research. Instead of trying to discover the functions of A1, S1 and V1, the goal of sensory neuroscience has been largely to determine the
Nonetheless, Campbell’s formulation is wrong. Moreover, it has been known to be an invalid account of primary sensory cortex for more than fifty years! To begin with, the high degree of consistency of evoked responses in the primary sensory fields is true only for the preparations in which they were studied, which is the deeply anesthetized animal. However, the anesthetized brain is not the brain that has evolved. While a useful preparation, it cannot be used to validate the belief that A1, S1 and V1 perform only the analysis of the physical attributes of sensory stimuli. And even if Locke’s separation of primary and secondary qualities of objects were accepted, it doesn’t follow logically that they have to be carried out in primary and secondary sensory cortical fields, respectively.
More compellingly, primary sensory fields are deeply involved in the interpretation, i.e., behavioral meaning, of sensory stimuli. For example, they develop neuronal plasticity during learning. In 1956, Galambos and co-workers  performed a simple experiment. They presented a sound followed by a mild aversive stimulus to cats, while recording from the primary auditory cortex. The animals quickly developed conditioned responses in this simple Pavlovian conditioning study, as expected. Importantly, these workers discovered that the
This simple demonstration initiated extensive research during the subsequent thirty years, during which all necessary controls for non-associative factors were investigated and ruled out. For example, the evoked potentials might have become larger if the acoustic stimulus inadvertently became louder, which could have happened if the cats had moved closer to the loudspeaker, or if they had simply relaxed their middle-ear muscles. Direct investigation eliminated even this very subtle potential artifact .
Studies were extended to positive as well as aversive reinforcement, various species, more complex tasks and other forms of recording. For example, two-tone discrimination experiments, both in classical and instrumental conditioning, resulted in the same type of increased cortical response to the reinforced tone CS+ (the tone represents the conditioned stimulus, CS) and also revealed that responses to the un-reinforced tone (CS–) decreased, whether evoked potentials or cellular discharges were recorded (reviewed in ). Furthermore, repeated presentation of the same sound produced a decrease in response, i.e., habituation of auditory cortical processing [72, 73]. Overall, these findings indicated that auditory cortical responses “tracked” the behavioral relevance of stimuli as interactions between animals and the environment were altered: increased responses to sounds of greater importance, decreased responses to sounds of lesser importance.
2.2. Contemporary status
While these types of findings were incompatible with traditional assumptions that primary sensory cortices were sensitive only to physical stimulus parameters, they were largely ignored. This lack of interest probably was due to two factors. Within the community of learning/memory workers attention was focused on structures such as the hippocampus and amygdala. Moreover, these researchers had no reason to question the prevailing dogma because sensory cortex was viewed as the domain of sensory physiology. And within the community of sensory workers, studies of learning-induced cortical plasticity were probably seen as irrelevant, because they could shed little light on critical issues about sensory coding. Why not? Because learning/memory studies typically employ one or two different stimuli during training, e.g., a CS+ and a CS–. Such a paucity of stimulus values could not reveal how the effects of learning might modify the encoding of a stimulus dimension, such as acoustic frequency. Thus, demonstrations that learning produced increased responses in primary sensory cortex were unhelpful to sensory neurophysiology.
It is a curiosity that within neuroscience, two disciplines are concerned with the “fate” of sensory stimuli: sensory neurophysiology and learning/memory. The former seeks the coding and processing of stimuli that underlie perception; the latter seeks the transformation of stimuli into behaviorally relevant objects, usually of sufficient import to gain access to the halls of memory. Although these lines of research have developed in parallel, their basic paradigms are actually complementary. Sensory neurophysiology varies the physical parameters of stimuli while keeping constant their psychological parameters; learning/memory does the converse: it varies the psychological parameter of stimuli while keeping constant their physical parameters (Figure 4).
Such juxtaposition of paradigms suggests a new experimental synthesis: use both approaches within the same experiment to gain a more comprehensive understanding of how sensory representations may be modified during learning. Specifically, a three-phase
Before describing the findings, it is important to realize that determination of the effects of learning on sensory representations has the potential to greatly increase our understanding of the neural substrates of learning and memory. In contrast to most neurophysiological studies of these processes, which provide information on whether neuronal responses were increased, decreased or not changed, sensory physiology provides the ability to examine a far more comprehensive domain. Not only can it determine the
This design was first used to study the effects of learning on frequency coding in sensory-association fields of the cat auditory cortex (“secondary” [AII] and “ventral ectosylvian” [VE]) during classical conditioning. The receptive field results showed specific changes to the frequency of the conditioned stimulus (CS), indicating that learning remodels the representation of a behaviorally relevant sensory dimension rather than facilitating responses across acoustic frequency . This finding attracted little attention because, in accordance with Campbell and general assumptions, it was expected that non-primary sensory cortex would change as the psychological meaning of a stimulus changed. However, this study did demonstrate the feasibility of the new approach.
The first study of the primary auditory cortex was conducted during classical conditioning (tone–shock pairing) in the guinea pig. It revealed a heretofore unexpected type of plasticity: tuning curves (frequency receptive fields) were
Subsequent studies validated and replicated such findings. For example, it might be thought that tuning shifts reflect instability and drift of cellular tuning . However, investigations of both short-term (30-120 minutes ) and long-term stability (weeks ) have failed to reveal spontaneous tuning changes. Moreover, tuning shifts were directed to, not also away from, the CS frequency in several species: bat , guinea pig , rat  and human [82-84].
As discussed above, modulation of memory by the BLA acts on memory traces stored elsewhere [1, 7]. However, there has been no direct study of the hypothesized changes in such traces. Representational plasticity in A1 provides such an opportunity because, alone of all electrophysiological correlates of learning, it has been comprehensively studied and found to exhibit the major characteristics of associative memory itself: in addition to being associative and specific, it can be rapidly induced (five trials), consolidates (grow stronger over hours and days after brief training) and exhibits long-term retention (weeks or months). It also develops in a wide variety of tasks, for all types of reinforcement (positive brain stimulation ) as well as standard reward and punishment (reviewed in ).
The findings also suggest that the actual area of representation of the CS in the tonotopic map of A1 should be increased because such maps are basically the distribution of neuronal tuning across the cortex. A direct test of both the “importance” and “area” hypotheses was conducted by varying the relative significance of a tone that signaled the availability of water reward in differentially water deprived rats. Indeed, area expansions were found and there was a significant relationship to behavioral importance: the greater the level of importance, the greater the area of its representation . Furthermore, the area of representation has been linked to the strength of memory: the greater the area of representational gain during learning, the greater the resistance to extinction, i.e., the stronger the memory .
Insofar as the BLA is a substrate of increased memory strength during consolidation, we hypothesized that activation of the BLA should be capable of enhancing specific memory traces, the magnitude of which appears to be a substrate of memory strength-
3. Short-term amygdala modulation of specific sensory memory representations
To determine the capability of the BLA to facilitate cortical memory traces, we began with a study of the short-term effects of BLA stimulation on frequency receptive fields in A1. As this was a highly novel “proof of concept” investigation, we wanted to achieve maximum control over experimental procedures and animal state. Therefore, our first study was conducted in acutely prepared animals that were maintained under general anesthesia (urethane) . Adult male rats (
To determine the effects of training on frequency representation, we obtained tuning curves immediately, 45 and 75 min after the training session. Insofar as prior findings had emphasized that associative learning shifts frequency tuning to favor a signal frequency , we calculated a “Shift Index” using the following formula:
where BFmax is the tone frequency/level combination that elicited the greatest number of spikes, Pre is the average of the pre-treatment responses, and Post is the average of responses at each of the post-treatment test intervals. A positive SI indicates a shift towards the CS, while a negative SI indicates a shift away from the CS. A complete shift to the CS frequency after training would produce an SI = 1.0.
Histological analysis revealed that 11/16 rats had placements of the stimulating electrodes in the BLA. Additionally, physiological verification of functional placements was evident in that BLA stimulation in all of these animals produced electro-cortical activation (“EEG desynchronization”) . In contrast, five animals had stimulating placements outside of the BLA, and in none of these cases did stimulation produce cortical activation. This latter group thus constituted a control group for the anatomical specificity of modulation of sensory memory representations.
Stimulation of the BLA did induce specific tuning shifts. Figure 6 provides a particularly clear example of consolidation dynamics during a marked shift to the frequency of the signal (conditioned) stimulus. The largest response (best frequency maximum, BFmax) before training was at 11.3 kHz. We chose 4.0 kHz for the frequency of the CS; this was actually at the edge of the frequency receptive field. When tuning was again determined immediately after training, the BFmax had shifted, but only very slightly and actually away from the CS, resulting in a negligible SI score of –0.06. However, the most pronounced effect was that tuning became broader toward the CS, now extending to include this frequency. Most relevant, response to the pre-training BFmax decreased while responses to the CS frequency increased (Figure 6A). It is these opposing modulations of receptive fields that is particularly characteristic of associative representational plasticity, that is, the systematic reorganization of sensory memory representations (e.g. ).
Had recording ceased immediately after training, as is often the case in neurophysiological studies of learning, the major effects of BLA modulation would have been missed. Instead, insofar as post-training consolidation is so characteristic of memory, we sought electrophysiological consolidation. Consolidation is customarily studied as post-event temporally-graded reduced susceptibility to interference. However, reduced susceptibility actually is an indirect behavioral index of increasing strength of underlying neural mechanisms of memory. Therefore, neural bases of memory strength should themselves become stronger over time after training. As representational plasticity in the form of signal-directed tuning shifts does meet the several criteria for a memory substrate (reviewed in ), it would be expected to exhibit consolidation. Indeed, this predicted characteristic has been found in the case of natural memory in the form of continued increased specificity of tuning shifts over time after training . Similarly, we found that the effects of BLA stimulation also produced specific neural consolidation.
Determination of tuning after a post-training silent period of 45 min revealed that the BFmax had shifted further, all the way
BLA stimulation produced tuning shifts across the group. Subjects with placements outside of the BLA did not show tuning shifts. This study revealed that, indeed, BLA stimulation has the capacity to reorganize the primary auditory cortex to increase the representation of an environmental stimulus. In particular, it revealed the short-term (e.g., 75 min) dynamics of BLA induced effects on cortical representations .
4. Long-term modulation of specific sensory memory representations by the BLA
The acute study in anesthetized animals clearly demonstrated that BLA activation can systematically modify
To address these issues, we performed an extensive series of observations on the effects of BLA activation in chronically prepared rats bearing multiple microelectrodes in A1, from whom daily recordings were obtained up to three weeks (21 days) after a single session in which a tone was paired with BLA stimulation. This constitutes a unique set of post-training neurophysiological observations, necessitated by the goal of achieving a comprehensive determination of temporal dynamics. Moreover, to determine if the effects were due to pairing per se, rather than merely BLA stimulation, we used a discrimination paradigm in which both paired tones were presented in random order. Training consisted of a single session of 60 trials of 30 trials each of a tone (2.0 s) paired with 0.2 s stimulation of the BLA (1.8 s interstimulus interval) (CS+) or tone alone (CS–). The frequency distance between the two tones was set to be relatively small (1.25 octaves), in order to require that any selective results would be obtained under rigorous circumstances.
As noted above, analysis of a primary sensory cortex provides a far more comprehensive understanding of the effects of training than even the degree of specific plasticity yields with tuning curves, as afforded in our study of short-term plasticity, which focused on modulation of frequency tuning. In the auditory system, it is possible to obtain frequency response areas (FRAs), which consist of the responses of neurons to a wide range of both frequency and intensity (“level”) values. In fact, FRAs essentially circumscribe the domain of neuronal responses to pure tones. Figure 7 presents an example of such a record. Note that the effects of a treatment, whether overt learning or brain stimulation, can be determined at threshold as well as above threshold. Moreover, at and near threshold, one can determine the effects on
5. Effects of BLA stimulation on specificity, sensitivity and selectivity
FRAs were obtained from several electrodes implanted in A1 of the animals, both pre-training and post-training, daily for 21 days (3 weeks). CFs (tuning at threshold) were obtained for each electrode and the mean CF was calculated for each day and averaged. First, we analyzed the results for Week 1 (7 days). Electrodes were divided into those showing an increase in the “shift index” from those showing a decrease, as follows:
A value of 1.0 would indicate a tuning shift from the pre-training CF all the way to the frequency of the CS+; a value of –1.0 would signify a shift to the CS–. Data were divided into three groups: mean increase, mean decrease and mean no change. To avoid including spurious small changes in tuning, we set a criterion of SI = ± 0.1 (i.e., a shift of 10% toward the CS+). Any electrodes exhibiting a mean response of less than this value were classified as “no change”, even if they exhibited much larger shifts on one or more days during the first week. Thus, our approach was conservative in order to reduce the probability of Type I errors.
A total of 55 electrodes (9 subjects) yielded reliable recordings. Of these, the majority (30) developed significant shifts toward the CS+ (increased SI mean value), 13 had no change and 12 shifted away from the CS+. However, the numbers in the three categories do not reveal the most important aspects of the data, i.e., the temporal dynamics. Shifts favoring the CS+ were evident at the first post-training test (24 h), increased over the next 2-5 days, and then were maintained for the balance of the three week recording period (Figure 8). In contrast, the less prevalent shifts away from the CS+ were transient, seen only at 24 h post-training and then diminishing toward no change during week 1, following a highly variable course thereafter.
As noted above, a marked advantage of determining the effects of modulatory processes on a primary sensory cortex is that the FRA yields information on
6. Effects of BLA stimulation on suprathreshold responses
The maximum response in an FRA is an important index of the effects of a treatment on the representation of acoustic information. As noted, we tracked the preferred frequency of BFmax for three weeks post-training. A total of 50 recordings yielded reliable suprathreshold data. Of these, 18 shifted toward the CS+ significantly during week 1, and they maintained this shift for the full 3 weeks of recording (Figure 10A). Nine recording sites were classified as shifts away from the CS+, but these failed to reach significance during Week 1 or thereafter. The largest group was classified as no change (
7. Central Nucleus modulation of memory representations in the auditory cortex
The central nucleus of the amygdala (CE) has also been implicated in learning and memory . However, considerable research indicates that it does not promote post-training memory consolidation, at least not to the extent to which the BLA is involved (e.g. [91–93]). To elucidate the capabilities of the CE to modulate representation in the cortex, we conducted a parallel study. Recordings were obtained from 45 sites in seven rats.
Tuning also was modified at threshold. Twenty-four sites developed post-training tuning shifts toward the CS+. Like the BLA, these developed rapidly, being clearly evident at the first recording session 24 h after training. Also like the BLA, they were maintained for three weeks (Figure 11). Recordings that exhibited either no change (
However, in contrast to the BLA, stimulation of the CE failed to produce any significant change in threshold (Figure 12A) or bandwidth (Figure 12B) for both BW10 and BW20. Also unlike the BLA, pairing the CS+ with CE stimulation did not produce as long lasting tuning shift toward the CS+ above threshold; the BFmax displayed a shift that decreased before Day 21 (Figure 12C).
It is now well established that the BLA can modulate memory that is stored in other brain regions (Introduction). However, the nature of exactly what is modulated has remained a mystery, largely because the presumed target memory representations had not been studied. The research reviewed in this chapter initiated a novel line of inquiry to synthesize knowledge of
neuroscience and learning/memory neuroscience are complementary approaches to understanding how the brain processes, represents and stores experiences. Memory traces are linked to representational plasticity in the primary auditory cortex (A1) because the representations of sounds (tone frequencies) are systematically modified to emphasize stimuli that gain behavioral importance as predictors of reinforcement. Moreover, tuning shifts possess cardinal attributes of memory: they are associative, specific, rapidly formed, consolidate over hours and days and can last indefinitely . Specific shifts of frequency receptive fields accomplish such increased emphasis by increasing the number of cortical neurons that respond preferentially to signal tones. Indeed, increased memory strength is encoded by an increase in the area of tonal representation in the tonotopic map of A1 . Therefore, we asked whether activation of the BLA following tone presentation could specifically modulate the representation of that stimulus in the auditory cortex.
8.1. The BLA produces coordinated modulation of cortical representations
The first experiment paired a tone with stimulation of the BLA in anesthetized rats, as a “proof of concept” study . This produced tuning shifts toward or even precisely to the “CS” frequency. Furthermore, tuning shifts developed over time, i.e., exhibited
Memory modulation has enduring effects on memories. Therefore, we extended this line of inquiry to chronic preparations. Rats were implanted with multiple microwires in the primary auditory cortex. They received a single session of tone either paired with BLA stimulation (CS+) or without any stimulation (CS–). We also analyzed the effects of stimulation on frequency response areas (FRAs), consisting of a matrix of responses to all frequencies and stimulus levels (intensities) to which cells responded. This comprehensive approach yielded not only potential shifts of tuning above threshold , but additionally cortical representations at the most sensitive region of neuronal response: tuning at threshold (characteristic frequency, CF), sensitivity (absolute threshold) and selectivity (bandwidth 10 and 20 dB above threshold). The inclusion of a CS– frequency further permitted the conclusion that any representational plasticity that emphasized the CS+ tone was attributable to the specific frequency that was followed by BLA activation.
A single session of pairing a tone with BLA stimulation produced shifted tuning toward the CS+. This shift in frequency preference is evident both at threshold (CF) and above threshold for the maximum response in the FRA (BFx). This
This representational plasticity is capable of increasing the amount of the auditory cortex that represents the CS+ while rendering the cortex more sensitive and selective to the CS+ tone. In short, the BLA is capable of increasing the number of neurons that represent an environmental stimulus while simultaneously enhancing the precision with which it is detected while rejecting similar non-reinforced stimuli by narrowing bandwidth. These changes constitute a
Therefore, the findings of both studies support the hypothesis that the BLA strengthens memory, at least in part, by modifying sensory cortical representations of stimuli, while also increasing both their sensitivity and selectivity. The result is an increase in memory strength for behaviorally important events.
8.2. Comparison of the basolateral and central nuclei of the amygdala
A parallel study conducted by pairing tone with stimulation of the CE revealed that activation of the latter was also effective in shifting tuning toward the CS+. Furthermore, like the BLA, such representational plasticity endured for at least three weeks. However, in distinction to the BLA, stimulation of the CE was less effective. While it shifted tuning at threshold to the same extent as the BLA, it did not reduce either threshold or bandwidth. Also, above threshold, its tuning shifts had decreased by the third week post-training. In short, the CE did not produce a coordinated, long term facilitation of response to frequencies near or at the CS+. Therefore, it might not be capable of strengthening memory by a comprehensive modification of sensory cortical representations.
8.3. Possible mechanisms
The capability of the amygdala to induce specific receptive field further supports a well-investigated model of auditory cortical receptive field plasticity [94–96]. It postulates that learning-dependent tuning shifts to behaviorally significant sounds first develop in the magnocellular medial geniculate nucleus of the auditory thalamus (MGm), which then projects its plasticity to the amygdala, which in turn projects facilitated neural responses to the cholinergic NB. The latter was hypothesized to release acetylcholine (ACh) into the cortical mantle, where convergence of the activation of muscarinic receptors on cells receiving frequency specific input from the conditioned stimulus produces selective synaptic strengthening. The result would be to increase responses to the CS thereafter, shifting tuning of many cells toward or even to the CS frequency. Across the tonotopic map, the effect would be an increase in the area representing this frequency.
This model has found support in numerous studies subsequent to its formulation. For example, specific receptive field tuning shifts do develop in the MGm during auditory conditioning , associative plasticity in the MGm has a shorter latency than in the amygdala , conditioned plasticity develops in the NB before it appears in the auditory cortex , stimulation of the NB enhances auditory responses in A1 , induces specific tuning shifts in A1 [101–104] and increases the cortical representation of the paired frequency . (For reviews, see [2, 106].)
The findings reviewed in this chapter provide the first test of the role of the amygdala in cortical representational plasticity. As summarized, stimulation of the BLA produces the same type of tuning shifts found during actual learning. Indeed, it goes beyond the mere demonstration of receptive field plasticity to reveal that even at threshold levels, tuning is shifted, threshold is decreased and bandwidth is narrowed. Moreover, the BLA is known to project to the NB [107, 108]. BLA stimulation also produces EEG activation in the cortex, an effect that is mediated by the NB , whose stimulation also produces EEG activation (e.g., ). These findings suggest that BLA modulation of frequency receptive fields in the auditory cortex is mediated, at least in part, via the NB.
These considerations raise the issue of whether or not the BLA actually modulates the strength of behaviorally-validated memory via its actions on sensory cortical representations which themselves have been closely linked to such memory. The following suggest that indeed the BLA may do so as an important component in the model that postulates a particular system level mechanism for the modulation of memory strength. First, tone paired with stimulation of the NB not only induces specific tuning plasticity, but also
This formulation is also concordant with the fact that lesions of the NB block the memory enhancing effect of norepinephrine injected into the BLA . Nonetheless, simply because research has deeply implicated the BLA, NB and ACh in memory storage and memory modulation should not be taken to exclude many other mechanisms that may act alone or in concert with these systems. For example, noradrenergic, dopaminergic and serotonergic axons engage cholinergic cells in the NB  and norepinephrine excites NB neurons . Cortical EEG activation and increased release of cortical ACh result from the application of histamine to the NB ( and , respectively). A gain in cortical representation of frequency can also be achieved by stimulation of the ventral tegmental area (VTA), perhaps by the release of dopamine .
8.4. Future directions
The findings reviewed in this chapter open up new avenues of research on memory modulation. They provide a beginning rather than a comprehensive, or even moderately complete, account. We believe that their potential importance lies in the use of primary sensory cortical representations, specifically those already strongly implicated as memory traces, as a target for achieving a far better understanding of the mechanisms of memory modulation than heretofore available. Most previous research has been focused on the
Future research will need to take at least two lines of investigation. Reductionistic studies, as usual, are needed to further delineate the cellular, circuit and systems mechanisms underlying the types of BLA modulations of cortical memory representations. Such studies must include direct manipulations of BLA and related structures in the amygdala, both to up-regulate and down-regulate modulation of representations in the cortex and perhaps in subcortical structures (e.g., hippocampus, striatum). Coordinated manipulation of cortical target areas are equally needed. For example, a comprehensive accounting of the role of neuromodulators other than ACh is surely necessary. Furthermore, the role of the CE is mysterious at this early stage of research. That the CE can shift tuning at threshold as well and as for as long a time (at least 3 weeks) as the BLA was both unexpected and at this point certainly unexplained. Equally intriguing are the failures of CE stimulation to have anything more than a transient effect above threshold, and to have no effect on either absolute threshold or bandwidth.
In addition to reductionistic studies, which can begin with the findings reviewed in this chapter, is the more difficult task of synthesis, i.e., bringing together apparently diverse and unrelated reports in the pursuit of a potentially new, perhaps even paradigm shifting, conceptual framework for memory and cortex. As noted in the Introduction, the traditional concept is that primary sensory cortices are stimulus analyzers while “higher” sensory and association fields are concerned with the psychological aspects of experience. The current findings of specific amygdala modulation of basic sensory parameters within frequency response areas should render this distinction obsolete. Prior studies of learning, memory and related cognitive processes are thus augmented by the results of amygdala modulation of A1 (reviewed in ). Together, they call for a new conceptualization of how and where memories are stored and how they are regulated. A more holistic and integrated approach to interacting brain systems is required. There is both challenge and great opportunity.
This study was funded by the NIDCD Grant #DC-05592 (NMW), NIMH Grant #MH-12526 (JLM) and the APA/DPN fellowship #5-T32-MH-18882 (CMC). We are grateful to Gabriel K. Hui for preparation of the manuscript.
Mcgaugh J. L The amygdala modulates the consolidation of memories of emotionally arousing experiences. 2004 27 1 28
Weinberger N. M Associative representational plasticity in the auditory cortex: A synthesis of two disciplinesLearning and Memory 2007 1 EOF
Mcgaugh J. L Memory and emotion: The making of lasting memories.New York: Columbia University Press; 2003
Mcgaugh J. L Involvement of hormonal and neuromodulatory systems in the regulation of memory storage. 1989 12 255 287
Mcgaugh J. L Memory- A century ofconsolidation. Science 2000 287 5451 248 251
Mcgaugh J. L Roozendaal B Drug enhancement of memory consolidation: Historical perspective and neurobiological implications 2009 3 EOF 14 EOF
Mcgaugh J. L Memory consolidation and the amygdala: A systems perspective 2002 25 9 456 461
Cahill L Alkire M. T Epinephrine enhancement of human memory consolidation: Interaction with arousal at encoding. 2003 79 2 194 198
Cahill L Gorski L Le K Enhanced human memory consolidation with post-learning stress: Interaction with the degree of arousal at encoding.Learning and Memory 2003 10 4 270 274
Cahill L Mcgaugh J. L Mechanisms of emotional arousal and lasting declarative memory.Trends in Neuroscience 1998 21 7 294 299
Cahill L Prins B Weber M Mcgaugh J. L Beta-adrenergic activation and memory for emotional events. 1994 371 6499 702 704
Mcgaugh J. L Roozendaal B Role of adrenal stress hormones in forming lasting memories in the brain. 2002 12 2 205 210
Roozendaal B Glucocorticoids and the regulation of memory consolidation 2000 25 3 213 238
The memory-modulatory effects of glucocorticoids depend on an intact striaterminalis. Brain Research Roozendaal B Mcgaugh J. L 1996 709 2 243 250
Quirarte G. L Roozendaal B Mcgaugh J. L Glucocorticoid enhancement of memory storage involves noradrenergic activation in the basolateral amygdala. 1997 94 25 14048 14053
Roozendaal B Okuda S De Quervain D. J-F Mcgaugh J. L Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions. 2006 138 3 901 910
Roozendaal B Quirarte G. L Mcgaugh J. L Stress-activated hormonal systems and the regulation of memory storage. 1997 821 247 258
Ferry B Mcgaugh J. L Clenbuterol administration into the basolateral amygdala post-training enhances retention in an inhibitory avoidance task. 1999 72 1 8 12
Ferry B Mcgaugh J. L Involvement of basolateral amygdala α2-adrenoceptors in modulating consolidation of inhibitory avoidance memory.Learning and Memory 2008 15 4 238 243
Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between β- and α1-adrenoceptors. Journal of Neuroscience Ferry B Roozendaal B Mcgaugh J. L 1999 19 12 5119 5123
Quirarte G. L Galvez R Roozendaal B Mcgaugh J. L Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs. 1998 808 2 134 140
Mcintyre C. K Hatfield T Mcgaugh J. L Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats 2002 16 7 1223 1226
Hatfield T Spanis C Mcgaugh J. L Response of amygdalar norepinephrine to footshock and GABAergic drugs using in vivo microdialysis and HPLC. 1999 835 2 340 345
Power A. E Mcintyre C. K Litmanovich A Mcgaugh J. L Cholinergic modulation of memory in the basolateral amygdala involves activation of both m1 and m2 receptors. 2003 14 3 207 213
Vazdarjanova A Mcgaugh J. L Basolateral amygdala is involved in modulating consolidation of memory for classical fear conditioning.Journal of Neuroscience 1999 19 15 6615 6622
Dalmaz C Introini-collison I. B Mcgaugh J. L Noradrenergic and cholinergic interactions in the amygdala and the modulation of memory storage. 1993 167 EOF 74 EOF
Introini-collison I. B Dalmaz C Mcgaugh J. L Amygdala β-noradrenergic influences on memory storage involve cholinergic activation. 1996 65 1 57 64
Power A. E Roozendaal B Mcgaugh J. L Glucocorticoid enhancement of memory consolidation in the rat is blocked by muscarinic receptor antagonism in the basolateral amygdala 2000 12 10 3481 3487
Hecker S Mesulam M. M Two types of cholinergic projections to the rat amygdala. 1994 60 2 383 397
Power A. E Mcgaugh J. L Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats 2002 77 3 372 388
LeDoux JEEmotion circuits in the brain. Annual Review of Neuroscience 2000 23 155 184
Vazdarjanova A Mcgaugh J. L Basolateral amygdala is not critical for cognitive memory of contextual fear conditioningProceedings of the National Academy of Sciences of the United States of America 1998 95 25 15003 15007
Berlau D. J Mcgaugh J. L Enhancement of extinction memory consolidation: The role of the noradrenergic and GABAergic systems within the basolateral amygdala 2006 86 2 123 132
Boccia M. M Blake M. G Baratti C. M Mcgaugh J. L Involvement of the basolateral amygdala in muscarinic cholinergic modulation of extinction memory consolidation 2009 91 1 93 97
Roozendaal B Castello N. A Vedana G Barsegyan A Mcgaugh J. L Noradrenergic activation of the basolateral amygdala modulates consolidation of object recognition memory 2008 90 3 576 579
Okuda S Roozendaal B Mcgaugh J. L Glucocorticoid effects on object recognition memory require training-associated emotional arousal. 2004 101 3 853 858
Salinas J. A Introini-collison I. B Dalmaz C Mcgaugh J. L Posttraining intraamygdala infusions of oxotremorine and propranolol modulate storage of memory for reductions in reward magnitude. 1997 68 1 51 59
Hsu E. H Schroeder J. P Packard M. G The amygdala mediates memory consolidation for an amphetamine conditioned place preference. 2002 93 EOF 100 EOF
Schroeder J. P Packard M. G Differential effects of intra-amygdala lidocaine infusion on memory consolidation and expression of a food conditioned place preferencePsychobiology 2000 28 4 486 491
Packard M. G Chen S. A The basolateral amygdala is a cofactor in memory enhancement produced by intrahippocampal glutamate injectionsPsychobiology 1999 27 3 377 385
Packard M. G Cahill L Mcgaugh J. L Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. 1994 91 18 8477 8481
LaLumiere RT, Buen TV, Bermudez-Rattoni F, McGaugh JL. Miranda M. I Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory 2003 18 9 2605 2610
Kilpatrick L Cahill L Modulation of memory consolidation for olfactory learning by reversible inactivation of the basolateral amygdala. 2003 117 1 184 188
Schroeder J. P Packard M. G Systemic or intra-amygdala injections of glucose facilitate memory consolidation for extinction of drug-induced conditioned reward 2003 17 7 1482 1488
Bergado J. A Rojas Y Capdevila V González O Almaguer-melian W Stimulation of the basolateral amygdala improves the acquisition of a motor skill. 2006 24 2 115 121
Chavez C. M Mcgaugh J. L Weinberger N. M The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex 2009 91 4 382 392
Price J. L Comparative aspects of amygdala connectivity. 2003 985 50 58
Labar K. S Beyond fear emotional memory mechanisms in the human brain. 2007 16 4 173 177
Roesler R Roozendaal B Mcgaugh J. L Basolateral amygdala lesions block the memory-enhancing effect of 8-Br-cAMP infused into the entorhinal cortex of rats after training.European Journal of Neuroscience 2002 15 5 905 910
Roozendaal B Mcgaugh J. L Basolateral amygdala lesions block the memory-enhancing effect of glucocorticoid administration in the dorsal hippocampus of rats 1997 9 1 76 83
Setlow B Roozendaal B Mcgaugh J. L Involvement of a basolateral amygdala complex-nucleus accumbens pathway in glucocorticoid-induced modulation of memory consolidation 2000 12 1 367 375
Fanselow M. S Conditioned fear-induced opiate analgesia: A competing motivational state theory of stress analgesia. 1986 467 40 54
RC. Rudy J. W Barrientos R. M O Reilly Hippocampal formation supports conditioning to memory of a context. 2002 116 4 530 538
Malin E. L Mcgaugh J. L Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshockProceedings of the National Academy of Sciences of the United States of America 2006 103 6 1959 1963
Mcintyre C. K Miyashita T Setlow B Marjon K. D Steward O Guzowski J. F Mcgaugh J. L Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. 2005 102 30 10718 10723
Guzowski J. F Lyford G. L Stevenson G. D Houston F. P Mcgaugh J. L Worley P. F Barnes C. A Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.Journal of Neuroscience 2000 20 11 3993 4001
Akirav I Richter-levin G Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.Journal of Neuroscience 1999 19 23 10530 10535
Akirav I Richter-levin G Mechanisms of amygdala modulation of hippocampal plasticity.Journal of Neuroscience 2002 22 22 9912 9921
Ikegaya Y Saito H Abe K High-frequency stimulation of the basolateral amygdala facilitates the induction of long-term potentiation in the dentate gyrus in vivo. 1995 22 2 203 207
Li Z Richter-levin G Stimulus intensity-dependent modulations of hippocampal long-term potentiation by basolateral amygdala priming. 2012 6 21 1 9
Dringenberg H. C Saber A. J Cahill L Enhanced frontal cortex activation in rats by convergent amygdaloid and noxious sensory signals. 2001 12 11 2395 2398
Dringenberg H. C Vanderwolf C. H Cholinergic activation of the electrocorticogram: An amygdaloid activating system. 1996 108 2 285 296
Dringenberg H. C Kuo M. C Tomaszek S Stabilization of thalamo-cortical long-term potentiation by the amygdala: Cholinergic and transcription-dependent mechanisms 2004 20 2 557 565
Weinberger N. M Specific long-term memory traces in primary auditory cortex.Neuroscience 2004 5 4 279 290
Campbell A. W Histological studies on the localisation of cerebral function.Cambridge: University Press; 1905
A history of the study of the cortex: Changes in the concept of the sensory pathway. In: Kimble GA, Schlesinger K (eds.) Topics in the history of psychology, Diamond I. T 1Hillsdale, NJ: Lawrence Erlbaum Associates; 1985ch8, 305 387
Locke J An essay concerning human understanding.London: Printed by Eliz. Holt for Thomas Basset; 1690.
Merzenich M. M Knight P. L Roth G. L Cochleotopic organization of primary auditory cortex in the cat. 1973 63 343 346
Galambos R Sheatz G Vernier V. G Electrophysiological correlates of a conditioned response in cats.Science 1956 123 3192 376 377
Ashe J. H Cassady J. M Weinberger N. M The relationship of the cochlear microphonic potential to the acquisition of a classically conditioned pupillary dilation response. 1976 16 1 45 62
Weinberger N. M Diamond D. M Physiological plasticity in auditory cortex: Rapid induction by learning. 1987 29 1 1 55
Marsh J. T Worden F. G Auditory potentials during acoustic habituation: Cochlear nucleus, cerebellum and auditory cortex. 1964 17 685 692
Westenberg I. S Weinberger N. M Evoked potential decrements in auditory cortex. II. Critical test for habituation. 1976 40 4 356 369
Diamond D. M Weinberger N. M Classical conditioning rapidly induces specific changes in frequency receptive fields of single neurons in secondary and ventral ectosylvian auditory cortical fields. 1986 372 2 357 360
Bakin J. S Weinberger N. M Classical conditioning induces CS-specific receptive field plasticity in the auditory cortex of the guinea pig. 1990 271 EOF 86 EOF
Kisley M. A Gerstein G. L Trial-to-trial variability and state-dependent modulation of auditory-evoked responses in cortex.Journal of Neuroscience 1999 19 23 10451 10460
Elhilali M Fritz J. B Chi T. S Shamma S. A Auditory cortical receptive fields: Stable entities with plastic abilities.Journal of Neuroscience 2007 27 39 10372 10382
Galván V. V Chen J Weinberger N. M Long-term frequency tuning of local field potentials in the auditory cortex of the waking guinea pig.Journal of the Association for Research in Otolaryngology 2001 2 3 199 215
Gao E Suga N Experience-dependent corticofugal adjustment of midbrain frequency map in bat auditory system. 1998 95 21 12663 12670
Edeline J-M Pham P Weinberger N. M Rapid development of learning-induced receptive field plasticity in the auditory cortex. 1993 107 4 539 551
Kisley M. A Gerstein G. L Daily variation and appetitive conditioning-induced plasticity of auditory cortex receptive fields.European Journal of Neuroscience 2001 13 10 1993 2003
Molchan S. E Sunderland T Mcintosh A. R Herscovitch P Schreurs B. G A functional anatomical study of associative learning in humans.Proceedings of the National Academy of Sciences of the United States of America 1994 91 17 8122 8126
Morris J. S Friston K. J Dolan R. J Experience-dependent modulation of tonotopic neural responses in human auditory cortexProceedings of the Royal Society B, Biological Sciences 1998 265 1397 649 657
Schreurs B. G Mcintosh A. R Bahro M Herscovitch P Sunderland T Molchan S. E Lateralization and behavioral correlation of changes in regional cerebral blood flow with classical conditioning of the human eyeblink response. 1997 77 4 2153 2163
Hui G. K Wong K. L Chavez C. M Leon M. I Robin K. M Weinberger N. M Conditioned tone control of brain reward behavior produces highly specific representational gain in the primary auditory cortex 2009 92 1 27 34
Rutkowski R. G Weinberger N. M Encoding of learned importance of sound by magnitude of representational area in primary auditory cortexProceedings of the National Academy of Sciences of the United States of America 2005 102 38 13664 13669
Bieszczad K. M Weinberger N. M Representational gain in cortical area underlies increase of memory strengthProceedings of the National Academy of Sciences of the United States of America 2010 107 8 3793 3798
Galván V. V Weinberger N. M Long-term consolidation and retention of learning-induced tuning plasticity in the auditory cortex of the guinea pig 2002 77 1 78 108
Edeline J-M Weinberger N. M Receptive field plasticity in the auditory cortex during frequency discrimination training: Selective retuning independent of task difficulty. 1993 107 1 82 103
Samson R. D Duvarci S Paré D Synaptic plasticity in the central nucleus of the amygdala. 2005 16 4 287 302
Da Cunha CRoozendaal B, Vazdarjanova A, McGaugh JL. Microinfusions of flumazenil into the basolateral but not the central nucleus of the amygdala enhance memory consolidation in rats. 1999 72 1 1 7
LaLumiere RTNguyen LT, McGaugh JL. Post-training intrabasolateral amygdala infusions of dopamine modulate consolidation of inhibitory avoidance memory: Involvement of noradrenergic and cholinergic systems 2004 20 10 2804 2810
Power A. E Vazdarjanova A Mcgaugh J. L Muscarinic cholinergic influences in memory consolidation. 2003 80 3 178 193
Weinberger N. M Dynamic regulation of receptive fields and maps in the adult sensory cortex. 1995 18 129 158
Reconceptualizing the primary auditory cortex: Learning, memory and specific plasticity. In: Winer JA, Schreiner CE (eds.) The auditory cortex. New York: Springer; Weinberger N. M 2011ch22, 465 491
Retuning auditory cortex by learning: A preliminary model of receptive field plasticity. Concepts in Neuroscience Weinberger N. M Ashe J. H Metherate R Mckenna T. M Diamond D. M Bakin J 1990 1 1 91 132
Edeline J-M Weinberger N. M Associative retuning in the thalamic source of input to the amygdala and auditory cortex: Receptive field plasticity in the medial division of the medial geniculate body. 1992 106 1 81 105
Hennevin E Maho C Hars B Neuronal plasticity induced by fear conditioning is expressed during paradoxical sleep: Evidence from simultaneous recordings in the lateral amygdala and the medial geniculate in rats. 1998 112 4 839 862
Maho C Hars B Edeline J-M Hennevin E Conditioned changes in the basal forebrain: Relations with learning-induced cortical plasticityPsychobiology 1995 23 1 10 25
Basal forebrain stimulation facilitates one-evoked responses in the auditory cortex of awake rat. Neuroscience Hars B Maho C Edeline J-M Hennevin E 1993 56 1 61 74
Bakin J. S Weinberger N. M Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis.Proceedings of the National Academy of Sciences of the United States of America 1996 93 20 11219 11224
Bjordahl T. S Dimyan M. A Weinberger N. M Induction of long-term receptive field plasticity in the auditory cortex of the waking guinea pig by stimulation of the nucleus basalis 1998 112 3 467 479
Dimyan M. A Weinberger N. M Basal forebrain stimulation induces discriminative receptive field plasticity in the auditory cortex. 1999 113 4 691 702
Ma X Suga N Augmentation of plasticity of the central auditory system by the basal forebrain and/or somatosensory cortex. 2003 89 1 90 103
Kilgard M. P Merzenich M. M Cortical map reorganization enabled by nucleus basalis activity.Science 1998 279 5357 1714 1718
Weinberger N. M The nucleus basalis and memory codes: Auditory cortical plasticity and the induction of specific, associative behavioral memory. 2003 80 3 268 284
Neural associations of the substantiainnominata in the rat: Afferent connections. Journal of Comparative Neurology Grove E. A 1988 277 3 315 346
The afferent connections of the substantiainnominata in the monkey, Macaca fascicularis. Journal of Comparative Neurology Russchen F. T Amaral D. G Price J. L 1985 242 1 1 27
Dringenberg H. C Vanderwolf C. H Neocortical activation: Modulation by multiple pathways acting on central cholinergic and serotonergic systems. 1997 116 1 160 174
Buzsaki G Bickford R. G Ponomareff G Thal L. J Mandel R Gage F. H Nucleus basalis and thalamic control of neocortical activity in the freely moving rat.Journal of Neuroscience 1988 8 11 4007 4026
rd, Miasnikov AA, Weinberger NM. Mclin D. E Induction of behavioral associative memory by stimulation of the nucleus basalisProceedings of the National Academy of Sciences of the United States of America 2002 99 6 4002 4007
Miasnikov A. A Chen J. C Gross N Poytress B. S Weinberger N. M Motivationally neutral stimulation of the nucleus basalis induces specific behavioral memory 2008 90 1 125 137
Miasnikov A. A Chen J. C Weinberger N. M Rapid induction of specific associative behavioral memory by stimulation of the nucleus basalis in the rat 2006 86 1 47 65
Miasnikov A. A Chen J. C Weinberger N. M Specific auditory memory induced by nucleus basalis stimulation depends on intrinsic acetylcholine 2008 90 2 443 454
Miasnikov A. A Chen J. C Weinberger N. M Behavioral memory induced by stimulation of the nucleus basalis: Effects of contingency reversal 2009 91 3 298 309
Miasnikov A. A Chen J. C Weinberger N. M Consolidation and long-term retention of an implanted behavioral memory 2011 95 3 286 295
Weinberger N. M Miasnikov A. A Chen J. C The level of cholinergic nucleus basalis activation controls the specificity of auditory associative memory 2006 86 3 270 285
Bieszczad K. M Weinberger N. M Extinction reveals that primary sensory cortex predicts reinforcement outcome.European Journal of Neuroscience 2012 35 4 598 613
Lesions of the nucleus basalis magnocellularis nduced by 192 IgG-saporin block memory enhancement with posttraining norepinephrine in the basolateral amygdala. Proceedings of the National Academy of Sciences of the United States of America Power A. E Thal L. J Mcgaugh J. L 2002 99 4 2315 2319
Monoaminergic-cholinergic nteractions in the primate basal forebrain. Neuroscience Smiley J. F Subramanian M Mesulam M. M 1999 93 3 817 829
Noradrenergic modulation of cholinergic nucleus basalis neurons demonstrated by in vitro pharmacological and mmunohistochemical evidence in the guinea-pig brain. European Journal of Neuroscience Fort P Khateb A Pegna A Mühlethaler M Jones B. E 1995 7 7 1502 1511
Dringenberg H. C Kuo M. C Histaminergic facilitation of electrocorticographic activation: Role of basal forebrain, thalamus, and neocortex 2003 18 8 2285 2291
Cecchi M Passani M. B Bacciottini L Mannaioni P. F Blandina P Cortical acetylcholine release elicited by stimulation of histamine H1 receptors in the nucleus basalis magnocellularis: A dual-probe microdialysis study in the freely moving rat.European Journal of Neuroscience 2001 13 1 68 78
Bao S Chan V. T Merzenich M. M Cortical remodelling induced by activity of ventral tegmental dopamine neurons. 2001 412 6842 79 83