Learning-induced physiological memory in adult primary auditory cortex: receptive fields plasticity, model, and mechanisms

It is well established that the functional organization of adult sensory cortices, including the auditory cortex, can be modified by deafferentation, sensory deprivation, or selective sensory stimulation. This paper reviews evidence establishing that the adult primary auditory cortex develops physiological plasticity during learning. Determination of frequency receptive fields before and at various times following aversive classical conditioning and instrumental avoidance learning in the guinea pig reveals increased neuronal responses to the pure tone frequency used as a conditioned stimulus (CS). In contrast, responses to the pretraining best frequency and other non-CS frequencies are decreased. These opposite changes are often sufficient to shift cellular tuning toward or even to the frequency of the CS. Learning-induced receptive field (RF) plasticity (i) is associative (requires pairing tone and shock), (ii) highly specific to the CS frequency (e.g., limited to this frequency +/- a small fraction of an octave), (iii) discriminative (specific increased response to a reinforced CS+ frequency but decreased response to a nonreinforced CS- frequency), (iv) develops extremely rapidly (within 5 trials, the fewest trials tested), and (v) is retained indefinitely (tested to 8 weeks). Moreover, RF plasticity is robust and not due to arousal, but can be expressed in the deeply anesthetized subject. Because learning- induced RF plasticity has the major characteristics of associative memory, it is therefore referred to as "physiological memory". We developed a model of RF plasticity based on convergence in the auditory cortex of nucleus basalis cholinergic effects acting at muscarinic receptors, with lemniscal and nonlemniscal frequency information from the ventral and magnocellular divisions of the medial geniculate nucleus, respectively. In the model, the specificity of RF plasticity is dependent on Hebbian rules of covariance. This aspect was confirmed in vivo using microstimulation techniques. Further, the model predicts that pairing a tone with activation of the nucleus basalis is sufficient to induce RF plasticity similar to that obtained in behavioral learning. This prediction has been confirmed. Additional tests of the model are described. RF plasticity is thought to translate the acquired significance of sound into an increased frequency representation of behaviorally important stimuli.     

Basal forebrain stimulation induces discriminative receptive field plasticity in the auditory cortex.

Learning alters receptive field (RF) tuning in the primary auditory cortex (ACx) to emphasize the frequency of a tonal conditioned stimulus. RF plasticity is a candidate substrate of memory, as it is associative, specific, discriminative, rapidly induced, and enduring. The authors hypothesized that it is produced by the release of acetylcholine in the ACx from the basal forebrain (BasF), caused by presentation of reinforced but not nonreinforced conditioned stimuli. Waking adult male Hartley guinea pigs (n?=?16) received 1 of 2 tones followed by BasF stimulation, in a single session of 30 pseudo-random order trials each. RFs from neuronal discharges before and after differential pairing revealed the induction of predicted plasticity, as well as increased responses to the paired tone and decreased responses to the unpaired tone. Thus, highly specific, learning-induced RF plasticity in the ACx may be produced by activation of the BasF by a reinforced conditioned stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rapid development of learning-induced receptive field plasticity in the auditory cortex.

Classical conditioning induces frequency-specific receptive field (RF) plasticity in the auditory cortex after relatively brief training (30 trials), characterized by increased response to the frequency of the CS and decreased responses to other frequencies, including the pretraining best frequency (BF). This experiment determined the development of this CS-specific RF plasticity. Guinea pigs underwent classical conditioning to a tonal frequency, and receptive fields of neurons in the auditory cortex were determined before and after 5, 15, and 30 CS–UCS (unconditioned stimulus) pairings, as well as 1 hr posttraining. Highly selective RF changes were observed as early as the first 5 training trials. They culminated after 15 trials, then stabilized after 30 trials and 1 hr posttraining. The rapid development of RF plasticity satisfies a criterion for its involvement in the neural bases of a specific associative memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Induction of receptive field plasticity in the auditory cortex of the guinea pig during instrumental avoidance conditioning.

Classical tone conditioning shifts frequency tuning in the auditory cortex to favor processing of the conditioned stimulus (CS) frequency versus other frequencies. This receptive field (RF) plasticity is associative, highly specific, rapidly acquired, and indefinitely retained—all important characteristics of memory. The investigators determined whether RF plasticity also develops during instrumental learning. RFs were obtained before and up to 24 hr after 1 session of successful 1-tone avoidance conditioning in guinea pigs. Long-term RF plasticity developed in all subjects (N?=?6). Two-tone discrimination training also produced RF plasticity, like classical conditioning. Because avoidance responses prevent full elicitation of fear by the CS, long-term RF plasticity does not require the continual evocation of fear, suggesting that neural substrates of fear expression are not essential to RF plasticity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Induction of long-term receptive field plasticity in the auditory cortex of the waking guinea pig by stimulation of the nucleus basalis.

Learning induces neuronal receptive field (RF) plasticity in primary auditory cortex. This plasticity constitutes physiological memory as it is associative, highly specific, discriminative, develops rapidly, and is retained indefinitely. This study examined whether pairing a tone with activation of the nucleus basalis (NB) could induce RF plasticity in the waking guinea pig and, if so, whether it could be retained for 24 hrs. Subjects received 40 trials of a single frequency paired with electrical stimulation of the NB at tone offset. The physiological effectiveness of NB stimulation was assessed later while subjects were anesthetized with urethane by noting whether stimulation produced cortical desynchronization. Subjects in which NB stimulation was effective did develop RF plasticity and this was retained for 24 hrs. Thus, activation of the NB during normal learning may be sufficient to induce enduring physiological memory in auditory cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.

The medial division of the medial geniculate body (MGm) projects to the lateral amygdala and the upper layer of the auditory cortex and develops physiological plasticity rapidly during classical conditioning. The effects of learning on frequency receptive fields (RFs) in the MGm of the guinea pig have been determined. Classical conditioning (tone–footshock), as indexed by rapid development of conditioned bradycardia, produced conditioned stimulus (CS)–frequency specific RF plasticity: increased response at the CS frequency with decreased responses at other frequencies, both immediately and after a 1-hr retention period. Sensitization training produced only general changes in RFs. These findings are considered with reference to both the elicitation of amygdala-mediated, fear-conditioned responses and the mechanism of retrieval of information stored in the auditory cortex during acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Classical conditioning with electrical stimulation of cerebellum as both conditioned and unconditioned stimulus.

Stimulating electrodes were implanted in rabbit cerebellum, providing an electrical conditioned stimulus (CS) activating cortical parallel fibers and thence Purkinje and other cells, and an electrical unconditioned stimulus (US) activating underlying white matter and eliciting unconditioned responses. Paired CS-US presentations led to the development of conditioned responses, which showed extinction following CS-alone trials and reacquisition with significant savings on reinstatement of paired trials. Increased local excitability as a result of paired training (but not following unpaired stimulus presentations) was observed in cerebellar cortex, as manifested in substantial decreases in CS threshold for response elicitation in all subjects. This preparation offers a model for the study of plastic neuronal interactions within cerebellar networks critically involved in associative learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An anatomically constrained neural network model of fear conditioning.

Conditioning of fear reactions to an auditory conditioned stimulus (CS) paired with a footshock unconditioned stimulus/stimuli (UCS) involves CS transmission to the amygdala from the auditory thalamus, the auditory cortex, or both. This article presents a simple neural network model of this neural system. The model consists of modules of mutually inhibitory nonlinear units representing the different relevant anatomical structures of the thalamo-amygdala and thalamo-cortico-amygdala circuitry. Frequency-specific changes produced by fear conditioning were studied at the behavioral level (stimulus generalization) and the single-unit level (receptive fields). The findings mirror effects observed in conditioning studies of animals. This computational model provides an initial grounding for explorations of how emotional information and behavior are related to anatomical and physiological observations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frequency-specific receptive field plasticity in the medial geniculate body induced by Pavlovian fear conditioning is expressed in the anesthetized brain.

Fear conditioning modifies the processing of frequency information; receptive fields (RFs) in the auditory cortex and the medial geniculate body (MGB) are altered to favor processing the frequency of the conditioned stimulus/stimuli (CS) over the pretraining best frequency (BF) and other frequencies. This experiment was designed to determine whether brief conditioning in the waking state produces RF plasticity that is expressed under general anesthesia. Guinea pigs bearing electrodes in the MGB received 20 trials on tone-shock pairing in a single training session. RFs were determined with animals under ketamine anesthesia before conditioning and 1–3 hrs and 24 hrs after conditioning. Frequency-specific RF plasticity was evident for both postconditioning periods: The BF shifted toward or to the CS frequency, responses to the BF decreased, and responses to the CS increased. Broadly tuned cells developed greater RF plasticity than narrowly tuned neurons. Results demonstrate that the specific neuronal results of brief learning experiences can be expressed in the anesthetized brain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of context in the expression of learning-induced plasticity of single neurons in auditory cortex.

Classical conditioning produces frequency-specific plasticity of receptive fields (RFs) of single neurons in cat auditory cortex (D. M. Diamond and N. M. Weinberger; see record 1987-14817-001). In this article we show that although plasticity may be observed during both training trials and determination of RFs, it is usually expressed in a qualitatively different form (e.g., decreased response during conditioning vs. increased response to this same conditioned stimulus in the postconditioning RF). This differential expression of learning-induced plasticity provides evidence for a role of context in neurophysiological mechanisms of learning in auditory cortex. A model of cortical neurons functioning within a mosaic of influences is presented. The Functional Mosaic model views the induction and expression of plasticity as separate processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disrupted eyelid conditioning in a patient with damage to cerebellar afferents.

A 54-year-old woman with damage to cerebellar circuitry resulting from a cerebrovascular accident underwent classical conditioning of the eye-blink response to a tone conditioned stimulus (CS) and an air-puff unconditioned stimulus (UCS). In contrast to 5 age-matched controls who readily acquired the conditioned response (CR), emitting a mean of 56.7 CRs over 70 trials, the patient emitted only 6 CRs in 100 trials and never emitted 2 consecutive CRs. There were no differences in spontaneous blink rate, sensitivity to the air puff, or sensitivity to the tone between the experimental subject and the control subjects. That conditioning of the eye-blink response is disrupted in a human with damage to cerebellar circuitry is consistent with an accumulating body of literature indicating that the cerebellum is the essential site of plasticity for classically conditioned somatic responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time course of cardiac conditioned responses in restrained rats as a function of the trace CS–US interval.

Two experiments aimed at understanding the temporal characteristics of trace-conditioned heart-rate responses to a 0.5-s tone (conditioned stimulus [CS]) in restrained rats. A CS paired with a tail-shock (unconditioned stimulus [UCS]) elicited lasting bradycardiac responses. The magnitude and extinction rate of conditioned responses (CR) were independent of the CS–US interval (interstimulus interval [ISI], 3 s to 20 s). Unreinforced test trials were analyzed for CR topography. Responding was delayed in groups with longer ISIs, but CR latencies, peak and decay times were not proportional to the ISI Response peaks tended to cluster either about 6 s after CS onset, or about 10 s with a slow decay, depending on the ISI. The authors postulated 2 components of auditory stimulus traces involved in cardiac conditioning, maximally active 6 s and 10 s respectively after CS onset. The topography of the CR could be constrained to combinations of associative strength and instantaneous activity of these 2 components. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reflex facilitation during eyeblink conditioning and subsequent interpositus nucleus inactivation in the rabbit (Orycotolagus cuniculus).

In eyeblink conditioning in the rabbit (Oryctolagus cuniculus), not only is a conditioned response (CR) acquired, but also the original reflex is modified as a function of training. In Experiment 1, by comparing unconditioned responses in unpaired and paired groups, 3 types of reflex facilitation were distinguished. One type was linked to exposure to the unconditioned stimuli (USs) and/or experimental setting. The 2nd type was related to the formation of the memory trace for conditioned eyeblink. The 3rd type was linked to the conditioned stimulus immediately preceding the US in the paired group. In Experiment 2, reversible inactivation of the interpositus nucleus (IPN) abolished the CR and reduced the CR-related reflex facilitation, indicating that the latter depends on the plasticity of the IPN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An associative process maintains reflex facilitation of the unconditioned nictitating membrane response during the early stages of training.

The presentation of a neutral or conditioned stimulus (CS) at an appropriate interval prior to the presentation of a corneal airpuff or a paraorbital shock (unconditioned stimulus, US) can facilitate the amplitude of the unconditioned nictitating membrane (NM) response in rabbits. In two experiments, it was demonstrated that an associative process mediates the maintenance of that facilitation during repeated CS–US pairings. Although CS-alone presentations produced a substantial decrease in the amount of reflex facilitation in animals not pretrained with the CS, pretraining that consisted of paired CS–US presentations prevented that decrease when CS-alone presentations were subsequently given. Conditioned facilitation of the unconditioned response occurred very rapidly (within 5–22 trials in these experiments) and long before the appearance of overt conditioned responses to the CS. In addition, it was demonstrated that conditioned facilitation can be relatively specific to the tonal frequency of the CS. These results indicate the first sign of conditioning of the NM response is exhibited in the amplitude of the unconditioned response. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Emotional memory systems in the brain

The neural mechanisms of emotion and memory have long been thought to reside side by side, if not in overlapping structures, of the limbic system. However, the limbic system concept is no longer acceptable as an account of the neural basis of memory or emotion and is being replaced with specific circuit accounts of specific emotional and memory processes. Emotional memory, a special category of memory involving the implicit (probably unconscious) learning and storage of information about the emotional significance of events, is modeled in rodent experiments using aversive classical conditioning techniques. The neural system underlying emotional memory critically involves the amygdala and structures with which it is connected. Afferent inputs from sensory processing areas of the thalamus and cortex mediate emotional learning in situations involving specific sensory cues, whereas learning about the emotional significance of more general, contextual cues involves projections to the amygdala from the hippocampal formation. Within the amygdala, the lateral nucleus (AL) is the sensory interface and the central nucleus the linkage with motor systems involved in the control of species-typical emotional behaviors and autonomic responses. Studies of cellular mechanisms in these pathways have focused on the direct relay to the lateral amygdala from the auditory thalamus. These studies show that single cells in AL respond to both conditioned stimulus and unconditioned stimulus inputs, leading to the notion that AL might be a critical site of sensory-sensory integration in emotional learning. The thalamo-amygdala pathway also exhibits long-term potentiation, a form of synaptic plasticity that might underlie the emotional learning functions of the circuit. The thalamo-amygdala pathway contains and uses the amino acid glutamate in synaptic transmission, suggesting the possibility that an amino-acid mediated form of synaptic plasticity is involved in the emotional learning functions of the pathway. We are thus well on the way to a systems level and a cellular understanding of at least one form of emotional learning and memory.     

One-Trial Learning and Superior Resistance to Extinction of Autonomic Responses Conditioned to Potentially Phobic Stimuli.

Human subjects were exposed to pictures of potentially phobic (snakes) and supposedly neutral (houses) objects as conditioned stimuli (CSs) in a Pavlovian conditioning experiment with shock as unconditioned stimulus (US), and skin conductance and finger pulse volume as dependent variables. The skin conductance responses conditioned to phobic stimuli were acquired after one CS-US pairing, and showed practically no extinction, whereas the responses to neutral stimuli showed very little resistance to extinction after both 1 and 5 reinforcements. The superior resistance to extinction of the phobic condition was interpreted to be a specific associative effect. In general, the skin conductance acquisition data showed tendencies similar to those during extinction. For finger pulse volume responses, however, there were very weak conditioning effects, and no effect of stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Motor cortex lesions do not affect learning or performance of the eyeblink response in rabbits.

The possible modulatory role of motor cortex in classical conditioning of the eyeblink response was examined by ablating anterior neocortex in rabbits and training them with an auditory conditioned stimulus (CS) and an airpuff unconditioned stimulus (US) in either a delay (Experiment 1) or a trace (Experiment 2) conditioning paradigm. Topographic measures such as amplitude and onset latency were assessed during conditioning sessions for conditioned responses (CRs) and on separate test days for unconditioned responses (URs) by using a range of US intensities. No lesion effects were observed for learning or performance measures in acquisition or retention of either delay or trace conditioning. During trace conditioning, lesioned rabbits did, however, exhibit a trend toward impairment and demonstrated significantly longer CR latencies. Damage to motor and frontal cortex does not significantly affect eyeblink response performance or learning in either a delay or a trace conditioning paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral and neural characteristics of short-latency and long-latency conditioned responses in cats.

Studied head movements to a tone to the left ear (conditioned stimulus [CS]) in 6 cats. An attempt was made to differentiate an orienting, short-latency (alpha) response from the long-latency conditioned (delayed) response. The unconditioned stimulus (UCS) was a brain stimulation to the lateral hypothalamus eliciting a specific, stereotypical head movement. These behavioral characteristics of the unconditioned head movement were used for differentiating it from the conditioned short-latency head movement. Paired conditioning and randomly unpaired control sessions (5 daily sessions each) were given in balanced order to each S. Evoked neural responses in the hippocampus and cingulate cortex were recorded simultaneously to compare the time–amplitude characteristics of evoked responses to earlier findings in multiple-unit recordings. The results supported the differentiation of the behavioral responses. The time–amplitude course of the evoked neural responses showed complex changes, appearing as an increase in the negativity during the alpha-response period and as an increase in the positivity during the long-latency period on omitted-UCS (CS-alone test) trials. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory effects on symptom reporting in a respiratory learning paradigm.

With odors as conditioned stimuli (CSs) and CO?-enriched air as the unconditioned stimulus, participants learned to exhibit respiratory responses and somatic complaints on presentation of only the odor CS+. Studied was whether complaints during CS+-only trials were inferred from the conditioned somatic responses or were based on activated memory of the complaints during acquisition. Participants (N?=?56) were either attentionally directed away or not from the complaints during acquisition, and the effects on somatic complaints during test were studied. Respiratory responses, heart rate, and somatic complaints were measured. No physiological conditioning effects were found. However, more complaints were reported to the CS+ than to the CS– odor, but only when the CS+ was foul smelling. This effect was modulated by the attention manipulation, showing that the learned complaints during the test phase were based on memory of the acquisition complaints and not on physiological responses during the test. (PsycINFO Database Record (c) 2010 APA, all rights reserved)